Immunoendocrinological control of murine leishmaniasis

Female DBA/2 mice have been shown to be relatively resistant to infection L. mexicana as compared with male mice (Alexander, 1988). The resistance of female mice was associated with the preferential expression of IFN-ƴ transcripts in then- draining lymph nodes. Susceptible male mice on the other hand had transcripts for IFN-ƴ, but only rarely produced transcripts for IFN-ƴ. At this time both the sexes had IL-4 and IL-12 mRNA transcripts. Administration of neutralising IFN-ƴ monoclonal antibodies to L. mexicana infected females enhanced lesion growth, whereas treatment of infected males with poly I:C, to induce IFN-ƴ production from NK cells, conferred partial protection. Further analysis revealed that females produced more parasite-specific IgG2a than males. Males displayed significant titres of IgG1 antibodies as early as week 6 post-infection. This antibody subclass could not be detected in females until week 10 and at level significantly less than males. Significantly, antigen stimulated lymph node cells from L. mexicana infected female mice produced IFN-ƴ, whereas this cytokine could not be detected in equivalent cultures from infected male mice. By 12 weeks post-infection B cell expansion was greater in male than female mice. Treatment of ovarectomised female mice with dihydroxy testosterone (DHT) resulted in exacerbation of L. mexicana infection. Sex differences in susceptibility to visceral leishmaniasis were also observed in noncure BALB/c and cure C57BL/10 ScSn mice following L. donovani infection. In both strains male mice were relatively susceptible to L. donovani infection as compared with females. As no differences could be observed in the production of IL-4 transcripts between resistant female and susceptible male DBA/2 mice following L. mexicana infection I used IL-4 gene deficient mice to evaluate the in vivo role of this cytokine during L. mexicana and L. donovani infection. Following infection with L. mexicana, XL-4+/+ mice developed large, non healing, cutaneous lesions, whereas no lesions whatsoever developed in IL-4-/- mice. The antigen stimulated lymph node cells from both IL-4+/+ and IL-4-/- mice produced IFN-7 and those from IL-4+/+ mice also produced IL-5. Furthermore, at this time point, antigen stimulated splenocytes from IL-4-/- mice produced significantly higher amounts of IFN-y as compared with those from IL-4+/+. This was also associated with the development of a significant delayed-type- hypersensitivity (DTH) response in IL-4-/- mice. As the infection progressed IL-4+/+ mice, unlike IL-4-/- mice developed significant titres of parasite-specific IgG1, indicating a Th2 influenced response in IL-4+/+ mice. Flowcytometric analysis revealed a significant increase in B cell population in the draining lymph nodes from IL-4+/+ mice. At the site of infection, IL-4-/- mice displayed substantial amounts of inducible nitric oxide synthase (iNOS) unlike immunocompetant control. Although, IL-4-/- mice failed to develop lesions following L. mexicana infection, viable parasites could be cultured from cutaneous inoculation sites in vitro. Following L. donovani infection IL-4-/- mice developed higher hepatic parasite burdens than their wild-type control counterparts. However, the differences were only significant at 15 days postinfection. Lastly, I compared the growth of L. mexicana and L.donovani in IFN-ƴR, TNFR1, IL-6 and MHC class II gene deficient mice with appropriate immunocompetant controls IFN-ƴR-I- mice developed non healing, cutaneous lesions which were significantly larger than in control mice. Following L. donovani infection IFN-yR-/- mice liver parasite burdens were less than the control mice. However, the differences were significant only at day 15 post-infection. No significant differences were observed in the cutaneous growth of L.mexicana between TNFR1-/- and TNFR1+/+ mice. At 4 months post-infection the lesions healed in TNFR1-/- mice but still persisted in TNFR1+/+ mice. There were no differences in the growth of L.donovani. No significant differences could be noted in disease progression of cutaneous and visceral leishmaniasis between IL-6-/- and IL-6+/+ mice. While control MHC class n+/+ mice developed large, non healing cutaneous lesions at week 4 post-infection following inoculation with L. mexicana, MHC class II -/- mice either developed no lesions or lesion development was greatly delayed compared with controls.

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