Requirement for T cells and effect of lymphokines in successful chemotherapy for an intracellular infection. Experimental visceral leishmaniasis.
Although directly microbicidal, pentavalent antimony has failed as treatment for visceral leishmaniasis in patients who also have AIDS or are receiving immunosuppressive therapy. To define the role of T cells in the successful host response to chemotherapy, we examined the efficacy of pentavalent antimony (sodium stibogluconate, Pentostam) in normal and T cell-deficient BALB/c mice infected with Leishmania donovani. In euthymic (nu/+) mice, single injections of 250 and 500 mg/kg of Pentostam induced the killing of 67% and 89% of intracellular liver amastigotes, respectively. In contrast, in athymic nude (nu/nu) mice, up to three injections of 500 mg/kg achieved no L. donovani killing and did not retard visceral parasite replication. Once nude mice were reconstituted with nu/+ spleen cells, however, Pentostam exerted strong leishmanicidal activity, an effect that appeared to be transferred by either L3T4+ or Lyt-2+ cells. Responsiveness to chemotherapy could also be induced by providing nude mice with either interferon-gamma or interleukin 2 alone. The absence of this T cell- and probably lymphokine-dependent mechanism is a likely explanation for treatment failures in immunocompromised patients infected with L. donovani and perhaps other systemic intracellular pathogens as well.
Murray
H W
HW
Division of Infectious Diseases, Cornell University Medical College, New York 10021.
Oca
M J
MJ
Granger
A M
AM
Schreiber
R D
RD
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D000967:Antimony Sodium Gluconate / Q000627:therapeutic use*; D001826:Body Fluids / Q000187:drug effects*; D005260:Female; D005942:Gluconates / Q000627:therapeutic use*; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D007424:Intracellular Fluid / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010641:Phenotype; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects* / Q000276:immunology
D000276:Adjuvants, Immunologic; D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D005942:Gluconates; D007376:Interleukin-2; D011994:Recombinant Proteins; D007371:Interferon-gamma; D000967:Antimony Sodium Gluconate