Immunolgy [full issue]

The magazine of the World Health Organization 26 Exploring inner space, by Dr N. K. Jerne 3 Antigens and antibodies, by Dr J. Sterzl 4 Protection for the millions, by Dr G. Edsall 6 The body against itself, by Prof. N. Rose 10 Living with new parts, by Dr J. Dausset 15 WHO : International research, by Dr H. C. Goodman 20 What the future holds, by Dr J. Humphrey Haemagglutination tests to mea- sure the effectiveness of vaccines. ( For more details see photo cap- tion p. 9) All correspondence should be addressed to "World Health", WHO, Avenue Appia, 1211 Geneva 27, Switzerland Contents Immunologists discussing a case at the University Hospital of Leiden (Netherlands). The slide indicated by the pencil is an electrophoretic analysis of blood serum, while the slide next to it is an immuno-electrophoretic pattern of the same serum. This technique is often used to disclose pathological alterations in serum proteins found in certain diseases such as rheumatoid arthritis. Exploring inner space by Dr Niels K. Jerne Head of the Institute for Immunology, Basle, Switzerland One of the striking features of immunology is the frequent and fruitful interaction bet- ween experimental or theoretical immu- nology on the one hand and medical diagnos- is and treatment on the other. In the last century, medical observations which led to the highly successful smallpox vaccination programmes also led to a more fundamental understanding of immunization, and the discovery in experimental animals of specific antibody molecules capable of neutralizing diphtheria toxin found immediate clinical application. A number of more recent inter- actions of this type could be listed. Thus, observations in human patients of immune deficiencies and of autoimmune components in many diseases have profoundly influenced basic immunological concepts such as the ability of the immune system of an individual to distinguish between "self" and "not self". Also, our present level of understanding and of dealing with the immunological pheno- mena of organ transplantation, allergic reac- tions and diseases in which the body's immune defences turn against one or more of its own tissues, such as in certain haemolytic anemias, has been reached by a continuous confrontation of medical and experimental observations. It has become clear that the immune system of an animal is essentially equivalent to the total population of its lymphoid cells. The central objects of basic immunological investigations are these lymphoid cells and the antibodies they produce. All natural organic substances, as well as an unlimited number of organic and non-organic prepara- tions, can induce the formation of specific antibodies when introduced into a vertebrate animal or man. This will occur if the substance (called the "antigen") is intro- duced into an individual in which it is not already a natural constituent. Antibodies combine with the antigenic substance that has induced their synthesis, i.e. specific antibodies "recognize" their corresponding antigens. Because of the large number of antigens, an individual must be able to synthesize an enormous number of different antibodies. This diversity has been a source of fascination for biologists who attempt to understand the generating and regulating mechanisms involved. At present, it would appear that each of the 1,000,000,000,000 lymphocytes in an adult is restricted to producing antibodies of one specificity (i.e. which react specifically with only one antigen), and that each cell possesses the structural genes necessary for this task. At the moment, two central problems remain: (1) to determine how the lymphocyte population of an animal acquires this large diversity of genes, and (2) to find out how the cells register an antigenic signal, and in which ways the entire system is kept under regulatory control. One of the complexities that has emerged from serological, bio-chemical and structural studies is the great heterogeneity even among antibodies possessing the same, or a similar, specificity for one antigen. For example, among the same antibodies, we can distin- guish several classes of molecules of different size and structure. Moreover, when many different animals of the same species respond to the same antigenic substance, the anti- bodies produced by a given animal are often different from those made by any of the other animals. These so-called "idiotypic" differ- ences can be demonstrated by isolating the specific antibodies made by one animal and comparing them to the antibodies made by another animal. One of the great difficulties in dealing with problems of immunology is simply the clumsy terminology used for their descrip- tion. Consequently, a revision of terminology and nomenclature is important for the com- munication of results and even for thinking about such matters. It has repeatedly been proved that the scientific community of the world is willing to follow WHO's nomen- clature proposals, and this can be expected to remain one of WHO's important continuing tasks. Recognizing the importance of immunol- ogy, the World Health Organization consid- ered ten years ago that it should not restrict its activities to the medical applications of immunology, but that it should also attempt to contribute to international aspects of experimental and theoretical immunology. A series of scientific groups, consisting of experts in basic immunology from various countries, were brought together and under- took as their initial task to survey the present state of knowledge in all areas of this science and to indicate the ways in which further developments might be fruitfully promoted. Notable contributions have been made du- ring the past nine years, particularly in the standardization of immunological nomen- clature, in the advancement of immunologi- cal training, both in developed and in developing countries, and in establishing collaboration by the exchange of personnel, knowledge, and biological materials between reference centres in particular area's of immu- nological study. In the following articles, many of the areas of clinical medicine where immunology has become increasingly important are described, as well future possibilities for the solution of some major public health problems. ■ 3 Thymus Bone marrow Gut Spleen BASIC FACTS Antigens and antibodies by Dr Jaroslav Sterzl Head, Department of Immunology, Institute of Microbiology, Czechoslovak Academy of Sciences, Prague When an animal comes in contact with bacteria or other foreign organisms— called antigens—it will produce globu- lins—called antibodies—which neutra- lize the harmful effect of the bacteria or of their products. In so doing, the animal becomes "immune". Studies on the development of immu- nity have established that foetuses are able to form antibodies very early in the gestational period. However, the number of cells competent to produce antibody is rather low. Following birth, the intesti- nal tract is colonized by micro-orga- nisms. These new germs cause stimula- tion that is amplified by antigens in the food. Such stimulation induces an unex- plained "maturation" of the lymphatic tissues which are responsible for the pro- duction of antibody. If individuals are protected from antigenic stimuli by means of germ-free conditions plus a non-antigenic diet, the lymphoid tissues remain immature and therefore the im- mune response is weaker. Valuable information has been obtai- ned from study of the development of the foetus and the newborn. The basic cells of the immune responses are found in the lymphatic tissues. They develop from primitive tissues which contain cells ca- pable of engulfing foreign material. These cells grow during embryonic develop- ment and are known as stem cells. Some of the stem cells migrate to the foetal thymus, become mature and deve- lop into lymphocytes. As these cells are processed by the thymus, they are called "thymus derived" lymphocytes or T- lymphocytes. Another population of stem cells matures in the bone marrow into lymphocytes and are called "bone marrow derived" lymphocytes or B-lym- phocytes. Very often these two cell popu- lations co-operate with one another, and their joint functions constitute the com- 4 A. 411 IMMUNOGLOBULINS (Ig) Antibody globulins of different classes. ANTITOXIN A type of antibody that can neutral- ize toxic substances produced by certain bac- teria. AUTOIMMUNITY A condition in which an indi- vidual's immune responses attack certain of his own tissues. LYMPHOCYTE A white blood cell produced in the lymphoid system as part of the immune res- ponse. PHAGOCYTE A cell that traps bacteria and other antigens. BONE MARROW Source of the primitive cells which mature into immunologically competent cells elsewhere in the body. THYMUS Organ essential for the development and maturation of immunologically competent cells. SPLEEN An organ of the lymphoid system containing phagocytic cells as well as the immunologically competent cells: lymphocytes and antibody-forming cells. LYMPH NODES Aggregates of lymphocytes and other cells of the immunological system stra- tegically situated throughout the body, e.g. in the lymph glands, tonsils and appendix. BLOOD Responsible for the circulation of im- munologically important cells such as lympho- cytes and phagocytes. plex events of immunity. The function of each cell type will be considered separa- tely later. Those cells which are capable of engul- fing foreign materials are known as pha- gocytes, and the function they perform is called phagocytosis. This process can trap bacteria and other foreign antigens, by means of various specialized cell types that are scattered throughout the body. The phagocytic cells are equipped with enzymes that digest foreign material after its engulfment. This is an early and effec- tive defence mechanism by the body's cells. The digested foreign material may then be either destroyed or passed along to other immunologically competent cells for the purpose of stimulating the appro- priate immune response. One function of T-lymphocytes is to co-operate with B- lymphocytes to produce antibody against certain antigens. Another is the tracking down and killing of invading organisms. Sometimes this process does not involve the production of the classical antibody globulins but the protection is due to the cell itself, and in this case it is called cell- mediated immunity. An entirely new area of research in immunology deals with mechanisms of immunity that func- tion in the absence of antibody. Bone marrow lymphocytes are those cells, such as the plasma cells, that are responsible for antibody formation. Upon receiving antigenic stimulation these cells begin to divide and multiply, and they proliferate into a population of antibody-producing cells. Such cells se- crete antibodies, and the antibodies rid the organism of foreign or undesirable antigens. There are at present five well-charac- terized biochemical classes of antibodies, or immunoglobulins (Ig), called IgM, IgG, IgA, IgE and IgD. The different classes of antibodies generally have diffe- Some technical terms ANTIGEN Any material that is recognized by the body's immunological system as being for- eign, and which therefore causes an immune response. ANTIBODY A protein (globulin) that is made by the body's immunological system and is capable of reacting to an antigen. GAMMA GLOBULINS A group of the proteins (globulins) in the blood which have antibody activity. ot A plasmq cell enlarged 20,000 times, t> as seen through an electron micro- scope. A major breakthrough was made in the forties, when it was discovered that plasma cells were responsible for making antibodies. The arrow on the picture indicates where antibodies are formed. "N" indicates the cell's nucleus. The en- doplasmic reticulum ( site of forma- tion of antibodies) is designated as " er" , and the Golgi apparatus (pro- bable site of the secretion of anti- bodies) is indicated