1
466 common in relation to the more than one million general anaesthetics administered each year in the U.K. Before cimetidine can be advocated as a routine prophylactic measure for every surgical patient we need to know from controlled trials whether it is more effective and safer than other methods. Physical means of preventing aspir- ation such as cricoid pressure, a gastric tube, and the semi-prone head-down position during recovery are the mainstay of prevention and unfortunately are still not being applied universally.2 Chemical and pharmacologi- cal methods, for the time being at least, must be regarded as adjuncts and not as substitutes for physical methods. CHAGAS’ DISEASE: POTENTIAL FOR IMMUNOPROPHYLAXIS INFECTION, with Trypanosoma cruzi (the haemoflagel- late responsible for Chagas’ disease) elicits a strong im- mune response sufficient to control the initial infection (acute stage). The parasites are not completely eli- minated but persist as a chronic low-level infection (chronic stage) in which parasites can be detected in the peripheral blood only by special techniques relying on a long period of multiplication in the insect host (xeno- diagnosis) or in a culture medium. Acute-stage Chagas’ disease is seldom fatal-indeed, epidemiological surveys3 reveal that about two-thirds of the 12 million infected individuals in Latin America had no symptoms at onset. However, years or decades later patients may present with the electrocardiographic ab- normalities and digestive disturbances characteristic of chronic Chagas’ disease that K6belel has ascribed to neuronal destruction. The central paradox. of Chagas’ disease is illustrated by the negative correlation between the severity of dis- ease and the level of parasitoemia. For example, patients between the third and fifth decades of life show the high- est rates of morbidity and mortality even though many have no parasites in the blood on repeated investiga- tion.5 This evidence, and reports of antibody and T-lym- phocyte autoreactivity to heart, nerve, and vascular structures, suggest that the immune response may be re- sponsible for the tissue damage seen in chronic Chagas’ disease. In 1975 Teixeira and his colleagues6 were able to reproduce the pathological findings seen in T. cruzi in- fected rabbits by repeated, long-term immunisation of normal animals with killed parasites or subcellular frac- tions. In the absence of direct toxic effects, Teixeira’,6 suggested that T. cruzi might share antigens with host tissues, and, although immunisation might elicit an anti- parasite cell-mediated response, the same response might also produce tissue damage. These findings indicated an immunopathogenesis with serious implications for those 3. Teixeira ARL, et al. 1978. Acquired cell-mediated immunodepression in acute Chagas’ disease. J Clin Invest 1978; 62: 1132-41. 4. Köberle F. Pathogenesis of Chagas’ disease. In: Trypanosomiasis and leish- maniasis with special reference to Chagas’ disease (Ciba Found Symp no. 20). Amsterdam: Excerpta Medica, 1974: 137-58. 5. Teixeira ARL. Chagas’ disease: trends in immunological research and pros- pects for immunoprophylaxis. Bull World Health Org 1979; 57: 697-710. 6. Teixeira ARL, Teixeira ML, Santos-Buch CA. The immunology of experi- mental Chagas’ disease IV. Production of lesions in rabbits similar to those of chronic Chagas’ disease in man. Am J Path 1975; 80: 163-78. groups -attempting to produce immunoprophylactic methods: vaccination might eliminate the infection but still produce the disease. Reports of two new lines of research seem to offer a more detailed understanding of the pathogenesis and provide a new stimulus for the development of candidate vaccines. It has been shown that T. cruzi antigens can adsorb to the surface of both infected and uninfected host cells.’ Although a wide variety of primary cultures and cell lines (of muscle, neuronal, and mammary tissue origin) adsorbed parasite antigens, uptake was not en- tirely non-specific-lymphocytes and erythrocytes showed no reactivity. Intriguingly, acquisition of para- site antigens rendered these host cells susceptible to cyto- lysis by humoral and cellular components of the host’s own antiparasite immune response.8 The initial anti- parasite response, developed by the 15th day after infec- tion, was followed at the 90th day after infection by the development of self reactive cytotoxic T lymphocytes able to lyse host cells in the absence of parasite antigens. This is consistent with the notion that parasite-modified host cells can be killed in vivo and release self com- ponents that are immunogenic, either alone or com- plexed with parasite antigens. This proposed mechanism of pathogenesis has two implications-firstly, a wide variety of cells could be destroyed, but neurone function would be especially vulnerable because the cells are not regenerated; and, secondly, the chronic phase of dis- ease would be initiated by events in the acute phase, and might be exacerbated by -secondary autoimmune mech- anisms. It is clear, therefore, that for a candidate vac- cine to be acceptable it would have to consist of T. cruzi components free of antigens that either cross-react with or bind to host cells. Scott and Snary9 have done some work in rodents with an antigen preparation that fulfils these criteria. They immunised mice with a T. cruzi cell-surface glyco- protein1O in either complete Freund’s adjuvant or saponin. Immunised mice showed a consistently reduced acute-stage parasitaemia and complete survival when challenged with the virulent parasite. Significantly, this cell surface antigen does not seem to show the mechan- ism of variation that enables African trypanosomes to evade the host immune response." I On existing evidence it seems that selective immunisa- tion with "protective" T. cruzi antigens might be pos- sible without provoking an autoimmune response. There is still, however, the major unresolved question of how good this protection must be before a vaccine can be considered of clinical value. If sterile immunity can be achieved then the clinical value is obvious. Partial pro- tection, giving a substantial reduction in acute-stage in- fection, might still be of value if it lessened the severity of chronic-phase disease. The absence of suitable animal models for chronic Chagas’ disease has so far precluded these important experiments. 7. Ribeiro dos Santos R, Hudson L. Trypanosoma cruzi: adsorption of parasite antigens to mammalian cell surfaces. Parasite Immunol 1980; 2: 1-10 8. Ribeiro dos Santos R, Hudson L. Trypanosoma cruzi: immunological conse- quences of parasite modification of host cells. Clin Exp Immunol 1980 40: 36-47. 9. Scott MT, Snary D. Protective immunisation of mice using cell surface gly- coprotem from Trypanosoma cruzi. Nature 1979; 282: 73-74. 10. Snary D, Hudson L. Trypanosoma cruzi cell surface proteins. identification of one major glycoprotein. FEBS Lett 1979; 100: 166-70. 11. Snary D. Trypanosoma cruzi: antigenic invariance of the cell surface glyco- protein. Exp Parasitol 1980; 49: 68-73.

