Regulation of parenchymal cell reprogramming associated with chronic allograft rejection.

Abstract

978 We have demonstrated that many of the myocytes in murine cardiac allografts that are accepted due to transient treatment with anti-CD4 mAb (GK1.5) or gallium nitrate (GN) undergo a functional reprogramming that may impair allograft function. This reprogramming is detectable as the substitution of a less efficient, fetal form of actin (alpha smooth muscle actin, SMA) for adult myocyte actin. In DBA/2 cardiac allografts of immunosuppressed B6 mice, myocyte reprogramming develops within 30 days post-transplant, and is histologically more prominent and pervasive than concurrently developing allograft vasculopathy. Like vasculopathy, this early myocyte reprogramming does not occur in cardiac isografts, suggesting the contribution of alloantigen-induced immunologic factors in its development. We have explored this contribution by performing cardiac allografts in B6 knockout mice deficient in IL2 or IL4. Most B6 IL2KO mice transiently treated with GN accept DBA/2 cardiac allografts, and these hearts develop allograft vasculopathy, interstitial fibrosis and myocyte SMA expression in the same manner and degree as wild type B6 recipients. In contrast, a smaller percentage of B6 IL4KO mice treated with GN accept DBA/2 hearts for as long as 60 days, and these hearts display prominent allograft vasculopathy and interstitial fibrosis, but no SMA+ myocytes. In this experimental system, IL4 contributes in an essential manner to the early development of myocyte reprogramming in accepted cardiac allografts, but is unnecessary for the vascular and interstitial remodeling that can develop concurrently in these allografts.