by "G". rent functions. Some immunization me- thods may primarily induce the forma- tion of IgM antibodies. This type of antibody usually appears first, and it has an important role in reactions that invol- ve the killing of bacteria and cells in the presence of serum. Later, the IgG anti- bodies with lower molecular weight are formed. They act in the intercellular spa- ces and are capable of many useful reac- tions such as the neutralization of toxic bacterial products. An advance occurred in 1959 when Prof. R. R. Porter reported studies which led to elucidation of the structure of IgG. Antibodies of the IgA type are formed in lymphoid tis- sues connected with the various mu- cous surfaces. IgA is equipped with a special protein that renders it resistant to enzymatic degradation, and it is there- fore more effective in protecting against infections in the gastrointestinal tract, for example. The role of antibodies of the IgE type is not altogether clear, but they are thought to be important in aller- gic reactions (see p. 10). Very few anti- bodies have been defined in the IgD class. A central feature of the immune res- ponse depends on the proliferation of cells that have been activated by antigen. The basis for an adequate immune res- ponse is usually established if an activa- ted cell begins to proliferate. However, an activated cell may become inhibited or the central supply of such cells may become exhausted. Methods to control the immune response are being actively studied. When more is learned about how to apply these methods to regulate certain aspects of antibody production, we may be able to stimulate or inhibit the course of an immune response. The im- plications of these developments for the control of immunity are discussed in the following pages. ■ 5 VACCINATION Protection for the rn by Dr Geoffray Edsall Superintendent, State Laboratory Institute, Boston (USA) Since the first hesitant employment of vaccination as a general health procedure much has been learned, but much still remains to be known. Millions have been protected against such killing diseases as diphtheria, tetanus, smallpox and polio. Protection has been afforded against the "white plague "—tuberculosis—and against measles, which, however, goes on killing children in the developing coun- tries. Other vaccines work less well but are being improved, as in the case of cholera and plague. However, the world-wide acceptance and use of immunization to control infectious diseases has led too many people to assume that all the problems of immunity have been solved. Almost every public health programme has set up a schedule of vaccinations, and in private practice the physician usually keeps a chart of what immunization a child has received and which he should receive next. In addition to the usual vaccines, there are vaccinations when needed against yellow fever, typhus, cholera, enteric fevers, plague, Japanese encephalitis, tularemia and, for those working with animals, brucellosis, anthrax and lepto- spirosis. Investigators exposed to rare diseases while carrying out laboratory studies may be protected by immuniza- tion of certain kinds. Yet many questions remain to be answered concerning immunization. Exactly when to begin routine immuniza- tion of infants is still being discussed. The correct number of doses has not been fully established for certain vac- cines. Sometimes the most effective pre- paration to use is still under study and more remains to be known concerning the way in which the best protection can be otained with any given agent. Many different types of preparations are used, varying with the nature of the disease, the state of progress in the preparation of vaccine, and other consid- erations. The most effective vaccines known are certain of the live attenuated virus vaccines, such as those used against yellow fever and measles; these produce a mild infection in the person vaccinated which stimulates his entire immunity system to react against the virus, and French caricature deriding vaccination at the end of the 18th century. The doctor is called Dr Vaccinando. provides him with a long-lasting, some- times life-long immunity. Almost as effective are vaccines made from bacte- rial toxins which have been modified so that they are no longer toxic but will still immunize, e.g. against diphtheria, teta- nus or botulism. The best of these modified toxins, or "toxoids ", as they are widely called, is tetanus toxoid, which gives well over 90 per cent protection when properly used. Less effective are vaccines made from killed suspensions of whole bacteria. These suspensions actu- ally include many antigens, only a few of which are essential for an effective immu- nity. Many of the other antigens are not only unessential but often undesirable. Such vaccines, like the toxoids, require repeated injections in order to build up the immune response to a level high enough to be protective. For a few bacterial diseases live atte- nuated vaccines have been developed, analogous to those mentioned above for measles and yellow fever, which will multiply in the body without doing damage and thus liberate sufficient an- tigen to produce an effective degree of immunity. The effectiveness of this im- munity may be enhanced by the fact that these antigens are intact, instead of being altered by chemical or physical forces, as is done in the inactivated vaccines that are treated with heat, phenol, etc. Some of these live bacterial vaccines, e.g. BCG, seem to work, not by producing immune substances or antibodies in the serum of the vaccinated person, but by altering the activity of the scavenger or phago- cytic white cells in the body so that they are alerted to the menace of similar virulent organisms, should they enter the body in the future. This is called "cellu- lar immunity ". For many immunologists, the ideal vaccine would be based upon a highly purified substance derived from the mi- crobe causing the disease, and capable of inducing a vigorous immune response in the body without causing undue reac- tions. Others, however, believe that the ideal vaccine will usually be an atte- nuated living agent, selected or modified for characteristics that enable it to multiply in the body without causing illness. In either case, extensive research is needed to reach these objectives. 6 iillions Scientists around the world are becoming very interested in the effects of nutrition on the immune response. This is necessary for the evaluation of the effectiveness of many vaccines: vaccination is needed to control infectious diseases in malnourished populations. Attenuated vaccines present several problems since they are generally un- stable, are easily destroyed by heat, and sometimes have a tendency to revert to their original virulent state, so that their use must be carefully monitored to ensure that they continue to be safe. Therefore a chemically purified antigen derived from the microbe in question has in some cases (e.g. anthrax) replaced the earlier use of attenuated vaccine. Much remains to be learned, however, even after the immunochemist has pre- pared a purified immunizing antigen. How much antigen is optimal for pro- ducing a good immune response? In what physical state will it be most effective—fluid, absorbed on mineral substances, linked into large molecular complexes, or modified in some other fashion? Various organic or inorganic substances called adjuvants can be used with antigens and will enhance the response to them, to varying degrees and for varying periods of time. All of these alterations change the ability of a sub- stance to produce an effective immune response, but their influence is not the same for each kind of antigen. Therefore careful study is required to determine the way in which to prepare antigens so that they will be most effective. There are many other factors that play a part in determining the efficiency of active immunization. The route of ino- culation and the intervals between suc- cessive inoculations have a great influ- ence on the response. The age at which immunization is started may also be important, not only because of supposed immunological immaturity in very young infants, but also because of the trans- placental passage of maternal antibodies, which in certain cases can interfere with immunization started too early in in- fancy. It has recently been discovered that in <The effectiveness of many vaccines can be measured by means of haemagglutination reactions in a test tube. The reaction in the tube is positive, which shows that the vaccine has been effective. A negative reaction would mean that the person was either not immunized, or that the immunization was not effective. Tests such as these are performed by coupling bacterial antigens to red blood cells. certain diseases the production of anti- bodies in the serum may be useless. The diseases to which this effect applies are, in general, diseases of the mucous mem- brane surfaces, e.g. the bronchial tract and the gastrointestinal tract. The recent discovery that there are special IgA antibodies, somewhat different in their structure from serum antibodies pro- duced locally and capable of acting directly upon infections of mucous-cov- ered surfaces, has opened up a whole new area of research which has already greatly altered the approach to immu- nization against diseases. The factors mentioned above are only a few of those indicating the need for further knowledge of basic immunology if its application in immunization or in other problems is to be made most effective. Not only does the future devel- opment of vaccination against infectious diseases depend on the preparation of effective antigens, but it also depends upon the knowledge of when and how to administer them, at what age and, wheth- er they can be combined with other antigens. These and many other ques- tions can only be answered through an understanding of basic immunology. The dramatic success of oral immunization in poliomyelitis emphasizes the need for the research necessary to discover whether oral immunization can be successful in cholera, typhoid and other enteric infec- tions. In closing, it should be emphasized that some vaccination procedures have been so successful that they have caused the virtual eradication of various dis- eases. For instance, in 1967 smallpox was found in 52 countries, but by 1970 it still existed in only 23 countries. The incidence of smallpox on a global level fell from 131,000 to 30,000 cases from 1967 to 1970. This has been almost entirely due to vaccination. ■ Responses to vaccination of great numbers of r> people can be rapidly measured. New and simple immunological techniques such as large scale haemagglutination tests have made this possible. When the reaction produces a dark circle, it is negative. If only the circle's ring is dark and the interior light, the reaction is positive. On the front cover of this issue, positive and negative reactions can easily be distinguished. ALLERGIES The body against itself by Noel Rose Professor of Microbiology and Director, Immunology Centre, State University of New York at Buffalo Traditionally, immunity has been thought of as a means of protecting the body against invading micro-organisms. More recently, we have learned that exaggerated or inappropri- ate immunological responses may give rise to immunological disease. The first clear exam- ple of an immunological disease was disco- vered by a team of French investigators at the turn of the century. In 1902, while studying the effects of certain animal toxins on dogs, Portier and Richet noticed to their surprise that on some occasions dogs were not protected, but became more sensitive to a second injection of the toxin than to the first. They referred to this reaction as hypersensiti- vity. Later they discovered that hypersensi- tivity could be induced not only by toxins but by otherwise harmless materials. Animals receiving a