Sex-determined resistance against Leishmania mexicana is associated with the preferential induction of a Th1-like response and IFN-gamma production by female but not male DBA/2 mice.

Abstract

Female DBA/2 mice are relatively resistant to infection with Leishmania mexicana compared with male mice. Following subcutaneous infection with 5 x 10(6) L. mexicana, amastigotes lesion growth in male and female DBA/2 mice was measured and the developing immune responses were monitored both in vitro and in vivo. Over the 10 week duration of the experiment all male DBA/2 mice developed rapidly growing non-healing lesions while female mice either developed no lesions whatsoever or developed smaller slower growing lesions than males. Both male and female mice produced parasite specific IgG2a during the course of the disease. However, significant titres of parasite specific IgG1 antibodies could be detected only in male mice indicating a Th2-influenced response in this sex. Furthermore, female mice, unlike male mice, developed significant parasite induced cutaneous delayed-type hypersensitivity footpad responses, indicating a Th1-influenced response in female mice. Although both male and female DBA/2 mice infected with L. mexicana displayed a significant increase in the number of cells in their draining lymph nodes at week 10 post-infection, no significant differences could be observed in the numbers of CD4+, CD8 + T cells as well as B cells between male and female DBA/2 mice. However. following in vitro stimulation, the lymph node cells from female mice displayed significantly higher antigen specific proliferative responses than the males and produced significant amounts of IFN-gamma which could not be detected in the equivalent culture supernatants from male mice. There were no significant differences in the levels of Th2-associated cytokines IL-4 and IL-5, produced by the lymph node cells of both sexes. Treatment of female DBA/2 mice with IFN-gamma neutralizing antibody following L. mexicana infection resulted in lesion growth equivalent to male mice. Conversely, intralesional injections of murine recombinant IFN-gamma significantly inhibited lesion growth in male mice.