Recent developments in the assessment of the immune response to malaria, especially as related to vaccination: Lethal Plasmodium yoelii malaria: the role of macrophages in normal and immunized mice

Bulletin ofthe World Health Organr6ation, 57 (Suppl 1) 245-246 (1979) Lethal Plasmodium yoelii malaria: the role of macrophages in normal and immunized mice J. H. L. PLAYFAIR' Mice were injected with silica or Corynebacterium parvum, whicih, respectively, inhibit and slimulate macrophages in vivo, in an attempr to study the role ofmacrophages in lethal Plasmodium yoelii Infection anrd in mice protected by iinmmtnization. In the normal infection, macrophages were able to control parasilaeinia for up to I week, whereas in im- inunized mice they appeared to inhibit the sterilizing immune response. A model isproposed in which this dual role ofactfiated macrophagesmay accountfor the chronic non-sterilizing course of natural malara infeclions. We have studied the mmunune response to a lcthal variant of the 17X strain of Plasinodium yoelii in (C57B1 x BALB/c) F, mice. Normal mice died during the second week of this infection, but they could be fully protected by vaccination (I). The most effective vaccine was an intravenous injection of 108 saponin- lysed, formalin-fixed, parasitized red cells, combined with 108 Bordetella pertussis organisms. Vaccinated mice showed normal or slightly enhanced parasitaemia for 4 days, then suddenly cleared their parasitaemia. After 10 days, subinoculation into fresh recipients did not reveal any livng parasites in blood, spleen, liver or bone marrow. Protection could be transferred to normal recipients by a mixture of serum and periph- eral blood cells from vaccinated donors that had re- covered. Vaccinated mice showed greatly increased antibody responses, especially in the IgG class, and also a strong delayed hypersensitivity to P. yoelii antigens (2). To investigate the possible role of phagocytic cells in protection, iiormal or vaccinated mice were injected with either 3 mg of silica intravenously,0 2 hours beforc infection, to suppress phagocytic cells, or with 1.4mg of Corynebacternumparvum intraperitoneally, 3 days before infection, to activate them. The effects of these two agents were different in normal and in vaccinated mice. In normal mice, silica acceLerated and C.parvum delayed the appearance of parasites in the blood (Fig. 1). Infectivity titrations showed that neither agent altered the miilimal infective dose of P. yoelii (Fig. 2), suggesting that killing of parasites was not the cause of the differences in parasitaemia. I Department of Immunology, Artbur Stanley House, Middlesex Hospital Medical School. 40-50 Tottenham Street, London WIP 9PG, England. 0 The silica, in the foim of quartz dust (< Spm), and instructions for its use were kindly pLovided by Dr A. C. AUlison. In vaccinaLed mice, however, silica accelerated and C. parvum delayed the cJearance of parasitaemia (Fig. 3), suggesting that macrophages, especially if activated, inhibited the development of sterilizing im- munity. Serum transfer experiments and immuno- --4~~~7 10 01 normal mice z _3mgsilica v t) / + ~~~~~~--O--1-4 mg C p2rvunm i.p. Lli EL ta. 17./ 2 3 4 5 6 7 8 DAYS AFTER INFECTION Fig. 1. The parasitaemia following infection of (C57B1 x BALBJc) F, mice with 104 P. yoeii;-parasitized red cells. Each poin; represents 7-25 mice from 3 separate experi- ments All the silica values up to da, 7 are significantiV dif- ferent from normal (P<O.0005); the C. parvum differences are significant {P< 0.025) except at day 6. Reproduced from PLAYFAIR, J. H. L. ET AL Parasite immunology (in press), by kind permission of the editors and Blackwell Scientific Publi- cations Ltd. 3895- - 246 J. H. L. PLAYFAIR fluorescent antibody measurements showed chat the principal effect of macrophages was to inhibit the secondary IgG response, rather than to suppress the final killing mechanism. It was concluded that macrophage activation, such as is known to occur in malaria, encourages control of 100 e10 w c80 IL z \ w60 - * normal mice IL 40 - 3mg silicaQv\V0 0 14mgCparvumap 20 100 10 1 01 NUMBER OF PARASITES INJECTED Fig. 2. Infectivity titrations of P. yoelii in (C57B1 x BALB/c) F, mice pretreated with silica or C. parvum. Each point rep- resents at least 20 mice. parasitaemia levels but ac the same time discourages the development of sterilizing immunity. Both these effects are obviously in the interests of the parasite. If a similar mechanism operates in natural infections, chronicity would be assured, and vaccination, to be effective, might have to be performed at a time when macrophages were not activated. 0.1~~~~~~~~~~~~~~~~~~~~~~1 < < a_ ~ ~ ~ ~ ~ ~ ~ ~ 1 1o 01 norrmal mice z 1fi1 --- 3mg silica v.v (3 --0-- 14 mg C pOrvum p XL "0^ = -- |, 2 3 4 5 6 7 & 9 DAYS AFTER INFECTION Fig. 3. The parasiteemia followng infection of (C57BI x BALB/c) F, mice with 104 P. youlii, 3 weeks after vacci- nation with 108 formalin-fixed P. yoii plus 10 B.pertussis organisms. The silica values are significantly different from the normal on days 5 IP< 0.01) and 6 (P = 0.0251; and the C.parvum values on days 5 (P = 0.01) and 6, 7 and 8 (P< 0.0005). Reproduced fromPLAYFAIR,J. H. L. ETALParM- site immunology (in press), by kind permission of the editors and Blackwell Scientific Publications Ltd. ACKNOWLEDGEMENTS This work was supported by a grant from the Medical Research Council, London. RPSUMV L'ACTION DES MACROPHAGES CHEZ LES SOURIS IMMUNISPIES EL NON IMMUNIStES DANS L'INFECTION LETALE APLASMODIUM YOELII Pour cette experience, les souris ont rerui une injection soil de silice-afin d'inhiber I'action des macrophages-soit de Corynebacterwum parvum destinee au contraire k renforcer cette action. Les deux types d'injection ont 6t6 op6res chez des souris immunisees et non immunis6es contre Plasmodium yoelii. ApTis infection par le variant l6tal de la souche 17X de Plasmodium yoetai, I'acivation des macro- phages aretard6 I'apparition de la parasitemie chez les souris non immunisees. Mais, chez les souris immunis6es, elle a re- tard6 la disparition de la parasitimie, ce qui permet de penser que les macrophages contarienL la reponse immunitaife. 11 est possible que, dans l'infection paludeenne naturelle, I'activation des macrophages aboutisse A la chronicit6, A la fois en contr6lant le niveau de parasitkmie eten empechant le d6veloppement de i'immunit6 vraie. REFERENCES 1. PLAYMAIR, J. H. L. ET AL Immunology, 33: 507 (1977). 2. COTTRELL, B. J. ErAL Clinical and expernental mmunolog.y, 34: 147 (1978).