second injection of some foreign substance would sometimes develop severe or even fatal reactions. To describe this experimental phenomenon Portier and Richet coined the term anaphy- laxis, the reverse of immunity. The animal most commonly used to demonstrate ana- phylaxis is the guinea pig, which can be sensitized by a very small amount of mate- rial. The first injection of a foreign substance is called the sensitizing dose. A latent period of ten to twelve days is necessary before any response can be detected. At that time a second injection of the same substance is given. This second dose should be injected by a route that allows for rapid absorption, for example, intravenously. Within a few minutes of the inoculation, the guinea pig will show symptoms of anaphylactic shock, including scratching, sneezing, and bristling of the fur. It appears restless, with laboured breathing. Convul- sions occur and it may die within a few minutes. If the shock is not fatal, the ani- mal is temporarily resistant to anaphylaxis, and in a state which is called " desensitized ". It is now realized that anaphylaxis is due to the production of an antibody against the foreign substance or antigen. Certain antibo- dies have the property of attaching them- selves firmly to the tissues of the antibody- producing animal. The latent period of anaphylaxis is necessary for the formation of these specialized antibodies and for their fixation to tissue. When a second dose of the foreign substance is given, a combination of antigen and tissue-fixed antibody occurs on the surface of tissue cells. This combination of antigen and antibody stimulates the release of cellular products with severe, far- reaching effects. The most prominent of these products is histamine, which causes the smooth muscles surrounding the blood ves- sels and air passages to constrict. Other substances released during anaphylaxis cause contraction of gastro-intestinal musculature and decreased clotting of blood. However, it is possible to combat most of the symptoma- tic effects of anaphylaxis by treating experi- mental animals with antihistamines or other drugs that antagonize the effects of these cellular products. There is a striking similarity between experimental anaphylaxis and certain human diseases known as allergies. Some individuals may become sensitized to innocuous substan- ces such as plant pollens, animal hair and feathers or mould spores through inhalation, injection, or ingestion. Upon later contact with these same substances they develop adverse symptoms such as the sneezing or running eyes and nose of hay fever, or the laboured breathing characteristic of asthma. Because of this clinical similarity, early investigators began to look for antibodies in human allergies similar to those that cause anaphylaxis. Although the first investigations were unsuccessful, it was finally possible to find such an antibody by means of a special test called a passive transfer. First, a small amount of serum from an allergic patient is injected into the skin of a normal person. A period of 24 hours is allowed for the anti- body of the allergic serum to affix to the recipient's tissue. Then the same site is challenged by an intradermal injection of the substance to which the donor is believed sensitive. Around this injection a white papule or weal and a red flare develop. The reaction to the particular substance is attri- buted to a special type of antibody referred to as skin-sensitizing (homocytotropic) anti- body. Recently these antibodies have been shown to belong to a unique class of immunoglobu- lins named IgE. They have the same basic structure as other antibodies but they are 10 Hay fever is more frequent in spring, when flowers bloom and pollen and dust are in the air. Certain families seem to have a tendency toward allergic disease. Studies have shown that if one parent has an allergy his child has one chance in five of developing an allergic disease. If both parents are allergic the child has two chances in five of developing an allergy. 11 more easily destroyed by heating. They have the unusual property of fixing firmly to cell surfaces of the same or closely related species. Human IgE fixes to human and monkey skin but not to the skin of most other animals. Since we are all exposed to pollens, spores or other foreign substances, it seems strange that one individual develops asthma or hay fever and others do not. Allergic persons seem to produce more IgE than normals. It would appear that in certain families there is a tendency toward allergic disease. Studies have shown that if one parent has an allergy his child has one chance in five of developing an allergic disease. If both parents are allergic the child has two chances in five of deve- loping an allergy. Human allergies can be serious. The sight of an asthmatic child gasping for breath is enough to convince anyone. Individuals with a tendency towards allergy must take great care with any injection. Useful and life- saving drugs such as penicillin or insulin may elicit adverse reactions in persons with a background of allergic disease. Even stings of insects such as bees may produce severe and sometimes fatal anaphylactic-like reactions. Many attempts have been made to remove or reduce the allergic response in affected individuals. At first, efforts were made to desensitize humans much as guinea pigs can be desensitized. However, this proved to be a dangerous and unpredictable procedure. The injection of foreign substances into an allergic human being must be done only by an expert who has taken every precaution. Because of the difficulty of desensitization, physicians have tried immunization. Small but increas- ing doses of antigens are given over long periods of time. They stimulate production of some antibodies (IgG or IgM), but not other ones (IgE). If the ordinary antibodies (IgG or IgM) can be elicited in sufficient concentration, they will combine with the foreign substances before there is an oppor- tunity to react with the tissue-fixed anti- bodies (IgE). This treatment has proved useful against certain human allergies such as hay fever. Another approach is to overcome the effects of the substances liberated during the allergic reaction. Antihistamines have been found of great value in treating certain types of human allergy. While these and other drugs do not cure the disease they may relieve most of the symptoms. In addition to anaphylaxis, other forms of hypersensitivy can be demonstrated in expe- rimental animals. An important example was discovered by the French investigator, Ar- thus, in 1903. He found that a rabbit extensively immunized with horse serum eventually developed a severe local reaction to injections of horse serum given into the 12 Persons who suffer from an allergy are highly sensitive to substances such as hay, wool or feathers which most people find harmless. flank. While this phenomenon at first seemed similar to anaphylaxis, several important differences were found. Rather than being an immediate reaction, the Arthus phenomenon took several hours to develop. It seemed to consist mainly of localized swelling, of invasion of tissue spaces by white cells from the blood, and of cellular injury. The Arthus reaction is due, not to a special tissue- fixing antibody, but to an ordinary circula- ting antibody (IgG or IgM). The first step in the Arthus reaction is a combination of the antigen with its antibody in tissue spaces. Next, a group of proteins in normal serum, called complement, fixes to the antigen- antibody complex. As a result, substances are released that attract white cells from the blood. These cells invade the tissue and release toxic products which are responsible for the local damage. Drugs that deplete animals of their circulating white blood cells can be used to inhibit the Arthus reaction, although they do not affect anaphylaxis. Conversely, antihistamines prevent anaphy- lactic reactions but do not reduce the Arthus phenomenon. Studies of the Arthus reaction have re- vealed that combinations of antigen and antibody occurring within the body can have deleterious effects. In man, an important example of this is the immunological disease, serum sickness. This sometimes occurs in patients being treated with injections of antitoxins (horse or other animal serum) or other drugs. In response to the injection the patient may develop circulating antibodies against the foreign protein or antigen. If the antigen remains within the body it will combine with these antibodies as they appear in the blood stream, thus producing com- plexes of antigen and antibody. These com- plexes fix the proteins called complement and localize themselves in the blood vessel walls of certain organs, especially the kidney, the heart and the large arteries, and the joint cavities. The resulting inflammation pro- duces fever, pains in the joints, impairment of kidney function, a skin rash or other manifes- tations. The realization that antigen-antibody com- plexes may be damaging has influenced thinking about other human disease. Certain diseases of the kidney look like serum sickness when the tissue structure is exam- ined. In glomerulonephritis, for example, the same type of inflammation can be seen as in serum sickness: immunological studies car- ried out on tissue from patients suffering from various kidney diseases show that antibody and complement are localized in the filtering surface of the kidney glomeruli. It is quite logical to assume, therefore, that many cases of glomerulonephritis are due to the deposit of antigen-antibody complexes. Occasionally, glomerulonephritis may follow a streptococcal infection. It is quite likely that streptococcal components are involved in the immunological kidney damage in these cases. Streptococcal antigens with their res- pective antibodies may be deposited in the kidney and give rise to glomerulonephritis. Similar mechanisms may cause kidney dam- age in malaria in Africa (see p. 23). All of these hypersensitivities depend upon circulating antibodies. But one type of hyper- sensitivity, delayed hypersensitivity, differs considerably from anaphylactic or Arthus reactions. It is not due to any known anti- body in the blood stream. Rather, delayed hypersensitivity seems to be associated with certain immunologically active blood cells. The factor which regulates delayed hyper- sensitivity is a lymphocyte, which manufac- tures and carries on its surface an antibody- like device that makes possible the specific recognition of antigens. On contact with the proper antigen, the immunologically stimula- ted lymphocyte releases chemicals that affect surrounding cells and give rise to the mani- festations of delayed hypersensitivity, a form of cellular immunity (see p. 4). Delayed hypersensitivity In 1890, the famous bacteriologist, Robert Koch, pointed out that when a normal guinea pig is injected subcutaneously with living tubercle bacilli no local reaction is visible for ten to fourteen days. On the other hand, a similar injection given to a tubercu- lous guinea pig elicits a violent response to the tubercle bacilli at the injection site. Within two days a necrotic ulcer may form. Koch's phenomenon reveals delayed hyper- sensitivity of an animal that has had previous contact with tubercle bacilli. Rather than injecting live tubercle bacilli, it is possible to elicit the local inflammatory response in tuberculous guinea pigs or hu- man beings by injecting an extract of killed tubercle bacilli. The tuberculin test is based on this principle. Individuals who have had or have been exposed to tuberculosis will develop a skin reaction to an injection of tuberculin. Since the reaction reaches its peak after twenty to forty hours it is referred to as delayed hypersensitivity. In addition to tu- berculosis, delayed hypersensitivity reactions seem to be prominent in many other infec- tious diseases of bacterial, fungal or viral origin. They may indicate the existence of a protective form of cellular immunity. They may provide useful diagnostic skin tests. On the other hand, delayed hypersensitivity may increase the ill effects of the invading micro- organism by intensifying the disease manifes- tations. Analogous to delayed hypersensitivity to micro-organisms is the common dermatitis 13 Two snakes found in Brazil. The big one above is a 20-foot long non-poisonous anaconda, Eunectes murinus, the right is a kind of viper, Crotalus durissus terrificus. Blood proteins known as complement are important in many allergic reactions. Certain diseases are caused by the absence of complement proteins and others are triggered by the overactivation of complement. Various biological substances are able to activate complement components. For instance, cobra venom neutralizes some components, and the venom of Crotalus durissus terrificus inactivates others. The control of complement metabolism would be an important step forward in immunological research: this is for the future. Meanwhile, in Brazil, the venom is being collected ( two drops are seen on the fangs in the photograph) and used to produce anti-venom antiserum. 