Pilot--UV immunosuppression in cutaneous leishmaniasis

Case Western Reserve University, Cleveland OH

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Abstract

UV exposure of the skin results in an immunosuppressive state and long- lasting immune tolerance. Epidermal Langerhans cells are depleted and replaced by infiltrating UV-macrophages (UV-mph) that are involved in UV-induced tolerance acquisition in the murine contact hypersensitivity model. These changes in APC function may also impair local or systemic resistance to cutaneous infections, a hypothesis that we propose to test in the well-characterized mouse model of cutaneous leishmaniasis. Leishmaniasis is a disease of the tropics responsible for a broad spectrum of disease, ranging form self-limiting skin ulcers to non-healing lesions to mutilating mucocutaneous leishmaniasis, depending on the immune response of the host. Healing of leishmania is dependent on Th1-type CD4+ T cells producing interferon-gamma (IFNgamma). Curative cellular immunity may be impaired by repeated UV exposure of the infected site or early lesion, a situation which may be common, given the high UV intensity in endemic areas and the fact that lesions invariably occur in unclothed, sun-exposed skin. Our preliminary data show that repeated UV exposures enhance the chronicity of infection with Leishmania major in normally highly resistant C3H mice. Disease severity was quantitated using skin thickness measurements, ultrasonagraphy and parasite load. There was evidence of impaired cellular using skin thickness measurements, ultrasonography and parasite load. There was evidence of impaired cellular immunity, as IL-12, iNOS and IFNgamma mRNA was decreased in the LN of UV-irradiated and infected mice compared to non-irradiated and L.major-infected mice. We propose to determine if UV exposure perturbs normally curative T cell responses by altering cutaneous accessory cell numbers of function (IL- 12/IL-10 cytokine production, co-stimulatory ability). The pathologic significance of these findings will be determined by interventions predicted to restore cure, such as in vivo repletion of Th1-promoting cytokines (IL-12 and by interventions predicted to restore cure, such as in vivo repletion of Th1-promoting cytokines (IL-12 and by interventions predicted to restore cure, such as in vivo repletion of Th1-promoting cytokines (IL-12 and IFNgamma) or depletion of Th1-suppressing cytokines (IL-10 and TGFbeta). C57BL/6 mice with intermediate resistance to L. major will be studied to identify if additional suppressive effects are mediated by T cell immune deviation in favor of Th2-type cytokines, IL-4 and IL-13. Finally, we propose to use subcutaneous infections with Flt3 ligand to increase the number of functional, IL-12 producing DC in early lesions and thereby enhance the response to L.major. We thus propose the murine leishmania model as a well-defined and relevant in vivo model for studying critical events of APC function in UV immunosuppression.