Blockade of CTLA-4 enhances host resistance to the intracellular pathogen, Leishmania donovani.

CTLA-4 has recently been shown to act as a negative regulator of T cell activation. Here we provide evidence that blockade of CTLA-4 can result in enhanced host resistance to an intracellular pathogen. The administration of anti-CTLA-4 mAb 4F10 to BALB/c mice, 1 day following infection with Leishmania donovani, enhanced the frequency of IFN-gamma and IL-4 producing cells in both spleen and liver, and dramatically accelerated the development of a hepatic granulomatous response.

Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection.

Infection with Leishmania, an obligate intracellular parasite of mononuclear phagocytes, stimulates the production of IFN-gamma from NK cells, via a pathway which is dependent upon IL-12 and IL-2. IL-12 is also essential for the development of host protective T cell responses to this parasite. However, previous in vitro studies have indicated that macrophages fail to make IL-12 following infection with Leishmania, and that subsequent to infection, macrophages become refractory to normal IL-12-inducing stimuli.

B7-2 blockade enhances T cell responses to Leishmania donovani.

Infection with Leishmania donovani has been reported to induce a dominant Th1-type response in all strains of mice examined, providing a model for examining the regulation of Th1 responses in the relative absence of Th2 cross-regulation. Here we demonstrate that blockade of the costimulatory molecule B7-2, but not B7-1, has significant effects on disease progression, measured as day 28 parasite burden in the liver. The effects of B7-2 blockade were associated with increased IFN-gamma production, as determined 1) following restimulation with specific Ag, 2) by enumeration of IFN-gamma-secreting cells using ELISPOT assays, and 3) by analysis of IFN-gamma mRNA by reverse transcription-PCR.

Strategies for immune intervention in visceral leishmaniasis.

Therapeutic intervention remains a major tool for control of visceral leishmaniasis (VL). Studies in murine models of VL have demonstrated the efficacy of various cytokines, either alone or in conjunction with antimony chemotherapy. Here, some basic aspects of the models used to study VL are summarized and the recent data in this field are reviewed.