14 that develops in some people whose skin is repeatedly exposed to foreign substances such as plant or animal extracts or even simple chemicals. When a patient comes into contact with an agent to which he has developed sensitivity, redness and swelling develop, often accompanied by itching. All of the immunological reactions de- scribed above are unwanted or unfortunate reactions to foreign substances. Another type of immunological disease has been recog- nized in recent years. It is based on unfortu- nate immunological reactions to cells in the individual's own body. Early attempts to immunize experimental animals against their own cells generally failed. This led investiga- tors to postulate that there must be some important mechanism of self-recognition. On occasion, however, the self-recognition mechanism fails and the individual forms antibodies against his own tissues. These antibodies in turn can give rise to auto- immune disease. Various theories for the origin of auto- immune disease have been proposed. They include the concepts that (1) antigens in the body tissues can be altered by toxins or infections, (2) invading micro-organisms stimulate the production of antibodies which attack the body's own tissues, and (3) the immunological recognition mechanism may undergo change, resulting in the loss of ability to differentiate self from non-self. Several mechanisms by which auto- immunity can give rise to disease are known. Sometimes the circulating antibody seems to be directly responsible for cell destruction. In other cases the action is more complex. For example, patients with the condition known as paroxysmal cold haemoglobinuria, when exposed to the cold and later returned to normal temperature, suffer from attacks of haemoglobinuria; that is, their bodies release a haemoglobulin into the urine. Donath and Landsteiner many years ago discovered an antibody in the serum of such patients which combined with the patient's own red blood cells when the temperature dropped below body temperature. When the temperature was returned to 370 damage to the red blood cells occurred, due to the action of the proteins known as complement. In other human diseases, although auto- antibodies have been found in the blood- stream, it has not been possible to prove that they are the direct cause of the disease. A good example is chronic thyroiditis. This inflammatory condition of the thyroid gland most often occurs in women of middle age. It is characterized by the presence of circulating auto-antibodies to the major protein of the thyroid gland, thyroglobulin. Sometimes antibodies to other constituents of the thy- roid cells may be found as well. These antibodies do not produce any apparent injury to thyroid cells in the body. Since thyroiditis is characterized by invasion of the thyroid gland by large numbers of lympho- cytes, most investigators feel that the disease is due to immunologically reactive lympho- cytes, very much like delayed hypersensiti- vity. Several other important human diseases seem to result from pathogenic mechanisms similar to thyroiditis. For example, perni- cious anaemia involves the invasion of the superficial layers of the stomach by lymphoid cells as well as the neutralization of the factor responsible for absorption of vitamin B-12. Sometimes degeneration of the adrenal glands or other organs, accompanied by lymphoid cell invasion, seems to be due to autoimmune reactions. Another disease in which autoimmune phenomena are prominent is a poorly under- stood condition involving skin rash and often inflammation of the kidneys and joints known as systemic lupus erythematosus. Rheumatoid arthritis is also a disease in which autoimmune phenomena are promi- nent. Thus several mechanisms of autoimmune tissue damage come into play. They include (1) direct effect of antibodies which destroy the body's own cells, as in haemolytic anae- mia, (2) antigen-antibody complex formation, as in lupus glomerulonephritis, and (3) in- vasion by sensitized lymphocytes, as in chronic thyroiditis. We are still left with the enigma of why autoimmunity exists. As in human allergy, it is reasonable to assume that certain human beings have a genetic tendency towards these unfortunate reactions. In sup- port of this notion certain highly inbred strains of mice have been found which have a great propensity to develop diseases like lupus erythematosus or haemolytic anaemia. Recently, a flock of chickens has been bred in which thyroiditis occurs in almost every animal. It is obvious that many mysteries still surround the development of immunological diseases, which include some of the most common and some of the most severe disorders that afflict mankind. They clearly deserve continued scrutiny by physicians and scientists. ■ Preservation of tissues in liquid nitrogen is a widely used technique. Depending on the tis- sue, it is now possible to preserve certain organs or specialized cells for many months. TRANSPLANT Living with new parts by Professor Jean Dausset Institut de Recherches sur les Maladies du Sang, Hopital Saint-Louis, Paris The idea of using the skin, blood, or organs of a living or dead person to help an injured or sick person is very old, and transplantation of red blood cells (blood transfusions) has long been an established practice, but organ transplantation be- came a practical reality only a decade ago. The transplantation story cannot be told without first defining certain terms. There is great difference between an autograft, in which the part that is grafted is taken from the recipient him- self, an allograft, in which the graft comes from another individual of the same species, and a xenograft, in which the graft is taken from another species. Autografts regularly take, but rejection is the general rule with allografts and xenografts, unless very special means are used to prevent it. The history of transplantation is very largely the history of research to prevent rejection. The mechanisms of graft rejec- tion are central to the problems of transplantation. The rejection of grafts was better understood once it was shown to be an immunological phenomenon. The host defends himself against the " aggression " of an implantation by the same means he uses when defending himself against bacteria or viruses. The cells of the host, particularly the lympho- cytes, react against the antigens of the donor. They invade the graft and even- tually destroy it. Thus a typical phenom- enon of cellular immunity is involved. The role played by antibodies present in blood plasma varies: sometimes it is unfavourable because antibodies re- inforce the cell action, and sometimes favourable because they counter the destructive action of the cells. The ex- perimental studies from which this pic- ture was built up are numerous. Research of considerable importance has been conducted for the past 20 years on mice, and led to the discovery of the genetic control of the transplantation antigens. When skin from a mouse of one inbred line is grafted onto a mouse of another inbred line, the immunological response of the recipient is directed against a limited number of differences in cell structures (antigens) situated princi- pally on the cell membranes. These antigenic structures on the cell surface are the transplantation antigens (also called tissue or histocompatibility anti- gens). One striking fact that has not yet been satisfactorily explained is that in all the species studied the histocompatibility antigens are governed by one small region of a chromosome. In other words, in each species there is one main genetic histocompatibility antigen system, desig- nated H-2 in the mouse, AgB in the rat, B in the chicken, DL-A in the dog, and HL- A in man. In addition to this main system, there exists a series of similar systems (about 14 in the mouse), but these are less important obstacles to transplantation because they can be more easily neutralized by various tech- niques of immunosuppression. Many methods have been used to inhibit the immune response of the recipient, including various techniques of destroying or " blockading ". X-ray treatment and drugs which affect cell reproduction have been employed with some success. But these methods are violent and non-specific: they produce a generalized immune insufficiency which leaves the recipient open to bacterial or viral infections against which he can no longer defend himself. However, an im- portant advance appears to have been made with the discovery of antilympho- cytic serum. This is a serum prepared in 15 an animal of another species against the lymphocytes of the species of the future recipient—for example, serum from a rabbit that has been immunized against the lymphocytes of a mouse. Purified antibodies contained in this serum dis- play remarkable activity against certain lymphocytes in the recipient mouse, specifically inhibiting the reaction of the cells against the transplant. It is on these two foundations— knowledge of the histocompatibility anti- gens, and methods of immunosuppres- sion—that the practice of transplanta- tion in man has been built up. Before doctors could pass from the experimental to the clinical stage, surgical techniques for the transplantation of a human organ had, of course, to be perfected. Much skill and technical proficiency have been acquired in this area. Even a method for bone-marrow transplantation has been devised. The greatest obstacle to transplanta- tion of organs is the existence of genetic differences in the histocompatibility anti- gens. Their complexity seems inextricable and yet, thanks to a remarkable co- operative international effort, this knot is on the point of being unravelled. We now know that the main histo-compati- bility antigen system in man—the HL-A system—is composed of two genes closely linked on the same chromosome. Each of these genes governs one histo-compati- bility antigen out of the 10 to 15 antigens for each gene. Since each of us has two chromosomes carrying the HL-A system (one from the maternal and one from the paternal side) and since each of those chromosomes governs two antigens, there are four antigens per person which make up his histocompatibility pattern. Using the 30 antigens known in the HL-A system, approximately 10,000 combina- tions are possible. This clearly shows the difficulty of finding a donor compatible with a patient, particularly since in addition to the HL-A antigens, the organ also possesses the antigens of the blood- group system which also have to be typed The Radiobiological Institute in Rijswijk (Ne- therlands), one of the biggest animal reserves for scientific research in Europe, keeps many monkeys for transplantation research. An ex- perimental bone marrow transplant is in pro- gress. The purpose of this work is to investi- gate immunological deficiency diseases in chil- dren. Several successful bone marrow trans- plants have been performed in humans. 