Secondary Logo

Institutional members access full text with Ovid®

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

Oura, Tetsu, MD, PhD1; Hotta, Kiyohiko, MD, PhD1; Rosales, Ivy, MD2; Dehnadi, Abbas, VMD1; Kawai, Kent1; Lee, Hang, PhD3; Benedict Cosimi, A., MD1; Kawai, Tatsuo, MD, PhD1

doi: 10.1097/TP.0000000000002417
Original Basic Science—General
Buy

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. 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 alone recipients were treated with aCD40/rapa for 4 months. All recipients then received a conditioning regimen including horse antithymocyte globulin 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 kidney transplant-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 of 5 recipients. In vitro assays showed no donor-specific regulatory T cell expansion, which has been consistently observed in tolerant recipients with our mixed chimerism approach.

Conclusions Despite displaying excellent immunosuppressive efficacy, costimulatory blockade with anti-CD40 monoclonal antibody (2C10R4) may inhibit the induction of renal or islet allograft tolerance via a mixed chimerism approach.

1 Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

2Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

3Department of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Received 19 March 2018. Revision received 15 June 2018.

Accepted 27 June 2018.

The authors of declare no conflicts of interest.

The present work was supported in part by the Canadian Foundation for Innovation and grant U19AI102405, part of the NIH NHP Transplantation Tolerance Cooperative Study Group sponsored by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases.

T.O. participated in the research design, writing the paper, performance of the research, data analysis. K.H. participated in the performance of the research. I.R. participated in the performance of the research. A.D. participated in the performance of the research. K.K. participated in the performance of the research. H.L. participated in the data analysis. B.C. participated in the research design and writing the article. T.K. participated in the research design, writing the article, and data analysis.

Correspondence: Tatsuo Kawai, MD, PhD, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114. (tkawai@mgh.harvard.edu).

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.