Patterns of de Novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment

J. Kwun, B. C. Oh, A. C. Gibby, R. Ruhil, V. T. Lu, D. W. Kim, E. K. Page, O. P. Bulut, M. Q. Song, A. B. Farris, A. D. Kirk, S. J. Knechtle, N. N. Iwakoshi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2641-2651
Number of pages11
JournalAmerican Journal of Transplantation
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

Keywords

  • Alemtuzumab
  • Allo-B cell
  • T cell depletion
  • alloantibody
  • chronic rejection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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    Kwun, J., Oh, B. C., Gibby, A. C., Ruhil, R., Lu, V. T., Kim, D. W., Page, E. K., Bulut, O. P., Song, M. Q., Farris, A. B., Kirk, A. D., Knechtle, S. J., & Iwakoshi, N. N. (2012). Patterns of de Novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment. American Journal of Transplantation, 12(10), 2641-2651. https://doi.org/10.1111/j.1600-6143.2012.04181.x