16 This patient, who is in a specially designed aseptic room, has received a bone marrow transplant for the cor- rection of a blood disease. Recent advances in immunological research have made this form of treatment possible. Her convalescence has been made more comfortable by progress in the design of such aseptic rooms. just as in a blood transfusion. It has been calculated that in order for there to be a 95 per cent chance of finding two identi- cal individuals, they would have to be sought out of a list of 32,000 persons. However, not complete identity, but only compatibility is necessary between donor and recipient. The donor must not have an antigen that the recipient does not have, or the recipient will react immunologically against it. Under those conditions, the figure of 32,000 is imme- diately reduced to about 2,500. This figure might be reduced further in prac- tice because among the 30 antigens of the system there are certain similarities. An antigen present in the donor may not constitute an incompatibility if another similar antigen exists in the recipient. Such " cross-reactions " between histo- compatibility antigens may prove to be of great importance for the future of transplantation. Much research is being conducted on the long-term preservation of human organs, which would make it possible to establish organ banks. It is at present impossible to keep an organ alive for more than five to seven hours. To circumvent this difficulty, waiting lists of patients ready for transplantation have been compiled. When an organ becomes available, the best possible recipient is quickly chosen. The organ is brought to the patient in the shortest time, some- times being flown from one town to another, and the operation is performed immediately. Kidney transplantation is already organized in this way at national and international levels. Over 3,000 kid- ney transplantations have been done in the world, and the number is constantly being increased, with ever greater per- centage of success. Sound organization will make it possible in the near future to treat a much larger number of patients. It must be borne in mind that some 5,000 kidney patients per year could benefit from such treatment in France alone. While the kidney is a comparatively easy organ to transplant, some successes have also been scored in heart transplan- tation. There is no basic theoretical difference in the problems of transplant- ing the two organs. However, when signs of kidney rejection appear, we can resort to a "substitute kidney "—dialysis—to keep the patient alive, whereas with the heart the slightest danger sign may mean sudden death. Better means of 1 4 A person who receives a transplant must have a tissue type that closely resembles the type of the donor. Cells for tissue typing are obtained from the blood by means of special techniques. These doctors are preparing blood cells in the Hopital Saint-Louis labora- tories, Paris. The recording, storing and matching of > information about cellular markers or gene- tic codes for transplantation purposes has been made possible by the computer. Pioneer work in this field was done by Prof J. van Rood, of Leiden University. controlling rejection phenomena will have to be found before the practice of heart transplantation is resumed. Other organs will eventually be added to the list of those which are transplantable: liver, pancreas, intestine, lung, and even en- docrine glands. Ablation surgery will give place to replacement surgery, until medicine and biology have made suffi- cient progress to prevent or cure the diseases which presently damage these organs and create the need to trans- plant substitutes. The successes achieved so far with bone-marrow transplants are still rather limited. This is because some of the transplanted cells are capable of reacting against the host. This "graft versus host" reaction is a considerable obstacle. A successful bone-marrow transplant theo- retically requires complete identity and not just compatibility between donor and recipient. We have seen the difficulty of finding two identical individuals in the general population. Fortunately, how- ever, one quarter of the brothers and r w sisters in a family are statistically identi- cal in respect of the HL-A system. For a patient, such siblings are the optimum donors of bone-marrow. There is certainly great scope for research in the field of transplantation. Scores of laboratories throughout the world are grappling with the problem, and their studies have led to discov- eries of fundamental importance in im- munology. It was only a few years ago that the immunophysiological role of the thymus and lymphocytes began to be understood. Much research still remains to be done before the immune mechanism is completely revealed. It can be predicted that present and future studies will lead to practical applications which will contribute greatly to successful transplantations. There are already two possible ways of manipulat- ing the immune system. They tend to reduce or eliminate the host's adverse response to the graft. Firstly, it is possible to prevent rhesus- negative women from becoming immu- nized to their children's rhesus-positive red blood cells by injecting antirhesus antibodies (see p. 31). These antibodies effectively " blockade " the antigen through a mechanism that at present is not yet well understood—perhaps simply by covering or masking it. It is possible that a similar method will prove applicable to transplantation of organs or bone-mar- row. This would consist of " passively " injecting the recipient with antibodies directed against antigens of the HL-A system (and other histocompatibility sys- tems) of the future donor. It would be done shortly before the transplantation to mask the donor's antigens, so that the recipient would not react against them immunologically. A variation of this method would be to find a way to immunize the recipient so that he manu- factures these so-called "facilitating" antibodies before the transplantation. The other technique makes use of the fundamental discovery that it is possible to induce a state of immune tolerance. Depending on its composition, its physi- cal state (soluble or articulate), the route of injection, and the administered dosage, an antigen can induce either a state of immune defence or a state of immune tolerance. The uses to which this fact might be put in transplantation are ob- vious. The chemical structure of the histocompatibility antigens is still un- known, but a big effort is being made to elucidate and isolate them in a soluble and purified state. Characterization of these antigens is an essential preliminary step in any practical uses of the phenom- enon of tolerance. Once we have suffi- cient quantities of soluble HL-A antigens we can expect to be able to induce a state of specific tolerance in the recipient for the antigens of the future donor. Despite the thousands of differences that exist between two individuals, it is almost exclusively those pertaining to the production of six genes (two in the ABO system and four in the HL-A system) that control the fate of organ transplants in man. This means that prospects in the field of transplantation are bright. ■ 19 International research by Dr H. C. Goodman Chief, Immunology, WHO There is no doubt that the flood of new knowledge that is being acquired through biomedical research in countries with highly developed technologies could be applied more effectively for the control of many of the diseases in the devel- oping countries of Africa, Asia and Latin America. To meet this challenge in the field of immunology, the WHO Immunology Research and Training Centres (IRTCs) were created. Their aim is to increase the small number of scientists capable of doing research in the immunology of the parasitic and other tropical diseases, which affect so large a part of humanity From this issue of World Health, it is easy to see why immunology was chosen as a discipline in which research and training centres should be developed: not only does immunology provide new insights into the mechanisms which the body has developed for protection against infectious agents, but often only a relatively short time is required to translate the results of basic research into means for diagnosing diseases, or vaccinating against them. The guiding aims and principles of the IRTCs are: To help develop a nucleus of immu- nologists in each of the several regions of the world where immunological research is needed but difficult to organize, so that the indigenous basic and medical scien- tists can devote their efforts to solving the disease problems peculiar to their own region. The WHO Immunology Research and Training Centres (IRTCs) can be visited not only by experienced immunologists but also by medical students from other countries, who can sometimes arrange to partici- pate in on-going research projects during their medical training. For details, write to the Immunology Unit, WHO, Geneva. To bring experienced immunologists from other regions to one of the centres to help in training students and to work in collaboration with local scientists doing research on diseases of special local significance, such as malaria, le- prosy and sleeping sickness. The visiting scientists learn of the challenging immu- nological problems relating to diseases in different areas of the world, and when they return to their own countries they often continue to work on research related to these problems. To carry out the initial training of immunologists in their own country or region. This reduces the risk of loss through emigration as a result of pro- longed training abroad and also in- creases the likelihood that their research will be directed towards the solution of regional or national disease problems. To create, with initial WHO support, an immunological centre of excellence that can become a continuing feature of the host institution. In a university setting, an immunology research and training centre can serve as a centre of experience and knowledge. It can also act as a means for maintaining direct con- tacts with other research workers throughout the world. To train enough local scientists in adequately equipped and supplied labo- ratories, so that when the WHO person- nel leave there will be an actively func- tioning unit which is an integral part of a medical school. 20 Immunology Research and Training Centres Ibadan Sao Paulo Mexico Singapore Beirut New Delhi Lausanne Basle* Rehovoth * (Nigeria) (Brazil) (Mexico) (Singapore) (Lebanon) (India) (Switzerland) (Switzerland) (Israel) LAUSANNE •• BASLE BEIRUT MEXICO • REHOVOTH • NEW DELHI' IBADAN • SINGAPORE SAO PAULO * Advanced training International Reference Centres Serology of autoimmune disorders London (United Kingdom) Buffalo (USA) Melbourne (Australia) Human Immunoglobulins Lausanne (Switzerland) Bethesda (USA) Prevention of rhesus sensitization 1. London (United Kingdom) Genetic Factors of Human Immunoglobulins Rouen (France) Lund (Sweden) Cleveland (USA) Tumour Specific Antigens 1. Moscow (USSR) Natural Resistance Factors 1. Prague (Czechoslovakia) CLEVELAND LONDON LUND )D• BUFFALO • w • MOSCOW *BETHESDAePRAGUE ROUEN /LAUSANNE MELBOURNE • 21 WHO Immunology Research and Training Centres have been designated in Ibadan, Nigeria (1965), Sao Paulo, Brazil (1966), Mexico City (1968), Singapore (1969), Beirut (1970) and New Delhi (planned for 1971). The WHO Interna- tional Reference Centre for Immuno- globulins in Lausanne, Switzerland, be- came a Research and Training Centre for advanced training in immunology in 1968. Two other centres for advanced training in immunology will probably be designated in 1971, at the Basle Institute of Immunology in Switzerland and at the Weizmann Institute in Reho- voth, Israel. As the oldest IRTC, the Ibadan Centre will be used as an example and described in some detail, although similarly important developments are taking place in Lausanne, Sao Paulo, Singapore, Mexico and in the newly established Beirut Centre. The Ibadan Centre in Nigeria, at the University College Hospital, an integral part of the University of Ibadan, just completed its fifth annual intensive post- graduate course in immunology. The course lasts for four months and each year up to eight participants (medical scientists from various fields including veterinarians) receive a thorough grounding in basic concepts and labo- ratory techniques in immunology. A WHO immunologist, Dr V. Houba, is head of the Centre, and has been ap- pointed visiting professor (a tribute to 22 Professor Elvin Kabat, from New York, lecturing on immunochemistry to a group of students at the WHO Immu- nology Research and Training Centre in Sao Paulo ( Brazil). 