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    Regulation of Alloreactive CD8 T Cell Responses by Costimulation and Inflammation

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    Authors
    Jangalwe, Sonal
    Faculty Advisor
    Dr. Michael Brehm
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Molecular Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2017-06-30
    Keywords
    transplantation tolerance
    costimulation
    inflammation
    CD8 T cell activation
    cytokines
    Immunity
    
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    Abstract
    CD8 T lymphocytes are a crucial component of the adaptive immune system and mediate control of infections and malignancy, but also autoimmunity and allograft rejection. Given their central role in the immune system, CD8 T cell responses are tightly regulated by costimulatory signals and cytokines. Strategies targeting signals that are critical for T cell activation have been employed in a transplantation setting to impede alloreactive T cell responses and prevent graft rejection. The goal of my thesis is to understand how costimulatory signals and inflammation regulate alloreactive CD8 T cell responses and how to target these pathways to develop more effective tools to prevent graft rejection. Costimulation blockade is an effective approach to prolong allograft survival in murine and non-human primate models of transplantation and is an attractive alternative to immunosuppressants. I describe a novel murine anti-CD40 monoclonal antibody that prolongs skin allograft survival across major histocompatibility barriers and attenuates alloreactive CD8 T cell responses. I find that the pro-apoptotic proteins Fas and Bim function concurrently to regulate peripheral tolerance induction to allografts. Activation of the innate immune system by endogenous moIecules released during surgery or infections in transplant recipients can modulate T cell responses. However, the direct impact of inflammation on alloreactive CD8 T cell responses is not clear. Using a T cell receptor (TCR) transgenic mouse modeI, I demonstrate that inflammatory stimuli bacterial lipopolysaccharide (LPS) and the viral dsRNA mimetic poly(I:C) differentially regulate donor-reactive CD8 T cell responses by generating distinct cytokine milieus. Finally I demonstrate the role of pro-inflammatory cytokines stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in improving human B cell development in humanized NOD-scid IL2Rγnull (NSG) mice.
    DOI
    10.13028/M2BD58
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32287
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2BD58
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