Innate and acquired immunity to Leishmania in humans : the role of the host versus the parasite

Detta är en avhandling från Stockholm : Karolinska Institutet, Microbiology and Tumor Biology Center (MTC)

Sammanfattning: Leishmania are intracellular protozoan parasites of macrophages which induce chronic diseases in man. The study of this parasite has been instrumental in elucidating many facets of the immune system. Our study set out to understand the immune regulatory mechanisms involved in resistance and susceptibility. We have used in vitro stimulation of peripheral blood mononuclear cells and measured cell proliferation, cytokine rnRNA or protein induction and analyzed phenotype of cells by flow cytometry. Our results show that there are innate elements of immune reactivity to Leishmania antigens in unexposed donors involving cellular proliferation of NK cells and IFN[gamma] secretion. These responses are neither induced by the abundant antigens on the surface of Leishmania promastigotes nor mycobacterial antigens tested. Low molecular weight fractions of Leishmania could induce proliferative and cytokine responses in cells of both healthy and infected individuals. However, response to the high molecular weight antigens was a feature of the healthy individuals. The relevance of an NK dominated response has been tested in a Leishmaniasis endemic area where the role for NK cells in protection has unfolded. Consistent with our previous findings, NK and CD8+ cells proliferated in response to Leishmania antigen stimulation. Our results also suggested the presence of a low background level of large NK cells as an important aspect of the protective mechanisms that operate in the Leishmaniasis-resistant endemic controls which is also established following cure from the disease. Based on the results obtained we concluded that NK cells are involved in protection from and healing of Ethiopian cutaneous Leishmaniasis. As part of the quest for identifying the stimulatory molecules of Leishmania to which PBMC from non-exposed healthy individuals respond, we have tested a Leishmania homologue of receptors for activated C kinase (LACK) from L major as well as three amastigote antigens from L. pifanoi. The immuno-dominant molecule LACK induced in vitro proliferation of NK and CD8 cells coupled with high levels of IFN[gamma] and IL- 10 production. Of the amastigote antigens, P-2 and, to a lesser extent, P-8 induced proliferation in cells of healthy individuals. These responses were reduced in the presence of anti-MHC class 11 antibodies. We tested whether properties of the infecting parasite could influence induced immune response. Our results showed that regardless of whether cells were derived from healthy individuals, or from patients with localized (LCL) or diffuse (DCL) cutaneous Leishmaniasis, DCL-promastigotes preferentially induced mRNA for IL-10 while induction of IFN[gamma] was a feature of LCL-promastigotes. The importance of the properties of the infecting parasite is illustrated in a case report where a slow growing form of Leishmania showed atypical clinical symptoms in a Swedish man 15 years after infection. The focus of this thesis has been the innate and acquired immune regulatory mechanisms involved in L aethiopica infection in human. The possible cross species immune response by proteins derived from other Leishmania species are investigated in an attempt to evaluate the potential use of such proteins in a universal vaccine.

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