111•11.11111111-1, 1' IMMO 1111Mframewr - *-111111111111 11/ftionnw . MINIIIMP•111 11•111111111111111• .1••■•••••• 1111111111ail•am 1111111••■••• 111.1111.111111011 010/0.116.411.• MIMOW 111111•1111mo 111116111111111111 1111•111■•• 111111111111111111111 an•••••• 111111/11111111•0 1•11•111111111111111 1111111111111•111111 41111111Mmnonm IN.MMEMMOR %.1•■•■•■••MIM inneMMIMIMET 11111111111111111111 111=11111 %........,■ 111111111111111111111M1 Waaaii, . MM. .1■10.111■11r Miiiliilig - - 1111/11111011111/111 111•■ ..■■■• - - ...IBM „Iminer 1111•1— ^NMI 3 I. Dr David Rowe lecturing to a group of students at the WHO Immunology Research and Training Centre in Lau- sanne (Switzerland). The participants are WHO fellows who have come from all over the world for a three weeks' course in basic and applied immunology. Students learning how to prepare tis- sue on a cryostat, a low temperature apparatus designed to cut very thin tis- sue sections ( Lausanne). The Butantan Institute, which houses the WHO Immunology Research and Training Centre in Sao Paulo. the contribution the Centre is making to the University's undergraduate and post- graduate training programme). He con- ducts the courses with the help of a WHO technician and short-term consultants, and collaborates in research with investi- gators in the medical and veterinary faculties of the University. A local counterpart for the immunological tech- nician has been trained, and the Univer- sity has already appointed an immunol- ogist to head the Centre when the WHO staff are eventually withdrawn. It is evident from discussions with the Vice- Chancellor, the Dean and the heads of several departments that activities of the Centre are well integrated with the University in its role as a post-graduate training institution and that, eventually, the Centre's activities will be taken over by the University. Research is concentrated on malaria and trypanosomiasis as well as on para- sitic diseases that may produce a high concentration in Africans' blood of a special class of antibody that is usually thought to be responsible for common allergic reactions. For malaria, three tech- niques are being compared as methods to test the level of antibodies against mala- ria parasites in a savannah area where malaria eradication procedures are being employed. The hope is that these blood tests will be more accurate, sensitive and specific for detecting exposure to malaria parasites than present methods of taking temperature to detect fever or examining thick blood smears to detect the presence of malaria parasites. Such tests could then be used to judge the success of malaria eradication programmes in other parts of the world. Another study in malaria is of the kidney disease (nephri- tis) that is frequent in parts of Africa and is apparently associated with certain types of malaria. Evidence has been collected that the complexes formed by malaria antigens and with anti-malaria antibodies have localized in the kidneys of such patients; these antigen-antibody complexes may well be what sets off the nephritic reaction (see p. 13). WHO immunologists also head the Lausanne and Singapore Centres, but in Mexico, Sao Paulo and Beirut the centres are run by local immunologists. They re- ceive support in the form of visits by consultant immunologists to help in train- ing and research in specialized areas of immunology. The Lausanne Centre (at the Institute de Biochimie and Institute Suisse pour Recherches experimentales sur le Cancer) runs courses for advanced training in immunology. At the 1970 course four- teen participants attended, from Brazil, Chile, Hungary, India, Japan, Lebanon, Mexico, Nigeria, Poland, Singapore, Spain, Thailand, Yugoslavia, and USSR. The Centre also serves as an immuno- globulin reference centre and provides reference reagents for measuring levels I 23 The molecular size and type of antibodies can be determined by spinning them in an ultracentrifuge. The research worker in the photograph is operating such a machine in the WHO Immunology Research and Training Centre at the University of Ibadan (Nigeria). He is studying antibodies that human beings form against malaria. Close student-teacher relationships are en- couraged in the WHO courses in basic and applied immunology. Research at the WHO centres is also directed towards immunological problems of regional importance, such as schistosomiasis, malaria and leprosy. V of the different classes of antibodies in human serum. Research projects in- clude studies of "local immunity ", e.g. the antibodies made locally in the gastro- intestinal tract which appear in intes- tinal secretions in cholera and in other enteric infections, and studies of the role of cellular immunity in resistance to leishmaniasis. In the Singapore Centre, participants from Singapore, In- donesia, Malaysia, Thailand, Burma, India, Japan, Ceylon, Taiwan, Fiji and the Philippines have learned techniques and concepts of modern immunology in three annual four-month courses. Re- search projects are varied. One is direct- ed to methods for detection of Australia antigen in hepatitis. Australia antigen was so named because it was first discovered in the blood of an Australian aborigine. The antigen is closely associated with serum hepatitis. This is of great poten- tial importance to blood transfusion because detection and exclusion of blood donors carrying the antigen could sig- nificantly reduce the risk of hepatitis from transfusions. Another study com- prises an attempt to discover why certain Chinese in Singapore have a higher incidence of nasopharyngeal cancer than other ethnic groups in that city. There are also research projects on population genetics and disease incidence, as well as cellular immunity in leprosy, filariasis and toxoplasmosis. In the Sao Paulo centre (Butantan Institute, University of Sao Paulo) a crippling skin disease, pemphigus, which is rare in North America and Europe but which is a public health problem in certain parts of Brazil, has been found to be associated with high levels of auto-antibodies to skin. Research on protective antibodies to snake venoms is under way. Par- ticipants from Argentina, Brazil, Chile, Peru and Uruguay have received instruc- tions in the latest immunological meth- ods. The Beirut Centre (American Univer- sity of Beirut) will provide training in immunology, and research projects will concern the important problem of the effect of nutritional deficiency on im- mune responses. Advanced training in specialized areas of immunology will be available at the Weizmann Institute in Short WHO Bibliography Research in Immunology. WHO Tech- nical Report Series. No. 286. Immunology and Parasitic Diseases. WHO Technical Report Series. No. 315. Immunotherapy of Cancer. WHO Tech- nical Report Series. No. 344. Teaching of Immunology in the Medi- cal Curriculum. WHO Technical Re- port Series. No. 358. Immunology of Malaria. WHO Tech- nical Report Series. No. 396. Genetics of the Immune Response. WHO Technical Report Series. No. 402. Cell-Mediated Immune Responses. WHO Technical Report Series. No. 423. Factors Regulating the Immune Res- ponse. WHO Technical Report Series. No. 448. In Press Prevention of RH Sensitization. WHO Technical Report Series. Immunological Problems on Leprosy Research. WHO Bulletin. Primary Immunodeficiencies. WHO Bulletin. Rehovoth, Israel and the Basle Institute of Immunology in Switzerland. In Mexi- co City, advanced training in the form of a three-year doctorate course in immu- nology is given, as well as shorter courses, such as in 1971 on the techniques used in clinical immunology. It is planned that the New Delhi Centre will also organize courses; research projects already under way there include studies of cellular immunology in leprosy and cancer. WHO fellowships support foreign trainees in the Centres, and small amounts of money are made available for reagents, glassware and some equip- ment. However, in all the Centres the laboratories and classrooms, the heavy equipment, specialized laboratory faci- lities and local counterpart personnel are supplied by the national host institution. It might be thought that a more efficient way of solving research prob- lems in immunology of a tropical disease would be to send in a research team, without taking the additional time and expense needed to train local people. However, in WHO's experience, such undertakings are usually effective only if co-operation is arranged with local scientists and practitioners who are in- cluded in the work and in the evalua- tion of the results, and if trained per- sonnel are prepared to carry on the research when the visiting team leaves. More and more graduates are return- ing to the developing countries and need the kind of further competent guidance and training that can be provided by research teams sponsored by national and international organizations. The effectiveness of any research programme will be increased by including guidance or training for graduates in the develop- ing countries, and the participation of local scientists in truly collaborative research projects will lead to better communication and form a bridge bet- ween developed and developing coun- tries. ■ One object of the immunology research and training centres is to bring together scientists from different countries who are striving to solve common regional problems through im- munology. V What the future holds by Dr John Herbert Humphrey Deputy Director and Head of Division of Immunology, National Institute for Medical Research, Mill Hill, London ammmEmmilumimonrminimimimmoisw The preceding articles have attempted to show how immunology has shed light on the cause and treatment of disease. They also may have explained why doctors and medical students are increas- ingly interested in this rapidly growing branch of medical science. The direction that immunology will take in the next ten or twenty years can be predicted to some degree—assuming of course that the effort and resources now devoted to it are not diminished. In general, we know that under certain circumstances we want to enhance the immune response—to achieve active im- munization against infectious diseases and against tumours. In other cases, such as autoimmune diseases and allergies, and for tissue transplantation, we want to diminish this response. This must be done selectively, since to abolish useful and protective reactions of the body along with those that are not desired might obviously do more harm than good. The difficulty is compounded by the fact that the more we learn about the immune response of man and other higher animals as organisms, rather than about their cells studied in isolation, the clearer it becomes that what has devel- oped in the course of evolution is a complex interplay of different forms of immune responses that simultaneously deal with a wide variety of needs. To manipulate these responses requires a much more precise understanding of how they occur and what controls