Recent advances indicate that, in various chronic inflammatory disorders, the activation of the immune system is triggered locally rather than in lymphoid organs. In this study, we have evaluated whether the humoral alloimmune response involved in chronic rejection is elicited within the graft. We used the rat aortic interposition model and microdissected the adventitia of the graft. Over time, the T cell infiltrate shifted toward a B helper phenotype. B lymphocyte clusters were detected and were the site of intense proliferation and apoptosis. Simultaneously, adventitial vascular endothelium acquired a high endothelial venule phenotype. Similar features were evidenced in the interstitium of chronically allografts (hearts and kidneys). Strikingly, ganocultured graft interstitial tissue was found to be the site of production of antibodies directed against donor MHC-I molecules. These findings, therefore, document the appearance of germinal centers in chronically rejected tissues. This lymphoid neogenesis implies that the graft is not only the target of the alloimmune response but also a site where this response actually develops, so as to optimize the communication between the targeted tissue and the immune effectors.chronic rejection ͉ transplantation ͉ B cells ͉ germinal centers ͉ adventitia D espite recent advances in transplantation, the long-term outcome of transplanted organs remains impeded by chronic rejection (1). Accumulating evidence suggests that humoral immunity (2-4) and, particularly, alloantibodies directed against donor MHC I molecules (5-8) are critical in the pathogenesis of chronic vascular rejection.Clinically, chronic rejection is responsible for a slow deterioration of graft function, which correlates with typical histological changes. Excluding organ-specific manifestations, the most common histopathological feature is chronic vascular rejection, also known as allograft arteriosclerosis, characterized by widespread and diffuse narrowing of the vascular lumen as a result of intimal proliferation of smooth muscle cells and fibroblasts and destruction of smooth muscle cells from the media (9-12). Chronic vascular rejection is also typified by an abundant adventitial inflammatory infiltrate (9). We therefore evaluated whether the humoral alloimmune response was elicited within the adventitia of the graft. In such case, chronic vascular rejection would be similar to other chronic inflammatory disorders in which tissue destruction results from a vicious circle maintained by an uncontrolled local immune response.We demonstrate the involvement of intragraft lymphoid neogenesis in the development of chronic rejection in an animal model, based on aortic transplantation between histoincompatible strains of rats (13-16). We show that the adventitial inflammatory infiltrate harbors a secondary lymphoid organ structure and that anti-donor MHC I antibodies are produced within these structures. Additionally, we provide insights into the clinical relevance of these observations because similar lymphoid str...

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Exposure of newborn animals to a foreign Ag may result in immunological tolerance to that specific Ag, a phenomenon called neonatal tolerance. We have previously reported that neonatal administration to Brown-Norway rats of mercury, a heavy metal toxicant, induces a dominant tolerance, specific for the chemical otherwise responsible for Th2 cell-mediated autoimmune responses in this susceptible strain of rats. Neonatal exposure to Ags can prime immunity, rather than inactivate or delete responses, and sustain regulatory functions effective against autoreactive T cells. Here, we address whether such a tolerant response is due to the generation of regulatory cells. The results suggest that the CD8+ T cell subset is involved in neonatal tolerance to mercuric salt-induced Th2 autoimmune disease. Thus, we demonstrate that in vivo CD8 depletion breaks tolerance following mercury recall in animals under a neonatal tolerance protocol. Furthermore, adoptive cotransfer of splenocytes from naive and tolerant rats as well as transfer of CD8+ T cells from tolerant animals prevent naive syngeneic rats from developing pathologic Th2 immune responses. These observations indicate that CD8+ T cells are endowed with regulatory functions in neonatal tolerance and mediate active suppression. Moreover, neonatal tolerance induced the expansion of CD8+CD45RChigh T cells and the emergence of a high percentage of IFN-γ-synthesizing CD8+ T cells, which probably reflects the implication of regulatory Tc1 cells. Thus, in vivo induction of neonatal tolerance suppresses Th2 autoimmune responses via generation of a CD8+ cell-mediated regulatory response.