We therefore stimulated BALB/c RAG/recipients with a variety of innate ligands before or after transplanting heart grafts from B6 RAG/donors (Table 1). of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell- dependent chronic rejection. == Conclusions == The innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology. Keywords:innate immunity, chronic rejection, NK cells, B-1 lymphocytes == 1. Introduction == Acute allograft rejection is dependent on the activation of donor-reactive host T cells [1]. T cell depletion or genetic T cell deficiency in mice prevents acute rejection and leads to long-term survival of transplanted organs Oroxin B [24]. Similarly, tolerance-induction strategies that induce T cell deletion or block T cell activation significantly prolong allograft survival [5,6], but chronic rejection is often observed despite demonstrable donor-specific T cell unresponsiveness [5,7]. Chronic rejection is also detected in patients presumed to be tolerant and in whom immunosuppressive drugs have been withdrawn [8]. Possible reasons for this paradox Oroxin B include vascular pathology caused by non-immunological factors such as hypertension, the presence of residual anti-donor T or B cell reactivity in the tolerant host, or persistent T and B cell-independent innate immunity to the graft [8,9]. That innate immune activation could lead to chronic allograft rejection was first suggested by a study showing that mice rendered tolerant during the neonatal period or through robust mixed hematopoietic chimerism develop chronic allograft vasculopathy [5]. The vasculopathy was mediated by natural killer (NK) cells and could be reproduced in T and B cell-deficient but NK-sufficient RAG/recipients. The same group later determined that NK-mediated chronic rejection did not take place unless Oroxin B RAG/hosts were concomitantly infected with lymphocytic choriomeningitis virus (LCMV) virus [10] or were reconstituted with recipient-matched CD4+T lymphocytes [11]. Since the latter observation was made in a transplantation model in which anti-donor T cell reactivity was absent (parental hearts transplanted to F1 recipients), the authors concluded that NK cells are necessary for the development of chronic allograft vasculopathy but are not sufficient – cooperation with CD4+T cells not responsive to donor alloantigens is required [11]. Additional support for a role of NK cells in rejection independent of T cell alloreactivity derives from studies showing that NK cells contribute to heart allograft rejection in gene knockout mice that lack a critical T cell costimulatory molecule, CD28 [12,13]. More recently, IL-15, a cytokine that significantly expands and activates NK cells, has been shown to precipitate skin allograft rejection in RAG/recipients when given in large excess [14]. These studies suggest that NK cells contribute to chronic rejection but do not clearly define whether NK cells do so in the absence of concomitant factors such as viral infection or excess cytokines, or whether their contribution is indirect and requires interaction with adaptive immunity. Here we re-addressed the question whether the innate immune system alone Oroxin B is sufficient for mediating chronic allograft rejection and re-examined the role of NK cells in this process. Using RAG/mice or mice that lack secondary lymphoid tissues as recipients of primarily vascularized cardiac grafts, we found that chronic rejection is an immunological process that does not occur in the absence of adaptive immune activation. Although NK cells were not sufficient to cause graft pathology, they predisposed healed allografts to T cell-dependent chronic rejection. == 2. Original Hypothesis == We hypothesized that sufficient activation of innate immunity or the presence of natural IgM antibodies in RAG/recipients of primarily vascularized cardiac allografts results in chronic allograft rejection Rabbit Polyclonal to 14-3-3 in the absence of adaptive Oroxin B immunity. We also speculated.