Background: NFkB activation in T cells regulates Th1 differentiation. Host T-cell NFkB inhibition blocks rejection with cardiac allografts but not skin allografts. This indicates that the requirement for NFkB-mediated T cell events in allograft rejection is graft-specific. Their importance in small bowel allograft rejection has not been evaluated. Methods: To determine whether host T cell NFkB activation is required for SB allograft rejection, we have developed a mouse model of orthotopic small bowel transplantation. Mutant IkappaBalpha transgenic mice (B6 background) with a T cell restricted defect in NF-kB translocation (TmIkBa) were transplanted with BALB/c SB allografts using no immunosupression. Wild type B6 recipients of BALB/c SB allograft served as controls. Graft tissues were evaluated at early time points (POD 5 - 9) and when severe rejection was evident using histology, immunopathology, and functional (sucrase) assays. Humoral responses were evaluated by measuring alloreactive antibodies in host sera using flow cytometry. Results: All B6 isografts (n=5) survival more than 100 days, while all allografts (n=4) died of graft failure by POD 9 with typical histologic features of SB allograft rejection. In contrast, BALB/c SB allografts transplanted into TmIkBa transgenic mice survived more then 60 days (median survival time = 61 days). When these grafts were examined on PODs 5-9 there was no histologic evidence of rejection and minimal graft infiltration by CD4+ T cells and macrophages compared to WT SB allografts. In evaluating the ultimate cause of graft lost in SB allografts transplanted into TmIkBa recipients, histological analyses revealed features of chronic rejection. Furthermore there was increased alloreactive antibodies of primarily IgG1 subtype detected in the host sera, and increased deposition of complement factor 3 detected in the SB allografts, in these transplants compared to controls. Conclusions: Inhibition of NF-kB activation in host T cells prevents acute SB allograft rejection and prolongs SB allograft survival in this model. Chronic rejection mediated by humeral responses may contribute to the late graft failure seen in these grafts, implicating B cell responses occurring independent of T cell NFkB activation. The model presented in this study may be valuable in exploring the mechanism of chronic SB allograft rejection.