CHAGAS' DISEASE: POTENTIAL FOR IMMUNOPROPHYLAXIS

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466

common in relation to the more than one million generalanaesthetics administered each year in the U.K. Beforecimetidine can be advocated as a routine prophylacticmeasure for every surgical patient we need to know fromcontrolled trials whether it is more effective and saferthan other methods. Physical means of preventing aspir-ation such as cricoid pressure, a gastric tube, and thesemi-prone head-down position during recovery are themainstay of prevention and unfortunately are still notbeing applied universally.2 Chemical and pharmacologi-cal methods, for the time being at least, must beregarded as adjuncts and not as substitutes for physicalmethods.

CHAGAS’ DISEASE: POTENTIAL FORIMMUNOPROPHYLAXIS

INFECTION, with Trypanosoma cruzi (the haemoflagel-late responsible for Chagas’ disease) elicits a strong im-

mune response sufficient to control the initial infection

(acute stage). The parasites are not completely eli-minated but persist as a chronic low-level infection

(chronic stage) in which parasites can be detected in theperipheral blood only by special techniques relying on along period of multiplication in the insect host (xeno-diagnosis) or in a culture medium.

Acute-stage Chagas’ disease is seldom fatal-indeed,epidemiological surveys3 reveal that about two-thirds ofthe 12 million infected individuals in Latin America hadno symptoms at onset. However, years or decades laterpatients may present with the electrocardiographic ab-normalities and digestive disturbances characteristic ofchronic Chagas’ disease that K6belel has ascribed toneuronal destruction.

The central paradox. of Chagas’ disease is illustratedby the negative correlation between the severity of dis-ease and the level of parasitoemia. For example, patientsbetween the third and fifth decades of life show the high-est rates of morbidity and mortality even though manyhave no parasites in the blood on repeated investiga-tion.5 This evidence, and reports of antibody and T-lym-phocyte autoreactivity to heart, nerve, and vascular

structures, suggest that the immune response may be re-sponsible for the tissue damage seen in chronic Chagas’disease.

