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Pretransplantation GAD-Autoantibody Status to Guide Prophylactic Antibody Induction Therapy in Simultaneous Pancreas and Kidney Transplantation

Ringers, Jan1; van der Torren, Cornelis R.2; van de Linde, Pieter1,3; van der Boog, Paul J.M.3; Mallat, Marko J.K.3; Bonifacio, Ezio4,5; Roep, Bart O.2; de Fijter, Johan W.3,6

doi: 10.1097/TP.0b013e3182a012cc
Clinical and Translational Research

Background Daclizumab and antithymocyte globulin (ATG) have been shown to reduce allograft rejection. We assessed the safety and efficacy of daclizumab or ATG prophylaxis in combination with triple immunotherapy in simultaneous pancreas-kidney transplant (SPKT) recipients.

Methods Thirty-nine type 1 diabetic patients scheduled for primary SPKT were randomized to receive prophylactic therapy with either daclizumab or ATG. A group of 27 patients without prophylactic antibodies was used for retrospective comparison. All patients received cyclosporine and mycophenolate mofetil and gradually tapered prednisone. Autoantibodies and cellular autoreactivity were measured to assess recurrent autoreactive responses.

Results Baseline and transplant characteristics were comparable among groups. Both daclizumab and ATG therapy resulted in a significant reduction in acute rejection episodes. The incidence of rejection episodes was significantly higher in pretransplantation GAD autoantibody-positive daclizumab-treated recipients compared with GAD autoantibody-negative or ATG-treated recipients. IA-2 islet autoantibodies showed no association with rejection. There were no significant differences between the groups for in vitro autoreactivity, clinical outcome, or functional parameters.

Conclusions Daclizumab or ATG combined with a maintenance immunosuppressive regime consisting of cyclosporine, mycophenolate mofetil, and prednisolone were well tolerated and equally effective in reducing the incidence of acute rejection episodes in SPKT recipients. Up to 3 years, no adverse sequelae of the immunoprophylaxis or clinical and ex vivo recurrent autoimmunity were observed. We propose that the pretransplantation existence of GAD65 autoantibodies serves as a marker guiding the choice for prophylactic therapy in pancreas transplantation.

1 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.

2 Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.

3 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

4 Department of Immunology of Diabetes Unit, San Raffaele Scientific Institute Milan, Italy.

5 Center for Regenerative Therapies Dresden, Dresden, Germany.

6 Address correspondence to: Johan W. de Fijter, M.D., Ph.D., Department of Nephrology, Leiden University Medical Center, C3-P22, P.O. Box 9600, NL-2300 RC Leiden, The Netherlands.

These studies were supported by the Dutch Diabetes Research Foundation, the Juvenile Diabetes Research Foundation, and the European Union (FP6 and FP7).

Trial registry information: Current Controlled Trials: ISRCTN44138942.

The authors declare no conflicts of interest.

E-mail:J.W.de_Fijter@lumc.nl

J.R. supervised clinical organ transplantation and wrote the article. C.R.v.d.T. and P.v.d.L. performed immunologic experiments, analyzed the results, and wrote the article. P.J.M.v.d.B. organized the study and patient care. M.J.K.M. performed statistical analyses. E.B. performed the islet autoantibody analyses. B.O.R. supervised cellular immunologic studies. J.W.d.F. conceived and supervised the clinical trial (principal investigator).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 3 April 2013. Revision requested 29 April 2013.

Accepted 11 June 2013.

Accepted August 2, 2013

© 2013 by Lippincott Williams & Wilkins