Abstract
Self-cure versus uncontrolled disease progression in experimental murine cutaneous leishmaniasis depends upon a delicate interplay among various activated cells of the host's immune system. Susceptibility or resistance to infection with Leishmania major is correlated with the ability of different inbred strains of mice to produce the characteristic spectra of lymphokines upon infection. Appropriate experimental interventions now allow the modulation of these reponses, providing the possibility to render genetically susceptible mice resistant to infection and, vice versa, to cause genotypically “healer” strains to express a “non-healer” phenotype. These experimental manipulations have proven to be powerful tools in the dissection of the underlying immune mechanisms and cellular parameters responsible for susceptibility and resistance, and will perhaps allow the identification of molecules of parasite origin that induce deleterious immune responses to infection with Leishmania, and thus to exclude them from future vaccines. More importantly, rational immune intervention could permit the diversion of established host-damaging immune responses to host-protective immunization.
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References
Anderson S, David JR, McMahon-Pratt D (1983) In vivo protection against Leishmania mexicana mediated by monoclonal antibodies. J Immunol 131:1615–1618
Antoine JC, Jouanne C, Lang T, Prina E, DeChastellier C, Frehel C (1991) Localization of major histocompatibility complex class II molecules in phagolysosomes of murine macrophages infected with Leishmania amazonensis. Infect Immun 59:764–775
Behin R, Mauel J, Sordat B (1979) Leishmania tropica: Pathogenicity and in vitro macrophage function in strains of inbred mice. Exp Parasitol 48:81–91
Belosevic M, Davis CE, Meltzer M, Nacy CA (1988) Regulation of activated macrophage antimicrobial activities. Identification of lymphokines that cooperate with IFN-γ for induction of resistance to reinfection. J Immunol 141:890–896
Belosevic M, Finbloom DS, VanderMeide PH, Slayter MV, Nacy CA (1989) Administration of monoclonal anti-IFN-γ antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol 143:266–272
Belosevic M, Finbloom DS, Meltzer MS; Nacy CA (1990) IL 2 a cofactor for induction of activated macrophage resistance to infection. J Immunol 145:831–839
Bogdan C, Moll H, Solbach W, Röllinghoff M (1990) Tumor necrosis factor-α in combination with interferon-γ, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes. Eur J Immunol 20:1131–1135
Bogdan C, Stenger S, Röllinghoff M, Solbach W (1991) Cytokine interactions in experimental cutaneous leishmaniasis. Interleukin 4 synergizes with interferon-γ to activate murine macrophages for killing of Leishmania major amastigotes. Eur J Immunol 21:327–333
Buchmüller-Rouiller Y, Mauel J (1987) Impairment of the oxidative metabolism of mouse peritoneal macrophages by intracellular Leishmania sp. Infect Immun 55:587–593
Champsi J, McMahon-Pratt D (1988) Membrane glycoprotein M-2 protects against Leishmania amazonensis infection. Infect Immun 56:3272–3279
Coffman RL, Chatelain R, Leal LMCC, Varkila K (1991) Leishmania major infection in mice: a model system for the study of CD4+ T cell subset differentiation. Res Immunol 142:36–40
Descoteaux A, Turco SJ, Sacks DL, Matlashewski G (1991) Leishmania donovani lipophosphoglycan selectively inhibits signal transduction in macrophages. J Immunol 146:2747–2753
Farrell JP, Müller I, Louis JA (1989) A role for Lyt2+ T cells in resistance to cutaneous leishmaniasis in immunized mice. J Immunol 142:2052–2056
Gajewski TF, Fitch FW (1988) Anti-proliferative effect of IFN-γ in immune regulation. I. IFN-γ inhibits the proliferation of Th2 but not Th1 murine HTL clones. J Immunol 140:4245–4252
Glaser T, Mukkada AJ (1992) Prolin transport in Leishmania donovani amastigotes: dependence on pH gradients and membrane potential. Mol Biochem Parasitol (in press)
Green SJ, Meltzer MS; Hibbs JB Jr, Nacy CA (1990) Activated macrophages destroy intracellular Leishmania major amastigotes by an l-arginine-dependent killing mechanism. J Immunol 144:278–283
Hamilton TA, Adams DO (1987) Molecular mechanisms of signal transduction in macrophages. Immunol Today 8:151–158
