Background. Mucosal or oral tolerance, an established method for inducing low-risk antigen-specific hyporesponsiveness, has not been investigated in vascularized composite allograft (VCA) research. We studied its effects on recipient immune responses and VCA rejection. Methods. Lewis rats ( ; TREATED) received seven daily intrajejunal treatments of splenocytes from semiallogeneic Lewis-Brown-Norway rats (LBN) or vehicle ( ; SHAM). Recipients’ immune responses were assessed by mixed lymphocyte reaction (MLR) against donor antigen and controls. Other Lewis ( ; TREATED/VCA) received LBN hindlimb VCA and daily intrajejunal treatments of LBN splenocytes, or LBN VCA without treatment ( ; SHAM/VCA), until VCAs rejected. Recipients’ immune responses were characterised and VCAs biopsied for histopathology. Immunosuppressants were not used. Results. LBN-specific hyporesponsiveness was induced only in treated Lewis recipients. Treatment significantly reduced MLR alloreactivity, significantly reduced VCA rejection on histopathology, and significantly delayed clinical VCA rejection ( ; TREATED/VCA mean 9.6 versus 6.0 days for SHAM/VCA). Treatment significantly increased immunosuppressive IL-10/IL-4/TGF-β production and significantly decreased proinflammatory IFN-γ/TNF-α. Conclusion. Jejunal exposure to antigen conferred donor specific hyporesponsiveness that delayed VCA rejection. This method may offer a low-risk adjunctive treatment option to help protect VCAs from rejection. 1. Introduction The technical feasibility of transplanting vascularized composite allografts (VCA) such as of hand/forearm, larynx, partial face, and others is not disputed [1–5]. However, reconstructive VCA is unlikely to become widely available until either the risk profiles of lifelong immunosuppressant drugs become more acceptable or a safe method of donor-specific VCA tolerance induction applicable to humans is devised [6, 7]. Although transplantation tolerance has been established in many experimental models and anecdotal incidents of tolerance in humans can be found in the literature, efforts to replicate the state safely and reliably in humans have proven futile [8, 9]. Another method to reduce the attendant risks of nonspecific immunosuppression may be to induce donor-specific hyporesponsiveness [7, 10]. Although this is not transplantation tolerance, such a state may decrease the dosages required to maintain the allotransplant. Enteral (usually oral) administration of appropriate antigens can specifically suppress development or progression of experimental autoimmunities such as
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