Addition of Anti-CD40 Monoclonal Antibody to Nonmyeloablative Conditioning With Belatacept Abrogated Allograft Tolerance Despite Induction of Mixed Chimerism

BACKGROUND We recently reported anti-CD40 monoclonal antibody and rapamycin (aCD40/rapa) to be a reliable, nontoxic, immunosuppressive regimen for combined islet and kidney transplantation (CIKTx) in nonhuman primates (NHPs). In the current study, we attempted to induce allograft tolerance through the mixed chimerism approach using a conditioning regimen with aCD40 and belatacept (Bela). METHODS Five CIKTx or kidney transplant (KTx) recipients were treated with aCD40/rapa for 4 months. All recipients then received a conditioning regimen including horse anti-thymocyte globulin (hATG) and aCD40/Bela. The results were compared with previous reports of recipients treated with Bela-based regimens. RESULTS All 3 CIKTx recipients developed mixed chimerism, which was significantly superior to that observed in the previous Bela-based studies. Nevertheless, all CIKTx recipients in this study lost their islet and renal allografts as a result of cellular and humoral rejection on days 140, 89, and 84. The 2 KTx-alone recipients were treated with the same conditioning regimen and suffered rejection on days 127 and 116, despite the development of excellent chimerism. B lymphocyte reconstitution dominated by memory phenotypes was associated with early development of donor-specific antibodies in 4/5 recipients. In vitro assays showed no donor-specific regulatory T cell (Treg) expansion, which has been consistently observed in tolerant recipients with our mixed chimerism approach. CONCLUSION Despite displaying excellent immunosuppressive efficacy, costimulatory blockade with anti-CD40 mAb (2C10R4) may inhibit the induction of renal or islet allograft tolerance via a mixed chimerism approach. Correspondence information: Tatsuo Kawai, MD, PhD, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, Phone: 617-817-3270, Fax: 617-724-3471, Email: tkawai@mgh.harvard.edu AUTHORSHIP: TO: Research design, writing the paper, performance of the research, data analysis KH: Performance of the research IR: Performance of the research AD: Performance of the research KK: Performance of the research HL: Data analysis BC: Research design, writing the paper TK: Research design, writing the paper, data analysis DISCLOSURE The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. This manuscript was also not prepared or funded by any commercial organization. Founding sources: This work was supported by NIH grant U19 AI102405-01. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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