Handman E, Goding JW (1985) The Leishmania receptor for macrophages is a lipid-containing glycoconjugate. EMBO J 4:329–336
Handman E, Ceredig R, Mitchell GF (1979) Murine cutaneous leishmaniasis: disease patterns in intact and nude mice of various genotypes and examination of some differences between normal and infected macrophages. Aust J Exp Biol Med 57:9–30
Handman E, Michell GF (1985) Immunization with Leishmania receptor for macrophages protects mice against cutaneous leishmaniasis. Proc Natl Acad Sci USA 82:5910–5914
Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM (1989) Reciprocal expression of interferon-γ or interleukin 4 during the resolution or progression of murine leishmaniasis. J Exp Med 169:59–72
Heinzel FP, Sadick MD, Mutha SS, Locksley RM (1991) Production of interferon-γ, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progresssive leishmaniasis. Proc Natl Acad Sci 88:7011–7015
Hill JO (1991) Reduced numbers of CD4+ suppressor cells with subsequent expansion of CD8+ protective T cells as a explanation for the paradoxical state of enhanced resistance to Leishmania in T cell-deficient BALB/c mice. Immunology 72:282–286
Hill JO, Awwad M, North RJ (1989) Elimination of CD4+ suppressor T cells from susceptible BALB/c mice releases CD8+ T lymphocytes to mediate protective immunity against Leishmania. J Exp Med 169:1819–1827
Holaday BJ, Sadick MD, Zhi-En Wang, Reiner SL, Heinzel FP, Parslow TG, Locksley RM (1991) Reconstitution of Leishmania immunity in severe combined immunodeficiency mice using Th1- and Th2-like cell lines. J Immunol 147:1653–1658
Howard JC, Hale LG, Liew FY (1981) Immunological regulation of experimental cutaneous leishmaniasis. IV. Prophylactic effect of sublethal irradiation as a result of abrogation of suppressor T cell generation in mice genetically susceptible to Leishmania tropica. J Exp Med 153:557–568
Huszar M, Shor R, Trau H, Gazit E, Passwell JH (1987) The T cell phenotype in the lesion of patients with cutaneous leishmaniasis. Clin Exp Dermatol 12:103–107
Liew FY (1986) Cell-mediated immunity in experimental cutaneous leishmaniasis. Parasitol Today 2:264–270
Liew FY (1989) Functional heterogeneity of CD4- T cells in leishmaniasis. Immunol Today 10:40–45
Liew FY, Singleton A, Cillari E, Howard JG (1985) Prophylactic immunization against experimental leishmaniasis. V. Mechanism of the anti-protective blocking effect induced by subcutaneous immunization against Leishmania major. J Immunol 135:2101–2107
Liew FY, Millott S, Lelchuk R, Cobbold S, Waldmann H (1989) Effect of CD4 monoclonal antibody in vivo on lesion development, delayed-type hypersensitivity and interleukin 3 production in experimental murine cutaneous leishmaniasis. Clin Exp Immunol 75:438–443
Liew FY, Li Y, Millott S (1990) Tumor necrosis factor (TNF-α) in leishmaniasis. II TNF-α-induced macrophage leishmanicidal activity is mediated by nitric oxide from l-arginine. Immunology 71:556–559
Liew FY, Parkinson C, Millott S, Severn A, Carrier M (1990) Tumor necrosis factor (TNF-α) in leishmaniasis. I. TNF-α mediate host protection against cutaneous leishmaniasis. Immunology 69:570–573
Liew FY, Millott S, Parkinson C, Palmer J, Moncada S (1990) Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from l-arginine. J Immunol 144:4794–4797
Liew FY, Yun Li, Millott S (1990) Tumor necrosis factor-α synergizes with IFN-γ in mediating killing of Leishmania major through the induction of nitric oxide. J Immunol 145:4306–4310
Locksley RM, Heinzel FP, Sadick MD; Holaday BJ, Gardner KD (1987) Murine cutaneous leishmaniasis: susceptibility correlates with differential expansion of helper T cell subsets. Ann Inst Pateur/Immunol 138:744–749
Locksley RM, Heinzel FP, Holaday BJ, Mutha SS, Reiner SL, Sadick MD (1991) Induction of Th1 and Th2 CD4+ subsets during murine Leishmania major infection. Res Immunol 142:28–32
Mauel J, Behin R (1987) Immunity: clinical and experimental. In: Peters W, Killick-Kendrick R (eds) The leishmaniases in biology and medicine, vol 2. Academic Press, London, pp 731–791
Mauel J, Ransijn A, Buchmüller-Rouiller Y (1991) Killing of Leishmania parasites in activated murine macrophages is based on an l-arginine-dependent process that produces nitrogen derivates. J Leukoc Biol 49:73–82
