Sozial- und Präventivmedizin

, Volume 40, Issue 1, pp 50–57 | Cite as

Experimental cerebral malaria: Possible new mechanisms in the TNF-induced microvascular pathology

  • Georges E. Grau
  • Jin Ning Lou


In order to contribute to the prevention of malaria morbidity and mortality, especially in endemic zones, we have carried out a series of studies on cytokine interactions in an experimental model of cerebral malaria (CM). This rapidly lethal syndrome develops, in some strains of mice, upon infection with Plasmodium berghei ANKA (PbA). A crucial mediator of neurovascular lesions appears to be TNF, found in high amounts in relation with cerebral complications, in both experimental and human CM1. In experimental CM, in vivo injections of anti-cytokine antibodies have been used to analyze the cascade of reactions leading to brain vascular damage1. In this review, we fill focus on the interplay of cytokines responsible for TNF overproduction in experimental malaria, therefore delineating the subset of T cells whose activation can lead to pathology, and effector mechanisms of neurovascular lesions characteristic of mouse cerebral malaria, with recent findings that appear to involve an unexpected cell type, the blood platelet.


Tumor Necrosis Factor Malaria Cerebrale Malaria Malaria Morbidity Cerebral Complication 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Mit dem Ziel zur Prävention von Malaria-Morbidität und-Mortalität beizutragen, wurde eine Serie von Studien über die Interaktionen von Cytokinen in einem experimentellen Modell für cerebrale Malaria (CM) durchgeführt. Dieses in kurzer Zeit tödliche Syndrom entwickelt sich, in einigen Mausstämmen, nach einer Infektion mit Plasmodium berghei ANKA (PbA). TNF scheint ein entscheidender. Vermittler für neurovasculäre Läsionen zu sein, der im Zusammenhang mit cerebralen Komplikationen sowohl bei experimenteller als auch humaner CM in grosser Menge gefunden wird. Bei experimenteller CM wurden in vivo Injektionen von anti-Cytokine Antikörpern verwendet um die Kaskade von Reaktionen zu analysieren, die zur Schädigung von Hirngefässen führen. In diesem Überblick werden wir uns auf das Zusammenspiel der bei experimenteller Malaria für die Überproduktion von TNF verantwortlichen Cytokine konzentrieren, und dazu die T-Zellpopulation darstellen deren Aktivierung zur Pathologie führen kann, und auf die Effektormechanismen von neurovasculären, für die cerebrale Malaria der Maus typischen Läsionen, mit neuen Befunden, die eine Beteiligung eines unerwarteten Zelltyps, der Blutplättchen, zu ergeben scheinen.


