The role extracellular matrix (ECM) proteins may play in the host immune cascade triggered by organ transplantation is largely unknown. We have employed well-defined rat cardiac allograft model to test the hypothesis that the expression of ECM components, such as fibronectin (FN) or laminin (LN), represents an integral part of the host rejection response in transplant recipients. Indeed, treatment of rats with anti-LN Ab profoundly affected lymphocyte recirculation pathways, and selectively decreased deposition of alloreactive lymphocytes at the graft site and in host peripheral lymph nodes. Moreover, cardiac rejection was accompanied by markedly increased intragraft expression of both LN and FN. The infiltrating mononuclear cells, however, accumulated selectively in FN-rather than LN-rich cardiac areas. We also observed distinct temporal expression and spatial distribution patterns of FN variants in rat cardiac allografts and isografts. The local synthesis of FN, in both allografts and isografts was increased as early as at 3 h post-transplant. The expression of FN in cardiac allografts but not in isografts, remained high during later intervals to the point of ultimate rejection. The newly synthesized FNs derived from graft infiltrating macrophages and arterioles, and included EIIIA +, EIIIB +, and CS-I + splicing variants. The EIIIA was preferentially enriched in the earlier, whereas EIIIB and CS-I were selectively enhanced in the later, rejection phases. Finally, treatment of rat recipients with synthetic FN-CS-I peptides prevented the incidence of early (acute) and late (chronic) rejection, supporting the notion that distinct FNs may play a fundamental role in the host immune cascade triggered by organ transplantation. These data offer potential novel sites for intervention in the control of transplant rejection, and contribute to the development of refined therapeutic strategies based upon new concepts of host immunosuppression.