McElrath MJ, Murray HW, Cohen ZA (1987) The local cellular immune response in experimental leishmaniasis. Ann Inst Pasteur 138:787–790
McElrath MJ, Murray HW, Cohen ZA (1988) The dynamics of granuloma formation in experimental visceral leishmaniasis. J Exp Med 167:1972–1937
McNeely TB, Turco SJ (1987) Inhibition of protein kinase C activity by the Leishmania donovani lipophosphoglycan. Biochem Biophys Res Comm 148:653–657
Milon G, Titus RG, Cerottini JC, Marchal G, Louis JA (1986) Higher frequency of Leishmania major-specific L3T4+ T cells in susceptible BALB/c mice than in resistant CBA mice. J Immunol 136:1467–1471
Mitchell GF (1984) Host protective immunity and its suppression in a parasitic disease: murine cutaneous leishmaniasis. Immunol Today 5:224–226
Mitchell GF, Curtis JM, Handman E, McKenzie IFC (1980) Cutaneous leishmaniasis in mice: disease pattern in reconsituted mice of several genotypes infected with Leishmania tropica. Aust J Exp Biol Med Sci 58:521–532
Modlin RL, Tapia FJ, Bloom BR, Gallinoto ME, Castes M, Rondon AJ, Rea TH, Convit J (1985) In situ characterization of the cellular immune response in American cutaneous leishmaniasis. Clin Exp Immunol 60:241–248
Moll H, Röllighoff M (1990) Resistance to murine cutaneous leishmaniasis in mediated by TH1 cells, but disease-promoting CD4+ T cells are different from TH2 cells. Eur J Immunol 20:2067–2074
Moll H, Scollay R, Mitchell GF (1988) Resistance to cutaneous leishmaniasis in nude mice injected with L3T4+ T cells but not with Ly-2+ T cells. Immunol Cell Biol 66:57–63
Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profile of lymphokine activities and secreted proteins. J Immunol 136:2348–2357
Müller I, Pedrazzini T, Louis JA (1988) Experimentally induced cutaneous leishmaniasis: are L3T4+ T cells that promote parasite growth distinct from those mediating resistance? Immunol Lett 19:251–260
Müller I, Titus R, Caldumbide I, Louis JA (1989) T cell responses in resistance and susceptibility to experimental infection with L. major. In: McAdam K (ed) Frontiers of infectious disease: new strategies in parasitology. Churchill Livingston, London, pp 158–175
Müller I, Garcia-Sanz JA, Titus R, Behin R, Louis J (1989) Analysis of the cellular parameters of the immune responses contributing to resistance and susceptibility of mice to infection with the intracellular parasite Leishmania major. Immunol Rev 112:95–113
Müller I, Pedrazzini T, Farrell JP, Louis JA (1989) T-cell responses and immunity to experimental infection with Leishmania major. Annu Rev Immunol 7:561–578
Müller I, Pedrazzini T, Kropf P, Louis JA, Milon G (1991) Establishment of resistance to Leishmania major infection in susceptible BALB/c mice requires parasite-specific CD8+ T cells. Int Immunol 3:587–597
Murray HW (1981) Susceptibility of Leishmania to oxygen intermediates and killing by normal macrophages. J Exp Med 153:1302–1315
Murray HW (1982) Cell-mediated immune response in experimental visceral leishmaniasis. II Oxygen-dependent killing of intracellular Leishmania donovani amastigotes. J Immunol 129:351–357
Nacy CA, Fortier AH, Pappas MG, Henry R (1983) Susceptibility of inbred mice to Leishmania infection: correlation of susceptibility with in vitro defective macrophage microbicidal activities. Cell Immunol 77:298–307
Nathan CF, Murray HW, Wiebe ME, Rubin BY (1983) Identification of Interferon-γ as the lymphokine that activates human macrophages oxidative metabolism and antimicrobial activity. J Exp Mewd 158:670–682
Pearson RD, Harcus JL, Sumes PH, Ranito R, Donowitz GR (1982) Failure of the phagocytic oxidative response to protect human monocyte-derived macrophages from infection by Leishmania donovani. J Immunol 129:1282–1287
Reiner NE, Ng W, McMaster WR (1987) Parasite-accessory cell interactions in murine leishmaniasis. II. Leishmania donovani suppresses macrophage expression of class I and class II major histocompatibility complex gene products. J Immunol 138:1926–1932
Roberts M, Kaye PM, Milon G, Blackwell JM (1989) Studies of immune mechanisms in H-11 linked genetic susceptibility to murine visceral leishmaniasis. In: Hart DT (ed) Leishmaniasis. The current status and new strategies for control; Nato ASI series 163. Plenum Press, New York, pp 259–266
