Anti-TGF-beta treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production

CB6F1 mice display intermediate susceptibility to Leishmania major infectio n compared with the highly susceptible BALB/c and resistant C57BL/6 parenta l strains. During early weeks of infection, these mice develop dominant Th2 type responses to L. major, although they eventually exhibit a Th2 to Th1 switch and spontaneously resolve their infections. In this study, we have e xamined the effects of either IL-12 or anti-TGF-beta therapy on the immune response and course of disease in chronically infected CB6F1 mice. Local tr eatment with IL-12 inoculated into the parasitized lesion at 4 wk of infect ion induced a marked increase in IFN-gamma production but did not result in a significant reduction in numbers of parasite or promote more rapid heali ng. However, local treatment with an Ab to TGF-beta led to both a decrease in parasite numbers and more rapid healing? despite the fact that such trea tment did not significantly alter the pattern of IL-4 and IFN-gamma product ion. Immunohistochemical studies showed that anti-TGF-beta treatment result ed in increased nitric oxide production within parasitized lesions. Our res ults suggest that TGF-beta may play an important regulatory role during chr onic stages of a L. major infection by suppressing macrophage production of nitric oxide and that, in the absence of TGF-beta, even the relatively low levels of IFN-gamma observed in mice with dominant Th2-type responses are sufficient to activate macrophages to destroy amastigotes within parasitize d lesions.