In 1975 Teixeira and his colleagues6 were able toreproduce the pathological findings seen in T. cruzi in-fected rabbits by repeated, long-term immunisation ofnormal animals with killed parasites or subcellular frac-tions. In the absence of direct toxic effects, Teixeira’,6suggested that T. cruzi might share antigens with hosttissues, and, although immunisation might elicit an anti-parasite cell-mediated response, the same response mightalso produce tissue damage. These findings indicated animmunopathogenesis with serious implications for those

3. Teixeira ARL, et al. 1978. Acquired cell-mediated immunodepression in

acute Chagas’ disease. J Clin Invest 1978; 62: 1132-41.4. Köberle F. Pathogenesis of Chagas’ disease. In: Trypanosomiasis and leish-

maniasis with special reference to Chagas’ disease (Ciba Found Symp no.20). Amsterdam: Excerpta Medica, 1974: 137-58.

5. Teixeira ARL. Chagas’ disease: trends in immunological research and pros-pects for immunoprophylaxis. Bull World Health Org 1979; 57: 697-710.

6. Teixeira ARL, Teixeira ML, Santos-Buch CA. The immunology of experi-mental Chagas’ disease IV. Production of lesions in rabbits similar to thoseof chronic Chagas’ disease in man. Am J Path 1975; 80: 163-78.

groups -attempting to produce immunoprophylacticmethods: vaccination might eliminate the infection butstill produce the disease.

Reports of two new lines of research seem to offer amore detailed understanding of the pathogenesis andprovide a new stimulus for the development of candidatevaccines. It has been shown that T. cruzi antigens canadsorb to the surface of both infected and uninfectedhost cells.’ Although a wide variety of primary culturesand cell lines (of muscle, neuronal, and mammary tissueorigin) adsorbed parasite antigens, uptake was not en-tirely non-specific-lymphocytes and erythrocytesshowed no reactivity. Intriguingly, acquisition of para-site antigens rendered these host cells susceptible to cyto-lysis by humoral and cellular components of the host’sown antiparasite immune response.8 The initial anti-

parasite response, developed by the 15th day after infec-tion, was followed at the 90th day after infection by thedevelopment of self reactive cytotoxic T lymphocytesable to lyse host cells in the absence of parasite antigens.This is consistent with the notion that parasite-modifiedhost cells can be killed in vivo and release self com-

ponents that are immunogenic, either alone or com-plexed with parasite antigens. This proposed mechanismof pathogenesis has two implications-firstly, a widevariety of cells could be destroyed, but neurone functionwould be especially vulnerable because the cells are notregenerated; and, secondly, the chronic phase of dis-ease would be initiated by events in the acute phase, andmight be exacerbated by -secondary autoimmune mech-anisms. It is clear, therefore, that for a candidate vac-cine to be acceptable it would have to consist of T. cruzicomponents free of antigens that either cross-react withor bind to host cells.

Scott and Snary9 have done some work in rodentswith an antigen preparation that fulfils these criteria.They immunised mice with a T. cruzi cell-surface glyco-protein1O in either complete Freund’s adjuvant or

saponin. Immunised mice showed a consistently reducedacute-stage parasitaemia and complete survival when

challenged with the virulent parasite. Significantly, thiscell surface antigen does not seem to show the mechan-ism of variation that enables African trypanosomes toevade the host immune response." IOn existing evidence it seems that selective immunisa-

tion with "protective" T. cruzi antigens might be pos-sible without provoking an autoimmune response. Thereis still, however, the major unresolved question of howgood this protection must be before a vaccine can beconsidered of clinical value. If sterile immunity can beachieved then the clinical value is obvious. Partial pro-tection, giving a substantial reduction in acute-stage in-fection, might still be of value if it lessened the severityof chronic-phase disease. The absence of suitable animalmodels for chronic Chagas’ disease has so far precludedthese important experiments.

7. Ribeiro dos Santos R, Hudson L. Trypanosoma cruzi: adsorption of parasiteantigens to mammalian cell surfaces. Parasite Immunol 1980; 2: 1-10

8. Ribeiro dos Santos R, Hudson L. Trypanosoma cruzi: immunological conse-quences of parasite modification of host cells. Clin Exp Immunol 198040: 36-47.

9. Scott MT, Snary D. Protective immunisation of mice using cell surface gly-coprotem from Trypanosoma cruzi. Nature 1979; 282: 73-74.

10. Snary D, Hudson L. Trypanosoma cruzi cell surface proteins. identificationof one major glycoprotein. FEBS Lett 1979; 100: 166-70.

11. Snary D. Trypanosoma cruzi: antigenic invariance of the cell surface glyco-protein. Exp Parasitol 1980; 49: 68-73.