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Author Notes:

Corresponding author: Stuart J. Knechtle, stuart.knechtle@emoryhealthcare.org

We thank Dr. Christian P. Larsen (Emory University, Department of Surgery) for insightful suggestions on the study.

The authors also would like to thank Drew Roenneburg (University of Wisconsin, Department of Surgery) for assistance in immunohistochemistry.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Subjects:

Research Funding:

This work was supported by the CHOA Pediatric Liver Transplant Research Program Support (to SJK) and Roche Transplant Research Foundation (ROTRF) Grant 962141545 (to NII).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Surgery
  • Transplantation
  • SURGERY
  • TRANSPLANTATION
  • Allo-B cell
  • alloantibody
  • chronic rejection
  • T cell depletion
  • Alemtuzumab
  • TRANSPLANTED MOUSE HEARTS
  • CD8(+) T-CELLS
  • CAMPATH-1H INDUCTION
  • MEDIATED REJECTION
  • HUMORAL IMMUNITY
  • VASCULOPATHY
  • MICE
  • ARTERIOSCLEROSIS
  • CLASSIFICATION
  • ASSOCIATION

Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

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Journal Title:

American Journal of Transplantation

Volume:

Volume 12, Number 10

Publisher:

, Pages 2641-2651

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection. The authors demonstrate that an endogenous de novo allo B cell response after isolated T cell depletion in a CD52 transgenic mouse cardiac allograft model leads to de novo alloantibody production and antibody-mediated chronic rejection. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Copyright information:

© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons. This is the peer reviewed version of the following article, which has been published in final form. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions .

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