TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) AND TNF-BETA AND THEIR RECEPTORS IN EXPERIMENTAL CUTANEOUS LEISHMANIASIS

Experimental infection of BALB/c mice with Leishmania major leads to l esions which progress without healing and visceralization, reproducing the most severe forms of human leishmaniasis, while resistant mice li ke CBA spontaneously resolve lesions and develop protective immunity. Given the conflicting data pertaining to the role of tumor necrosis fa ctor alpha (TNF) in Leishmania infection, we analyzed the expression o f TNF, tumor necrosis factor beta (lymphotoxin), and TNF receptor type I (TNF-RI) and type II (TNF-RII) genes in vivo and correlated TNF gen e expression in vivo with the production of biologically active TNF by lymphoid cells in vitro. No significant difference in the expression of TNF mRNA was found between susceptible and resistant strains of mic e during the course of infection. The depletion of CD4(+) T cells in v itro did not change the level of TNF mRNA in BALB/c lymph node cells b ut led to the total disappearance of TNF mRNA in CBA mice. Unprimed sp leen cells did not produce detectable amounts of TNF, whereas 1 week a fter infection, TNF bioactivity was detected and increased in both str ains of mice until 5 weeks of infection. While neutralization of TNF a ctivity in vivo did not alter the course of infection in BALB/c mice, in CBA mice it led to an increase in lesion size and a delay in the he aling process but did not interfere significantly with the outcome of infection. Finally, no significant difference in the levels of lymphot oxin, TNF-RI, or TNF RII mRNA expression was found between both strain s. The information resulting from these investigations supports the no tion that, in vivo, TNF is not the decisive factor responsible for the resistant versus susceptible phenotype in leishmania infection.