Requirement for T cells and effect of lymphokines in successful chemotherapy for an intracellular infection. Experimental visceral leishmaniasis.

Abstract

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-'y 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.

Drug Resistance in Leishmaniasis

“…This has proven to be of particular importance in relation to pentavalent antimonial treatment of DCL (59) and coinfections with HIV in the visceral form (12,48), where there is an absence of a specific T-cellmediated immune response and mutual exacerbation of infection. The basis for this lack of activity of pentavalent antimonials has been explored in immunodeficient mouse models for which the effects are probably due to deficiencies of both Th1-cell-mediated and macrophage responses (109). Experimental models have shown that the antileishmanial activity of pentamidine is also T-cell dependent whereas those of amphotericin B and miltefosine are T-cell independent (61,108).…”

Immunochemotherapy in American cutaneous leishmaniasis: immunological aspects before and after treatment

“…Murray et al (1989) demonstrated that T cell-deficient mice were unable to control L. donovani proliferation when treated with Pentostam®, suggesting that these cells (probably through cytokine production) are involved in the healing process following treatment. In humans, CD8+ T cells are, apparently, involved in the healing process and elevated IFN-γ production at the end of the treatment has also been shown (da Cruz et al 1994a).…”

Effects of sodium stibogluconate on differentiation and proliferation of human myeloid leukemia cell lines in vitro

“…22 It was known that SS selectively kills intracellular leishmania but not the free living form of the protozoa 23 and that its anti-leishmania activity was severely impaired in immune deficient hosts. 24 These observations suggest that SS targets host cellular molecules that mediate its activity. Our recent studies demonstrate for the first time that SS is a potent inhibitor of PTPases and augments signaling of various hematopoietic growth factors and cytokines.…”