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ROLE OF COSTIMULATION IN EXPERIMENTAL LEISHMANIA MEXICANA INFECTION

Tuladhar, Rashmi
http://rave.ohiolink.edu/etdc/view?acc_num=osu1395619402

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Microbiology.
Cutaneous leishmaniasis (CL) is a disease caused by Leishmania spp. that presents as chronic ulcerating lesions. The annual global burden of CL is estimated at 1.2 million cases. L. mexicana is the main cause of CL in the New World. Murine studies indicate that following Leishmania infection, development of CD4+ T cells into Th1 or Th2 phenotype leads to resolution or chronicity respectively. During antigen presentation, costimulatory molecules B7-1/B7-2 which signal T cell via CD28/CTLA4 have been implicated in inducing Th2 bias in CL caused by L. major. L. major and L. mexicana both cause CL but significant differences exist between the two species. We explored the previously unstudied roles of B7-1/B7-2-CD28/CTLA4 costimulation in L. mexicana CL. Using mice on C57BL/6 background which are susceptible to L. mexicana, we compared infection of B7-1/B7-2 knock out (KO), CD28/CTLA4 KO, B7-1 KO and B7-2 KO mice with wildtype (WT) mice. While B7-1 KO mice mimicked WT mice in their susceptibility to CL, the rest of the groups resolved CL. Further, susceptible mice produced significant levels of the Th2 response indicative cytokine, IL-4 and the immunosuppressive cytokine, IL-10. The CL resolving mice had low levels of IL-4 and IL-10, indicating B7-2 is essential for Th2 induction. Using a CD28 mimic peptide that competitively blocks CD28 but not CTLA4 signaling, we found that blockade of CD28 did not rescue the susceptible phenotype exhibited by WT mice infected with L. mexicana. It is thus likely that CTLA4 and not CD28 acts in concert with B7-2 to induce susceptibility to L. mexicana. Using flowcytometric staining, we demonstrated that macrophages of mice susceptible to L. mexicana expressed high levels of B7-2 but not B7-1 upon activation. We also explored the early responses shown by B7-1, B7-2, B7-1/B7-2 KO antigen presenting cells (APC) in an in vitro model of antigen presentation. OVA and L. mexicana infected APCs from B7-1, B7-2, B7-1/B7-2 KO and WT mice were co-cultured with OVA specific CD4+T cells. The co-cultures with APC from resistant B7-1/B7-2 KO and B7-2 KO mice induced pronounced CD4+T cell proliferation while IL-2 yield was low, which could likely be a consequence of IL-2 use for cell proliferation. B7-1/B7-2 KO APC co-cultures exhibited reduced Th2 responses, however, B7-2 KO APC co-cultures yielded Th2 responses comparable to B7-1 and WT APC co-cultures. These results established that a simplistic model of cytokine induced early bias of Th1-Th2 response during antigen costimulation does not completely account for Th2 responses induced by B7-2. While further studies are needed to clarify the exact mechanistic role of B7-2, our study adds to understanding of L. mexicana immune regulation via B7-1/B7-2-CD28/CTLA4 pathway and potentially indicates the possibility of use of this knowledge for novel ways to treat CL.
Abhay Satoskar, PhD (Advisor)
Pravin Kaumaya, PhD (Committee Member)
William Lafuse, PhD (Committee Member)
Marshall Williams, PhD (Committee Member)
168 p.
Immunology; Microbiology; Parasitology
Leishmania; costimulation; cutaneous lesihmaniasis; B7-1; B7-2; OX40L; OX40

Recommended Citations

Citations

  • Tuladhar, R. (2014). ROLE OF COSTIMULATION IN EXPERIMENTAL LEISHMANIA MEXICANA INFECTION [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1395619402

    APA Style (7th edition)

  • Tuladhar, Rashmi. ROLE OF COSTIMULATION IN EXPERIMENTAL LEISHMANIA MEXICANA INFECTION . 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1395619402.

    MLA Style (8th edition)

  • Tuladhar, Rashmi. "ROLE OF COSTIMULATION IN EXPERIMENTAL LEISHMANIA MEXICANA INFECTION ." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1395619402

    Chicago Manual of Style (17th edition)

osu1395619402
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