Under the proper pharmacologic conditions mice will accept cardiac allografts. In contrast, they spontaneously accept renal allografts. In both situations, regulatory T cells are found in these mice and are thought to contribute to graft acceptance. Evidence suggests that immune regulation is unstable, and that allograft acceptance is probably represents immune deviation, rather than immune tolerance. The studies in this proposal are designed to determine how regulatoryT cells contribute to the immune conditions of metastable allografi acceptance and stable allograft tolerance.
In Specific Aim 1, we will use murine models of cardiac and renal allografl acceptance test the hypotheses a) that early expression of immune regulation mediates metastable allograft acceptance and promotes secondary development of stable allografl tolerance and b) that therapeutic strategies which induce or simulate hematopoietic chimerism may facilitate the transition from metastable allograft acceptance to stable immune tolerance.
In Specific Aim 2, we focus on the immunobiologv of metastable allografl acceptance as it develops in murine renal and cardiac allograft acceptors. We will test a paradigm of renal allograft acceptance that is based on the hypotheses that the constitutive production of TGFbeta by murine kidneys creates an anti-inflammatory immune condition that facilitates systemic development of TGFbeta-mediated immune regulation and promotes the development of metastable renal allograft acceptance. We will compare this to immune events that occur in cardiac allografts, which do not enjoy endogenous TGFbeta expression.
In Specific Aim 3, we will study the intragraft and systemic components of metastable allograft acceptance. Studies will test the hypothesis that the immune disposition toward donor alloantigens is a balance between anti-inflammatory and pro-inflammatory responses, and that this balance can be independently influenced at either the systemic or local level. We will challenge allograft acceptors with additional skin and cardiac allografts to determine how perturbations of the systemic or intragraft immune disposition can affect allograft survival.
In Specific Aim 4, we will determine how intragraft CMV infection and metastable allograft acceptance impact one another. We will determine if metastable allograft acceptance extends to CMV, permitting lethal infection, or if anti-CMV responses upset metastable allograft acceptance, causing allograft rejection. In general, these studies will explore the immunobiology of murine allograft acceptance and its relationship to allograft tolerance.
