The complement cascade, traditionally considered a component of the innate immune system involved in host defense against invading pathogens, contributes to allograft rejection. In addition to acting as an effector arm of antibody initiated injury to a transplant, graft-derived complement impacts ischemia reperfusion injury, regulates B cell activation and antibody isotype switching and influences alloreactive T cell immunity. These observations are inadequately understood and have important implications for transplantation. In conjunction with collaborators, we recently published several papers that explain the observed link between complement and T cell immunity. We showed that immune cell-derived, local complement activation is required for T cell activation, expansion, differentiation and survival. The in vivo relevance was demonstrated by our group and by others in several models of autoimmunity and infectious pathogens, but how local complement activation relates to allograft injury is not well understood. New preliminary data show that complement has important effects on T cell mediated-allograft rejection;enhancing local complement activation through genetic targeting of the cell-surface complement regulator, decay accelerating factor, (DAF, CD55) accelerates rejection, donor deficiency of complement component C3 or factor D (fD) synergizes with sub-therapeutic immunosuppression to markedly prolong allograft survival, and C3a receptor/C5a receptor double knockout T cells do no reject heart allografts. Together, these published and preliminary data support the following hypothetical working model to be tested in this proposal: Following transplantation, graft-derived and immune cell-produced complement activates locally yielding the anaphylatoxins C5a and C3a which through binding to their receptors on immune cells regulates T cell activation, differentiation, migration and memory cell formation, thereby functioning as key mediators of allograft injury. In this revised application we will test this hypothesis with the following 3 specific aims: 1. To assess mechanisms of prolonged cardiac allograft survival induced by deficiency of donor complement. 2. To delineate the role of immune cell-derived complement as molecular mediators of T cell help. 3. To determine how T cell expressed C5aR and C3aR impact effector and memory T cells in transplantation. The results of the studies will improve comprehension of immune mechanisms that result in allograft injury, specifically addressing the impact of locally activated complement. We will gain new information that has the potential to guide therapeutic inventions aimed a prolonging graft survival, first in animal models and ultimately in humans. Complement components and/or their receptors could become viable targets for adjunctive immunosuppression aimed at limiting T cell alloimmunity and thus prolonging transplant survival.
The proposed studies will evaluate novel immune mechanisms that cause transplant rejection. Once these issues are understood in more detail it will be possible to better design therapies, first in animal models and ultimately in humans, aimed at altering the strength of the immune response directed at the transplant so as to be able to prolong the survival of the organ and the patient. In addition, the delineated mechanisms could have broad reaching implications for understanding adaptive immunity, including anti-pathogen immunity and autoimmunity.
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|Cravedi, Paolo; Heeger, Peter S (2014) Complement as a multifaceted modulator of kidney transplant injury. J Clin Invest 124:2348-54|
|Kalache, Safa; Lakhani, Parth; Heeger, Peter S (2014) Effects of preexisting autoimmunity on heart graft prolongation after donor-specific transfusion and anti-CD154. Transplantation 97:12-9|
|van der Touw, William; Cravedi, Paolo; Kwan, Wing-hong et al. (2013) Cutting edge: Receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol 190:5921-5|
|Cravedi, Paolo; van der Touw, William; Heeger, Peter S (2013) Complement regulation of T-cell alloimmunity. Semin Nephrol 33:565-74|
|Cravedi, P; Lessman, D A; Heeger, P S (2013) Eosinophils are not required for the induction and maintenance of an alloantibody response. Am J Transplant 13:2696-702|
|Kwan, Wing-hong; van der Touw, William; Paz-Artal, Estela et al. (2013) Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med 210:257-68|
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