MACROPHAGE T-CELL INTERACTION IN EXPERIMENTAL VISCERAL LEISHMANIASIS - FAILURE TO EXPRESS COSTIMULATORY MOLECULES ON LEISHMANIA-INFECTED MACROPHAGES AND ITS IMPLICATION IN THE SUPPRESSION OF CELL-MEDIATED-IMMUNITY

The most important immunopathological consequence of infection with Le ishmania seen in murine and human hosts is the suppression of Tcell-me diated immune responses to both mitogens and leishmanial antigens. It has been suggested that this suppression is mediated by macrophages, e ither by defective antigen processing and presentation or by the elabo ration of suppressive mediators like prostaglandins. Optimum activatio n of T helper cells requires not only T cell receptor occupancy by the antigen-Ia complex, but also costimulatory signals provided by the an tigen-presenting cells. We investigated the status of several costimul atory molecules on infected macrophages from both genetically suscepti ble BALB/c and resistant C57BL/6 mice, Our results demonstrate that up on parasitization, the macrophages become unable to deliver costimulat ory signals to T helper cells, and that this effects is mediated by pr ostaglandins, as the inhibition of its synthesis by indomethacin recov ered the defect. Upon infection with L. donovani, B7-1 expression was decreased, while ICAM-1 was marginally increased in BALB/c macrophages and there was no significant change in the expression of B7-1 and ICA M-1 in Leishmania-infected C57BL/6 macrophages. Expression of VCAM-1 d id not change during infection. This selective alteration in the expre ssion of costimulatory molecules on L. donovani-infected BALB/c macrop hages was caused by the living parasite, as shown by the fact that kil ling of the parasites by stibogluconate led to no alteration in the le vels of costimulatory molecules. We found that the change in B7-1 expr ession on the surface of infected macrophages resulted in the inhibiti on of delayed-type hypersensitivity-mediating functions of T helper ce lls from BALB/c mice. The results described in this study not only thr ow light on the possible mechanism of leishmanial pathogenesis, but al so open up the possibility of immunotherapy of leishmaniasis by select ive manipulation of costimulatory molecules.