them than we now have. For this reason, even setting aside intrinsic interest, basic re- search on the mechanism of the immune response must continue. Since immunology has caught the imagination of scientists concerned with the problem of how the cells of higher organisms become specialized for their different functions and how they interact with each other and their environment, there is little doubt that the necessary research will continue. In this article I would venture to suggest some possible future developments, confining myself to diseases of man rather than animals, although diseases of animals are not fundamentally different. Immunization against infectious diseases In principle, preventive immunization can be applied to any disease where the natural infection gives rise to long-lasting resistance against reinfection, as in small- pox. Although reasonably effective pro- phylactics are available against most of the important diseases in this category in temperate zones, there are several in the tropics, those caused by arbo-viruses among them, that could certainly be controlled if the money and effort were put into it. With viral infections the success of live, attenuated vaccines that multiply harmlessly in the vaccinated person has been so great that this procedure is likely to set the pattern for the future. Potentially safer vaccines will perhaps be made from the purified noninfective protein coat of viruses, the part that stimulates effective immunity. This mate- rial is not able to reproduce itself and multiply as would a live vaccine, therefore more of it would have to be administered to provoke successful immunization. The method would thus be uneconomical unless ways were found to improve the immunizing capacity of the antigens involved by including what are known as adjuvants—agents that act with the anti- gens to diminish their destructive capaci- ties and increase their ability to simulate the production of lymphocytes. Some adjuvants are already being used but the most effective ones cause too much tissue damage to be acceptable. Moreover, we are not quite sure how they act. Less toxic and more potent adjuvants will probably be developed, although I doubt that they will ever be able to make dead vaccines as effective as live vaccines. Furthermore, if, in future, live viral vaccines are grown in cultures of care- fully selected human cells, the risk of their being contaminated by other un- wanted viruses—their main drawback at present—will be virtually eliminated. Nevertheless, the use of improved adju- vants as well as the exploitation of new knowledge about the way in which different cells co-operate in antibody production will also make it possible to produce lasting immunity with smaller amounts of more highly purified bacte- rial antigens than are now necessary. 26 Intense immunological research now going on throughout the world should provide answers to many important health problems. This would not only diminish undesir- able toxic side effects but could also achieve the very desirable aim of devel- oping prophylactics that are effective in a single dose, instead of two or three. Immunization against diseases caused by several different types of viruses (such as dengue fever) may become more prac- tical if sufficiently small amounts of each type of virus can be combined in one vaccine without losing their effect. The rhino-viruses that cause the common cold comprise one group that might be handled in this way. Since it has been recognized that antibodies produced and secreted in the mucosal surfaces such as the respiratory tract are more effective in conferring protection against respiratory diseases than antibodies circulating in the blood, prophylactic immunization against such diseases as influenza will probably be- come more effective when given in droplets inhaled as mists or sprays rather than by injection. Locally produced antibodies are also more effective in the gut, and future vaccines against enteric infections such as typhoid, dysentery and cholera may well be given by mouth (see P. 9)- Among the most difficult infections to control by natural means are those in which the causative bacteria are able to remain alive within the body's phagocytic cells—white cannibal cells that normally devour invading organisms. Leprosy, tuberculosis, brucellosis and typhoid are among these diseases. Most of them can be treated, but this is often long and expensive: ideally, the best way to deal with such an infection would be to eradicate the agent, but until we have learned how to do this successfully preventive immunization of populations at risk can diminish the incidence and severity of the disease. The record of BCG (bacillus Calmette-Guerin) vacci- nation against tuberculosis, in spite of its limitations, shows that some success can be achieved. In such diseases immuniza- tion by vaccination does not result in antibodies circulating in the blood but in a type of cellular immunity whose mech- anism we are only just beginning to understand. It is safe to say that further knowledge will make it possible to devise methods of immunization for this group that are just as effective as is BCG for tuberculosis. As the incidence of each important infectious disease dwindles—along with improved sanitation, preventive immuni- zations and effective treatment—the time will come when the reservoir of infection has almost vanished and new cases become so rare that it hardly seems necessary to continue to apply prophy- lactic measures. Then critical decisions must be made. If, for example, immuni- zation against diphtheria or smallpox is discontinued, the population will become increasingly susceptible to infection. Un- less the causative agent has been entirely eradicated, a new infection, probably from an unexpected source, could sud- denly spread and take on epidemic proportions. If the available treatment were sufficiently rapid and effective the risk would be slight. Even so, it would be wise to stockpile or have the means to quickly produce enough vaccine to im- munize the whole population. It seems clear that if adequate treatment were not available it would be wiser not to discontinue preventive immunization. Immunization against parasitic diseases The eradication of diseases caused by parasites—malaria, schistosomiasis, try- panosomiasis, leishmaniasis—depends primarily on preventing their transmis- sion, both by using sanitary measures to eliminate the intermediate host of the parasite and by reducing the reservoir of human infection with good treatment. These, in the main, are the measures being taken in the WHO-sponsored worldwide malaria eradication cam- paign, as a result of which 80 per cent of the people in the formerly malarious areas of the world are no longer exposed to this disease. Where sufficient energy and money have been made available, suc- cesses have also been registered in clear- ing large areas of other parasitic diseases. But where they still remain endemic—as in many parts of the world—the inhabi- tants eventually achieve levels of clinical immunity at great human cost because of repeated or prolonged illnesses. It seems that this immunity builds up very slowly. In malaria and trypanosomiasis, the 27 parasites may be present in many anti- genically different forms and immunity to all of them must be acquired before it becomes solid: in schistosomiasis the parasites soon acquire a coating which masks them and prevents them from being recognized as foreign to the host. The tricks by which parasites avoid immune rejection are legion, but once they are discovered—and we have now begun to find them out—it will be mainly a question of time and effort before means are found for producing immunity comparable to that now obtainable against viral diseases, poliomyelitis among them, and bacterial infections such as diphtheria. It certainly would be worth making the effort, and the work could probably best be done by immu- nologists in countries where parasitic diseases are prevalent. If, in some cases, successful methods should prove to be too drastic for human use, it is more than likely that they could be applied in veterinary medicine. The barrier to success in transplants is primarily immunological and not surgi- cal, in spite of the high degree of skill that is necessary. The crux of the problem is that all people differ to a greater or lesser degree in the structure of some of their molecules—the transplantation antigens which make up the surface layer of their tissue cells. When tissues are transplanted from one person to another the recipient's lymphocytes recognize the foreign mole- cules and the ensuing immune reaction causes the graft to be rejected (see p. 15). There are three ways of overcoming this. One is to ensure that the transplan- tation antigens of donor and recipient differ as little as possible. The better the match, the better the prospects of success, provided that the donor tissue is healthy. However, the potential recipient may be far away when a suitable organ for transplantation becomes available. Much thought has been given to ways of preserving organs in a viable state for long periods so that " banks " of typed tissues are available just as banks of rare kinds of blood are stored frozen for transfusion. A great technical effort would be required, but this probably could be done. Without such banks, however, there is little prospect of the supply of well matched tissues ever equal- ling the demand. A second method of overcoming the rejection of a graft is to suppress the body's immune reaction with drugs, to prevent lymphocytes from multiplying. The drugs now available act indiscrimi- nately and diminish all immune res- ponses, including the useful ones against microbes, leaving the body a prey to infection. More selective drugs are al- ready showing promise of success. The third way is to prevent the recipient of the transplant from making the kind of immune response which damages the graft, while at the same time leaving all his other responses intact. Experimental models indicate that this can be done by treating the recipient beforehand with the antigens of the graft. This can have two results: first, the elimination of all the lymphocytes that could recognize these antigens as foreign to the body so that he becomes tolerant to them; and, second, the encouragement of antibodies which might hinder the development of damaging cell-mediated immunity. A combination of all three methods of overcoming graft rejection may provide the best answer in the long run. There are now good grounds for optimism, since by careful application of the first two pro- cedures four out of five kidney grafts are proving successful, the criterion being that recipients who would otherwise have died are alive and well two years later. Immunology and cancer Tumours develop when some of the body cells escape the mechanisms that normally control their ordered develop- ment and when they begin to invade and destroy neighbouring tissues. Such cells have long been known to have certain abnormalities, such as their nutritional requirements and the manner in which they divide. Recently it also has been recognized that the composition of their outer surface differs in subtle ways from that of normal cells and, in fact, is often noticeably foreign. Logically these tumour cells should thus evoke an im- mune response and be rejected by the body, as would a tissue graft. There is much evidence that an im- mune response does occur, but when tumours continue to grow this response has manifestly been insufficient. A grow- ing number of immunologists are turning their attention to the search for ways of making the immune response more effec- tive (the opposite of the requirement for successful tissue graft). This new ap- proach is likely to be of the utmost importance, for even by employing exist- ing or foreseeable methods of surgery, irradiation or drug