Innate immunity via Toll Like Receptors (TLRs) is the first line of defense against microbial invasion and is essential for pathogen detection. Our preliminary data, using experimental murine systems, also demonstrates that TLR dependent immunity is important for alloimmune responses by allowing the maximal function of dendritic cells (DCs), specifically the production of proinflammatory cytokines that subsequently initiate TH1 alloimmunity. Although these effects are critical for the rejection of minor mismatched skin allografts they are not essential for the rejection of fully allogeneic skin and cardiac allografts. However, the role of innate immunity in transplantation tolerance remains unexplored. Since a prior report, using non-transplant in vitro models, demonstrated that T regulatory cell (T reg) function changes in the presence of TLR stimulated DCs, our preliminary data investigate the impact of innate immunity on transplantation tolerance and show that absence of MyD88, an important TLR signal adaptor, is critical for tolerance induction. We provide evidence that this occurs via a regulatory mechanism that is associated with increased numbers of CD4+CD25+ T cells and a reduced proinflammatory milieu. Therefore, this proposal will employ a murine experimental transplant model and will examine the mechanisms by which defective innate immunity facilitates transplantation tolerance.
Aim 1 of this proposal will examine whether the absence of MyD88 operates in synergy with the tolerance protocol (costimulatory blockade), tipping the balance towards tolerance rather than immunity, by increasing the generation and function of T regs.
Aim 2 will investigate whether MyD88 deficiency, by reducing the proinflammatory cytokine environment, increases T effector susceptibility to regulation leading to tolerance induction. Therefore, this proposal will critically address whether an absence of innate MyD88 signaling promotes transplantation tolerance, a previously unexplored concept in the field of transplantation. The information generated will support a new paradigm in the field of transplantation and has the potential to provide future therapeutics translatable to human allograft transplantation and autoimmunity (e.g., MyD88 blockade at the time of tolerance induction).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI064660-05S1
Application #
8091757
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2010-08-02
Project End
2011-07-31
Budget Start
2010-08-02
Budget End
2011-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$116,454
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Shen, Hua; Heuzey, Elizabeth; Mori, Daniel N et al. (2015) Haptoglobin enhances cardiac transplant rejection. Circ Res 116:1670-9
Mori, Daniel N; Kreisel, Daniel; Fullerton, James N et al. (2014) Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 258:132-44
Kreisel, Daniel; Goldstein, Daniel R (2013) Innate immunity and organ transplantation: focus on lung transplantation. Transpl Int 26:2-10
Song, Yang; Shen, Hua; Schenten, Dominik et al. (2012) Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 32:103-9
Walker, Wendy E; Bozzi, Aaron T; Goldstein, Daniel R (2012) IRF3 contributes to sepsis pathogenesis in the mouse cecal ligation and puncture model. J Leukoc Biol 92:1261-8
Shen, Hua; Song, Yang; Colangelo, Christopher M et al. (2012) Haptoglobin activates innate immunity to enhance acute transplant rejection in mice. J Clin Invest 122:383-7
Goldstein, Daniel R (2011) Inflammation and transplantation tolerance. Semin Immunopathol 33:111-5
Goldstein, Daniel R (2011) T cell costimulation blockade and organ transplantation: a change of philosophy for transplant immunologists? J Immunol 186:2691-2
Du, Wei; Shen, Hua; Galan, Anjela et al. (2011) An age-specific CD8+ T cell pathway that impairs the effectiveness of strategies to prolong allograft survival. J Immunol 187:3631-40
Walker, Wendy E; Booth, Carmen J; Goldstein, Daniel R (2010) TLR9 and IRF3 cooperate to induce a systemic inflammatory response in mice injected with liposome:DNA. Mol Ther 18:775-84

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