Indefinite survival of fully allogeneic cardiac grafts induced by antigen delivery through the alimentary tract.

O ral administration can induce unresponsiveness to protein antigens.1 We have already shown that oral delivery of donor splenocytes induces prolonged survival of allogeneic or xenogeneic grafts when delivered with a nondepleting anti-CD4 monoclonal antibody (anti-CD4).2,3 Intravenous injection of a single major histocompatibility complex (MHC) molecule has been shown to induce prolongation of fully MHC-mismatched grafts.4 This phenomenon can be explained by the linked suppression,4,5 in which tolerance to strain (AxB)F1 is also established when recipients become tolerant to strain A. Therefore, we have examined whether a single donor MHC antigen or soluble ovalbumin (OVA) could induce survival of fully MHC-mismatched cardiac grafts when delivered into the alimentary tract with anti-CD4. Mice (8-12 weeks of age) were purchased from Sankyo (Tokyo, Japan) and housed in conventional facilities of the Biomedical Services Unit, Teikyo Hospital, Tokyo, and used in accordance with the Animal Care Guidelines of Teikyo University. Mouse hearts were transplanted into the abdomen of a recipient by means of a microsurgical technique.2 Naive CBA (H2k) mice fully rejected allogeneic C57BL/10 (H2b) cardiac grafts, with 8 days of median survival time (MST; Table 1). When CBA mice were fed with 1 × 107 C57BL/10 splenocytes (day –7) combined with intraperitoneal injection of a nondepleting anti-CD4 (days –8 and –7, 200 μg per dose, YTS 1772; hybridoma kindly provided by H. Waldmann, Oxford, United Kingdom), the majority of grafts survived indefinitely (MST >100 days, Table 1), whereas mice pretreated orally with splenocytes alone or with anti-CD4 alone rejected their grafts (MST = 8 and 7.5 days in Table 1). Intravenous injection of C57BL/10 splenocytes combined with the anti-CD4 was less effective (MST = 15 days, data not shown), suggesting that alloantigen delivery though the alimentary tract is essential to