treatment, it will often be impossible to eradicate every tumour cell in a patient; but if the body can be stimulated to finish the job itself a radical cure will have been achieved. So far no great successes can be attributed to immunotherapy in man, but findings in experimental animals are sufficiently 28 American scientists at the Cancer Research Laboratory, National Institutes of Health (USA), are exploring the theory that some human cancers may be caused by viruses. If this is true various methods of immunotherapy, such as preventive vaccination, could be developed. Soviet scientists at the Cancer Research Institute, Moscow, studying the immunology of various tumours. Some of this work is directed towards an understanding of the spontaneous tumours that occur in animals. Methods for protein separation and purification are used in all types of immunolo- I gical research. The scientist here is doing a special type of electrophoresis that is able to separate antibodies according to their molecular size and electrical charge. This technique is known as electrophoresis on polyacrylamide gels, and is seen here applied in the Gamaleja Institute in Moscow. V promising to warrant not only intensified research but also much optimism. Many tumours in animals have been found to be caused by viruses, although the virus itself is very hard to detect. There is a strong suspicion, yet un- proved, that at least some human cancers, such as acute leukaemia, are also caused by viruses. Since experimental animals can be protected by immunization with the so-called oncogenic or cancer-pro- ducing viruses against the tumours these viruses induce, it is reasonable to suppose that human beings could be similarly protected once the hypothetical causative viruses had been discovered. Major re- search efforts are certain to continue in this field but it is too early to predict the outcome. However uncertain are the hopes for immunotherapy or immunoprophylaxis of cancer, advantage has been taken of the fact that immune responses do occur in human cancer and a diagnostic test for liver cancer has already been developed (see photo, p. 31). A similar test for colon cancer is being actively evaluated, and there is much hope that immuno- diagnostic tests can be developed to help in the early diagnosis of many other cancers. A whole new chapter in the history of medicine opened when it was realized that a number of diseases whose causes had been obscure were due to, or aggravated by, an immune reaction of the body against some of its own cells or constituents. The diseases of this nature that were first recognized were unusual afflictions—rare forms of anaemia and thyroid disorders. The list now includes more common conditions like rheuma- toid arthritis and certain chronic liver and kidney diseases. There are various reasons why the body's normal state of self-tolerance breaks down. In our cur- rent state of knowledge we can only guess how the immune response is con- trolled. Sometimes it seems that there is a failure of the regulatory mechanisms, with the result that lymphocytes react with the body's normal cells. In other instances the immune mechanism is normal but is stimulated by cells that have been altered or damaged in some way. At present, treatment consists either in damping down the immune response with the sort of drugs used in organ transplantation, which can be strikingly successful, or in using drugs that diminish the inflammation caused by the anti- bodies reacting on the body. Both, without doubt, will be improved. It may become possible, for example, to destroy the action of the complement (a complex 29 <I Organs to be transplanted, such as kidneys, can be kept in a functional state for a short period of time while donor and recipient are being matched for their respective tissue types. Such storage is possible in a specially designed machine that also monitors the organ's func- tion. The one used here is at the University Hospital of Leiden ( Netherlands). Certain tumours produce an immunologically r, detectable substance known as a foetal pro- tein. This is very useful in the diagnosis of these tumours. Professor G. Abelev of the Gamaleja Institute in Moscow has significant- ly contributed to work in liver cancer. auxiliary mechanism of serum proteins largely responsible for the inflammation) and to abolish the damaging inflamma- tory reactions. This could break the vicious circle. It is unlikely that any long-acting miracle drug will solve the problem of this inflammation, since it is an essential protective reaction and to abolish it completely for a long period would probably do more harm than good. The best solution may turn out to be the discovery of a method to prevent the onset of autoimmune diseases and, as a corollary, to restore the specific self-tolerance that has been lost. This depends on learning more about the immune response itself. People can suffer anything from mild discomfort to crippling disability because they have become sensitized to materials in the environment which otherwise would be harmless. These substances invoke exaggerated immune reactions when introduced into the body that has been sensitized against them. Actually the terms "immunization" and "sensiti- zation" are hardly appropriate here, although the process that is described is identical. Allergy, a word first coined by von Pirquit more than 60 years ago, is generally used instead. Pollens, moulds and excreta of mites, all of which are likely to be inhaled, are commonly res- ponsible, especially if the air contains contaminated dust. Many other mater- ials may be involved and they may enter the body through the skin or gut, as well as the nose and lungs. The consequences are hay-fever, rashes, eczema, asthma, inflammation of the lungs and other symptoms. Relief can often be obtained with drugs when exposure cannot be avoided. These drugs counteract the effect of the powerful agents released in excess in the body by the assault of the external substance to which the body is " allergic". The more we learn about these agents and the way they are produced the greater the possibility of discovering better antagonists. There also are other ways of dealing with severe allergies. One is "desensitization": this involves alter- ing the subject's responses so that they actually make more antibodies but of a kind that are less violently reactive than those responsible for the allergic re- actions. The antibodies responsible for the commoner forms of allergies are present only in minute amounts and belong to a special class (IgE) quite recently dis- covered. Their biological properties are such that they become attached to cer- tain cells. It may be possible to block this attachment with its consequent sensitiza- tion by administering an excess of similar molecules lacking the harmful antibody activity. Immunological deficiency diseases The commonest cause of severe im- munological deficiency—failure of lym- phocytes to develop properly—is con- genital and indeed often hereditary. The results show up in children towards the end of the first year of life, when the immunity conferred by the mother's antibodies received before birth has waned. These children readily succumb to microbial infections that a normal child would throw off without any difficulty. When antibody production alone is affected such children can be kept in good health by regular trans- fusions of antibodies from normal adults who have recovered from most of the infections present in the community. In other cases the lymphocytes them- selves may be at fault, and fail to perform their normal functions. The reasons are various. They are more susceptible than most other cells in the body to overdoses of X-rays, for example. Then again the defect may lie in the thymus gland, an organ essential for the development of some forms of lymphocytes. Curing congenital diseases that involve the immune system is difficult, since it means supplying a function which the body lacks and we often do not know what it is. Quite often the defect has turned out to be much simpler than expected—the absence of a single enzyme or hormone, for example—and in the foreseeable future it may be possible to transplant the tissue which produces the missing material. The matter of preventing conception is now so much in the news that mention must be made here of some theoretical possibilities. It has been shown that some women who desire to become pregnant cannot do so because of immunological mechanisms, such as antibodies against spermatozoa. In the laboratory it is possible to sterilize male animals by immunizing them with their own sperma- tozoa and to make females infertile by immunizing them against the seminal fluid of their mates. Broader applications of this biological phenomenon have been suggested for control of conception, but their significance has yet to be established in humans. Developments in this aspect of immunology may have greater ramifi- cations in the future. Whether they will ever have practical applications is not known. However, there is no question but that research in this area will be important in understanding naturally occurring infertility that may be caused by a faulty immune response. The one foreign graft that succeeds without the help of a surgeon and flourishes without signs of immune rejec- tion is the foetus in its mother's womb. A child inherits half its characteristics from its father and thus is inevitably different from its mother, who rejects a skin graft from her child as readily as from her husband. The explanation for this re- markable phenomenon lies in a very subtle barrier that separates the tissues of the child from the mother's, without impeding the passage of nutrients or antibodies. This placental barrier may leak during pregnancy and even break down sufficiently during childbirth to allow substantial amounts of the infant's blood to enter the mother, stimulating the production of antibodies and causing the mother to become immunized against her own child's blood cells. If these antibodies are produced during pregnancy and happen to be passed back to the child they can destroy its blood cells sufficiently to cause jaundice and even death: they could similarly affect a subsequent child. Only certain differ- ences between the cells of the mother and child give rise to this sort of trouble, for well understood but complicated rea- sons. It occurs most frequently when the child's red blood cells have the rhesus factor but the mother's have not. It has recently been found that this accident, that is the immunization of the mother by her child's red blood cells, can almost always be prevented by giving the mother an injection of human antibodies against the rhesus factor shortly after birth takes place. When this treatment becomes routine, " rhesus " disease in babies will largely disappear. The incom- patibility between mother and child will, of course, remain, and it will be necessary to treat mothers at risk in every genera- tion. The fact that by means of one injection rhesus disease of the new-born can be prevented is one of the major public health advances of our time. Its implications for the future are far reach- ing: thousands of deaths and exchange transfusions in critically ill infants can now be prevented, and reassurance given to rhesus-negative mothers. ■ Photo Credits WHO/J. GOODMAN, p. 5. WHO/UNRWA, front cover, pp. 7, 8, 9. WHO/E. SCHWAB, pp. 2, 15, 16, 17, 18, 19, 27, 30. WHO, pp. 5, 14, 23, 24, 25. WHO/T. FARKAS, p. 5. BIBLIOTHEQUE DE L'ARSENAL, PARIS, p. 6. WHO/E. MANDELMANN, p. 7. WHO/J. MOHR, pp. 11, 12. WHO/M. JACOT, p. 12. WHO/ C. HUBER, pp. 22, 24. wHo/usts, pp. 28/29. WHO/NOVOSTI, back cover, pp. 28/29, 31. 31 • An investigator at Moscow labelling topes. Many immu dioactive substance the workers from th e Gamaleja Institute in tibodies with radioiso- logical tests employ ra- The lead bricks protect danger of radiation.