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Oral delivery of xenoantigen combined with non-depleting Anti-CD4 monoclonal antibody induced significant prolonged survival of concordant skin xenografts
Oral Delivery of Xenoantigen Combined With Non-Depleting Anti-CD4 Monoclonal Antibody Induced Significant Prolonged Survival of Concordant Skin Xenografts M. Niimi, N. Shirasugi, K. Hamano, K. Esato, K. Matsumoto, Y. Ikeda, T. Shatari, H. Takami, and S. Kodaira
O
RAL administration can induce unresponsiveness to protein antigens.1 We have already demonstrated that oral delivery of alloantigen plus nondepleting anti-CD4 monoclonal antibody (MAb) treatment induced indefinite survival of fully allogeneic cardiac grafts, generated CD4⫹ regulatory cells, and suppressed activity of cytotoxic T cells and production of alloantibodies.2 Therefore, in this study, we examined whether oral administration of xenoantigen could induce the prolonged survival of xenogeneic skin grafts. MATERIALS AND METHODS Skins from SD rats were transplanted into CBA (H2k) recipients. Mice were given 1 ⫻ 107 rat splenocytes orally 7 days before transplantation in the presence or absence of a nondepleting anti-CD4 MAb (YTS 177, 200 g/per dose, ⫺8 and ⫺7 days).3
RESULTS
All skin grafts survived over 40 days when xenoantigens were administered orally in combination with anti-CD4 MAb. However, all grafts were rejected within 60 days (mean survival time [MST] ⫽ 52 days). Mice treated with anti-CD4 MAb alone or oral administration of xenoantigen alone induced modest prolonged survival of rat skin (MSTs ⫽ 18 and 19 days, respectively). Naive mice rejected rat skin acutely (MST ⫽ 12 days). To examine the fate of orally delivered cells4, carboxyfluorescein succimimidyl ester (CFSE)-labeled xenogeneic splenocytes were given to mice. CFSE⫹ cells were detected in spleen when delivered intravenously (IV) but not orally, suggesting that orally delivered cells were destroyed and xenoantigens presented via the indirect pathway. To investigate one of the mechanisms, the presence of serum antibodies reactive with
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 1035 (2000)
xenoantigens was measured by flow cytometry 50 days after transplantation of skin. Oral administration alone or combined with anti-CD4 MAb reduced the level of xenoantibody compared to that in untreated mice. Xenogeneic mixed leukocyte response was reduced when splenocytes from mice pretreated with oral administration of xenogeneic cells were used as responder compared to that in untreated mice. CONCLUSIONS
Oral delivery of xenoantigen plus nondepleting anti-CD4 MAb can induce prolongation of concordant xenogeneic skin grafts. Although orally delivered cells were destroyed and xenoantigens were presented via the indirect pathway, oral delivery of xenogeneic cells inhibited the generation of antibody specific for xenoantigens and xenogeneic mixed leukocyte reaction. REFERENCES 1. Weiner HL: Immunol Today 18:335, 1997 2. Niimi M, Morris PJ, Wood KJ: Transplant Proc 31:892, 1999 3. Qin S, Wise M, Cobbold SP, et al: Eur J Immunol 20:2737, 1990 4. Niimi M, Jones ND, Pajaro OB, et al: Transplant Immunol 6:177, 1998 From the First Department of Surgery, Teikyo University (M.N., N.S., Y.I., T.S., H.T., S.K.), Tokyo, First Department of Surgery, Yamaguchi University (K.H., K.E.), Yamaguchi, and Department of Surgery (K.M.), Keio University, Tokyo, Japan. Address reprint requests to M. Niimi, First Department of Surgery, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan. E-mail: [email protected].
0041-1345/00/$–see front matter PII S0041-1345(00)01104-0 1035
O
RAL administration can induce unresponsiveness to protein antigens.1 We have already demonstrated that oral delivery of alloantigen plus nondepleting anti-CD4 monoclonal antibody (MAb) treatment induced indefinite survival of fully allogeneic cardiac grafts, generated CD4⫹ regulatory cells, and suppressed activity of cytotoxic T cells and production of alloantibodies.2 Therefore, in this study, we examined whether oral administration of xenoantigen could induce the prolonged survival of xenogeneic skin grafts. MATERIALS AND METHODS Skins from SD rats were transplanted into CBA (H2k) recipients. Mice were given 1 ⫻ 107 rat splenocytes orally 7 days before transplantation in the presence or absence of a nondepleting anti-CD4 MAb (YTS 177, 200 g/per dose, ⫺8 and ⫺7 days).3
RESULTS
All skin grafts survived over 40 days when xenoantigens were administered orally in combination with anti-CD4 MAb. However, all grafts were rejected within 60 days (mean survival time [MST] ⫽ 52 days). Mice treated with anti-CD4 MAb alone or oral administration of xenoantigen alone induced modest prolonged survival of rat skin (MSTs ⫽ 18 and 19 days, respectively). Naive mice rejected rat skin acutely (MST ⫽ 12 days). To examine the fate of orally delivered cells4, carboxyfluorescein succimimidyl ester (CFSE)-labeled xenogeneic splenocytes were given to mice. CFSE⫹ cells were detected in spleen when delivered intravenously (IV) but not orally, suggesting that orally delivered cells were destroyed and xenoantigens presented via the indirect pathway. To investigate one of the mechanisms, the presence of serum antibodies reactive with
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 1035 (2000)
xenoantigens was measured by flow cytometry 50 days after transplantation of skin. Oral administration alone or combined with anti-CD4 MAb reduced the level of xenoantibody compared to that in untreated mice. Xenogeneic mixed leukocyte response was reduced when splenocytes from mice pretreated with oral administration of xenogeneic cells were used as responder compared to that in untreated mice. CONCLUSIONS
Oral delivery of xenoantigen plus nondepleting anti-CD4 MAb can induce prolongation of concordant xenogeneic skin grafts. Although orally delivered cells were destroyed and xenoantigens were presented via the indirect pathway, oral delivery of xenogeneic cells inhibited the generation of antibody specific for xenoantigens and xenogeneic mixed leukocyte reaction. REFERENCES 1. Weiner HL: Immunol Today 18:335, 1997 2. Niimi M, Morris PJ, Wood KJ: Transplant Proc 31:892, 1999 3. Qin S, Wise M, Cobbold SP, et al: Eur J Immunol 20:2737, 1990 4. Niimi M, Jones ND, Pajaro OB, et al: Transplant Immunol 6:177, 1998 From the First Department of Surgery, Teikyo University (M.N., N.S., Y.I., T.S., H.T., S.K.), Tokyo, First Department of Surgery, Yamaguchi University (K.H., K.E.), Yamaguchi, and Department of Surgery (K.M.), Keio University, Tokyo, Japan. Address reprint requests to M. Niimi, First Department of Surgery, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan. E-mail: [email protected].
0041-1345/00/$–see front matter PII S0041-1345(00)01104-0 1035