Dans le but de contribuer à la prévention de la morbídlté et de la mortalité due au paludisme, en particulier dans les zones endémiques, nous avons mené une série d'études sur les interactions entre cytokines dans un modèle expérimental de paludisme cérébral (CM pour cerebral malaria). Ce syndrôme rapidement mortel survient chez certaines souches de souris à la suite d'une infection par Plasmodium berghei ANKA (PbA). Un médiateur particulièrement important des lésions neuro-vasculaires semble être le Tumor Necrosis Factor (TNF) que l'on retrouve en quantité importante dans les cas présentant des complications cérébrales (CM), aussi bien chez l'homme que chez l'animal d'expérience. Dans les CM expérimentales, des injections in vivo d'anticorps anti-cytokines ont été utilisées pour analyser la séquence des événements menant aux lésions vasculaires cérébrales. Dans cette revue, nous nous concentrons sur les interactions entre cytokines responsables de la surproduction de TNF dans le paludisme expérimental qui, de ce fait, définissent le sous-groupe de cellules T dont l'activation peut conduire à des manifestations pathologiques, et les mécanismes effecteurs des lésions neuro-vasculaires caractéristiques du paludisme cérébral chez la sourís, avec la découverte récente du rôle d'une cellule inattendue, la plaquette sanguine.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Grau GE, Piguet PF, Vassalli P, Lambert PH. Tumor necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. Immunol Rev 1989;112: 49–70.Google Scholar
  2. 2.
    Mosmann TR, Coffman RL, Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7:145–173.Google Scholar
  3. 3.
    Scott P, Pearce E, Cheever AW, Coffman RL, Sher A. Role of cytokines and CD4+ T cell subsets in the regulation of parasite immunity and disease. Immunol Rev 1989;112:161–182.Google Scholar
  4. 4.
    Heizel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 1989;169:59–72.Google Scholar
  5. 5.
    Pond L, Wassom DL, Hayes CE. Evidence for differential induction of helper T-cell subsets during Trichinella-spiralis infection. J Immunol 1989;143:4232–4237.Google Scholar
  6. 6.
    Langhorne J, Meding SJ, Eichmann K, Gillard SS. The response of CD4+ T cells to Plasmodium-chabaudi-chabaudi. Immunol Rev 1989;112:71–94.Google Scholar
  7. 7.
    Grau GE, Heremans H, Piguet PF, Pointaire P, Lambert PH, Billiau A, Vassalli P. Monoclonal antibody against interferon-gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc Natl Acad Sci USA 1989;86:5572–5574.Google Scholar
  8. 8.
    Grau GE, Piguet PF, Engers HD, Louis JA, Vassalli P, Lambert PH. L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol 1986;137:2348–2354.Google Scholar
  9. 9.
    Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 1987;237:1210–1212.Google Scholar
  10. 10.
    Grau GE, Kindler V, Piguet PF, Lambert PH, Vassalli P. Prevention of experimental cerebral malaria by anticytoline antibodies. IL-3 and GM-CSF are intermediates in increased TNF production and macrophage accumulation. J Exp Med 1988;168:1499–1504.Google Scholar
  11. 11.
    De Kossodo S, Grau GE. Profiles of cytokine production in relation with susceptibility to experimental cerebral malaria. J Immunol 1993;151:4811–4820.Google Scholar
  12. 12.
    Waki S, Uehara S, Kanbe K, Ono K, Suzuki M, Nariuchi H. The role of T-cells in Pathogenesis and Protective Immunity to Murine Malaria. Immunology 1992;75:646–651.Google Scholar
  13. 13.
    Chizzolini C, Grau GE, Geinoz A, Schrijvers D. Lymphocyte-T interferon-gamma production induced by Plasmodium-falciparum antigen is high in recently infected non-immune and low in immune subjects. Clin Exp Immunol 1990;79: 95–99.Google Scholar
  14. 14.
    Peterson JD, Waltenbaugh C, Miller SD. IgG subclass responses to theiler's murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains. Immunology 1992;75: 652–658.Google Scholar
  15. 15.
    Pearce EJ, Caspar P, Grzych JM, Lewis FA, Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma-mansoni. J Exp Med 1991;173: 159–166.Google Scholar
  16. 16.
    Pandita R, Pocsik E, Aggarwal BB. Interferon-gamma induces cell surface expression for both types of tumor necrosis factor receptors. FEBS Lett 1992:312:87–90.Google Scholar
  17. 17.
    Grau GE, Pointaire P, Piguet PF, Vesin C, Rosen H, Stamenkovic I, Takei F, Vassalli P. Late Administration of Monoclonal Antibody to Leukocyte Function-Antigen 1 Abrogates Incipient Murine Cerebral Malaria. Eur J Immunol 1991;21:2265–2267.Google Scholar
