SEX-DETERMINED SUSCEPTIBILITY AND DIFFERENTIAL IFN-GAMMA AND TNF-ALPHA MESSENGER-RNA EXPRESSION IN DBA 2 MICE INFECTED WITH LEISHMANIA-MEXICANA/

Female DBA/2 mice have been shown to be relatively resistant to infect ion with Leishmania mexicana when compared with male mice. In order to determine the immunological basis behind this difference the draining lymph nodes from male and female DBA/2 mice were excised and the RNA extracted at different time-points following infection. Following reve rse transcription, the polymerase chain reaction (PCR) was used to ide ntify mRNA transcripts for interferon-gamma (IFN-gamma), tumour necros is factor-alpha (TNF-alpha), interleukin-4 (IL-4), IL-10 and IL-12. Th e evolution of cytokine mRNA production was slow in both male and fema le mice as no newly synthesized transcripts were identified 5 weeks af ter infection. IL-10 was expressed constitutively in noninfected mice and was present throughout the experiment in all animals. By week 8, a clear dichotomy in cytokine mRNA expression was emerging between the resistant female and susceptible male mice. Whereas all females expres sed IFN-gamma and one also expressed TNF-alpha only two out of five ma les expressed IFN-gamma and four out of five expressed TNF-alpha. The greatest lesion sizes at this time were recorded from those mice expre ssing TNF-alpha but not IFN-gamma. No differences in IL-4 or IL-12 wer e noted with transcripts for both cytokines present in both sexes at w eek 8. By week 12 males had developed large non-healing nodules and in females lesions had either disappeared or were slow growing. At this time only transcripts for TNF-alpha were present in males and only tho se for IFN-gamma were detected in females. Treatment of female mice fo llowing infection with IFN-gamma neutralizing antibody resulted in les ion growth equivalent to male mice. IFN-gamma production would, theref ore, appear sufficient to limit the growth of L. mexicana in female DB A/2 mice while TNF-alpha production in the absence of IFN-gamma confer s no protection to DBA/2 male mice.