Rosen H, Milon G, Gordon S (1989) Antibody to the murine type 3 complement receptor inhibits T lymphocyte-dependent recruitment of myelomonocytic cells in vivo. J Exp Med 169:535–548
Sacks D, Louis JA, Wirth D (1992) Immunology and cell biology of leishmaniasis. In: Warren K, Agabian N (eds) Immunology and molecular biology of parasitic infections. Blackwell Scientific Publication, Oxford London (in press)
Sadick MD, Locksley RM, Tubbs C, Raff HV (1986) Murine cutaneous leishmaniasis: resistance correlates with the capacity to generate interferon-γ in response to Leishmania antigens in vitro. J Immunol 136:655–661
Sadick MD, Heinzel FP, Shigekane M, Fisher WL, Locksley RH (1987) Cellular and humoral immunity to Leishmania major in genetically susceptible mice after in vivo depletion of L3T4+ T cells. J Immunol 139:1303–1309
Sadick MD, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM (1990) Cure of murine leishmaniasis with anti-interleukin-4 monoclonal antibody. Evidence for a T-cell-dependent, interferon-γ-independent mechanism. J Exp Med 171:115–127
Schütze S, Nottrott S, Pfizenmaier K, Krönke M (1990) Tumor necrosis factor signal transduction. Cell-type-specific activation and translocation of protein kinase C. J Immunol 144:2604–2608
Scott P (1991) IFN-γ modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol 147:3149–3155
Scott P, Natovitz P, Coffmann RL, Pearce E, Sher A (1988) Immunoregulation of cutaneous leishmaniasis: T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med 168:1675–1684
Scott P, Pearce E, Cheever AW, Coffmann RL, Sher A (1989) Role of cytokines and CD4+ T cell subsets in the regulation of parasite immunity and disease. Immunol Rev 112:161–182
Solbach W, Forberg K, Kammerer E, Bogdan C, Röllinghoff M (1986) Suppressive effect of cyclosporin A on the development of Leishmania tropica induced lesions in genetically susceptible BALB/c mice. J Immunol 137:702–707
Stenger S, Solbach W, Röllinghoff M, Bogdan C (1991) Cytokine interactions in experimental cutaneous leishmaniasis. II. Endogeneous tumor necrosis factor α production by macrophages is induced by the synergistic action of interferon (IFN)-γ and interleukin (IL)-4 and accounts for the antiparasitic effect mediated by IFN-γ and IL-4. Eur J Immunol 21:1669–1675
Stern JJ, Oca M, Rubin BY, Anderson SL, Murray HW (1988) Role of L3T4+ and Lyt2+ cells in experimental visceral leishmaniasis. J Immunol 140:3971–3977
Titus RG, Kelso A, Louis JA (1984) Intracellular destruction of Leishmania tropica by macrophages activated with macrophage activating factor/interferon. Clin Exp Immunol 55:157–165
Titus RG, Lima GC, Engers HD, Louis JA (1984) Exacerbation of murine cutaneous leishmaniasis by adoptive transfer of parasite-specific helper T cell populations capable of mediating Leishmania major-specific delayed-type hypersensitivity. J Immunol 133:1594–1600
Titus RG, Ceredig R, Cerottini JC, Louis JA (1985) Therapeutic effect of anti-L3T4 monoclonal antibody GK 1.5 on cutaneous leishmaniasis in genetically susceptible BALB/c mice. J Immunol 135:2108–2114
Titus RG, Milon G, Marchal G, Vassalli P, Cerottini JP, Louis JA (1987) Involvement of specific Lyt-2+ T cells in the immunological control of experimentally induced murine cutaneous leishmaniasis. Eur J Immunol 17:1429–1433
Titus RG, Sherry B, Cerami A (1989) Tumor necrosis factor plays a protective role in experimental murine cutaneous leishmaniasis. J Exp Med 170:2097–2104
Titus RG, Müller I, Kimsey P, Cerny A, Behin R, Zinkernagel RM, Louis JA (1991) Exacerbation of experimental murine cutaneous leishmaniasis with CD4+ Leishmania major-specific T cell lines or clones which secrete interferon-γ and mediate parasite-specific delayed-type hypersensitivity. Eur J Immunol 21:559–567
Zilberstein D, Dwyer D (1985) Protonmotive force-driven active transport of d-glucose and l-proline in the protozoan parasite Leishmania donovani. Proc Natl Acad Sci USA 82:1716–1720
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Müller, I., Fruth, U. & Louis, J.A. Immunobiology of experimental leishmaniasis. Med Microbiol Immunol 181, 1–12 (1992). https://doi.org/10.1007/BF00193391
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DOI: https://doi.org/10.1007/BF00193391