  18. 18.
    Grau GE, Piguet PF. Tumor necrosis factor in cerebral and non-cerebral malaria. In: Fiers W, Buurman WA, eds. Tumor necrosis factor: molecular and cellular biology and clinical relevance. Basel: Karger, 1993:162–171.Google Scholar
  19. 19.
    Dudek R, Kibira S, Kahler J, Bing RJ. The effect of immune mediators (cytokines) on the release of endothelium-derived relaxing factor (EDRF) and of prostacyclin by freshly harvested endothelial cells. Life Sci 1992;50:863–873.Google Scholar
  20. 20.
    Myers PR, Wright TF, Tanner MA, Adams HR. EDRF and nitric oxide production in cultured endothelial cells-direct inhibition by E-Coli endotoxin. Am J Physiol 1992;262:H710-H718.Google Scholar
  21. 21.
    Rockett KA, Awburn MM, Aggarwal BB, Cowden WB, Clark IA. In vivo Induction of nitrite and nitrate by tumor necrosis factor, lymphotoxin, and interleukin-1 — possible roles in malaria. Infect Immun 1992;60:3725–3730.Google Scholar
  22. 22.
    Senaldi G, Kremsner PG, Grau GE. Nitric oxide and cerebral malaria. Lancet 1992;340:1554–1555.Google Scholar
  23. 23.
    Kremsner PG, Nussler A, Neifer S, Chaves MF, Bienzle U, Senaldi G, Grau GE. Malaria antigen and cytokine-induced production of reactive nitrogen intermediates by murine macrophages: no relevance to the development of experimental cerebral malaria. Immunology 1993;78:286–290.Google Scholar
  24. 24.
    Porta J, Carota A, Pizzolato GP, Wildi E, Widmer MC, Margairaz C, Grau GE. Immunopathological changes in human cerebral malaria. Clin Neuropathol 1993;12:142–146.Google Scholar
  25. 25.
    Radomski MW, Palmer RMJ, Moncada S. Modulation of Platelet Aggregation by an L-Arginine Nitric Oxide Pathway. Trends Pharmacol Sci 1991;12:87–88.Google Scholar
  26. 26.
    Herbaczynskacedro K, Lembowicz K, Pytel B. NG-Monomethyl-L-Arginine Increases Platelet Deposition on Damaged Endothelium Invivo — A Scanning Electron Microscopic Study. Thromb Res 1991;64:1–9.Google Scholar
  27. 27.
    Gimbrone MAJR, Aster RH, Cotran RS, Corkery J, Jandl JH, Folkman J. Preservation of vascular integrity in organs perfused in vitro with a platelet-rich medium. Nature 1969;222:33–36.Google Scholar
  28. 28.
    Yamazaki H, Fujimoto T, Suzuki H, Akamatsu N, Katagiri Y, Yamaguchi A, Tanoue K. Interaction of platelets and blood vessels — vascular injuries induced by platelet activation in vivo. Jpn Circ J 1992;56:178–186.Google Scholar
  29. 29.
    Grau GE, Lou J. TNF in vascular pathology: importance of plateletendothelium interactions. Res Immunol 1993;144:355–363.Google Scholar
  30. 30.
    Falanga PB, Butcher EC. Late treatment with anti-LFA-1 (CD11a) antibody prevents cerebral malaria in a mouse model. Eur J Immunol 1991;21:2259–2263.Google Scholar
  31. 31.
    Grau GE, Tacchini-Cottier F, Vesin C, Milon G, Lou J, Piguet PF, Juillard P. An active role for platelets in microvascular pathology of severe malaria. Eur Cytokine Netw 1993;4:415–419.Google Scholar
  32. 32.
    Pongponratn E, Riganti M, Harinasuta T, Bunnag D. Electron microscopy of the human brain in cerebral malaria. Southeast Asian J Trop Med Public Health 1985;16: 219–227.Google Scholar
  33. 33.
    Piguet PF, Rosen H, Vesin C, Grau GE. Effective treatment of the pulmonary fibrosis elicited in mice by bleomycin or silica with anti-CD11 antibodies. Am Rev Respir Dis 1993;147:435–441.Google Scholar
  34. 34.
    Piguet PF, Vesin C, Ryser JE, Senaldi G, Grau GE, Tacchini-Cottier F. An effector role of platelets in the local or systemic LPS-induced toxicity mediated by a CD11/CD18 dependent interaction with the endothelium. Infect Immun 1993;61:4182–4187.Google Scholar
  35. 35.
    Johnson SA, Balboa RS, Dessel BH, Monto RM, Siegesmund KA, Greenwalt TJ. The mechanism of the endothelial supporting function of intact platelets. Exp Mol Pathol 1964;3:115–127.Google Scholar
  36. 36.
    Wojcik JD, Van Horn DL, Webber AJ, Johnson SA. Mechanism whereby platelets support the endothelium. Transfusion 1969;9: 324–335.Google Scholar
  37. 37.
    Ellison D, Gatter K, Heryet A, Esiri M. Intramural platelet deposition in cerebral vasculopathy of systemic lupus erythematosus. J Clin Pathol 1993;46:37–40.Google Scholar

Copyright information

© Birkhäuser Verlag 1995

Authors and Affiliations

  • Georges E. Grau
    • 1
  • Jin Ning Lou
    • 1
  1. 1.WHO-IRTC, Department of Pathology, Faculty of MedicineUniversity of GenevaGeneva 4

Personalised recommendations