Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig

J. Chen, H. Yin, J. Xu, Q. Wang, K. L. Edelblum, Roger Sciammas, A. S. Chong

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Alloantibodies mediate acute antibody-mediated rejection as well as chronic allograft rejection in clinical transplantation. To better understand the cellular dynamics driving antibody production, we focused on the activation and differentiation of alloreactive B cells in the draining lymph nodes and spleen following sensitization to allogeneic cells or hearts. We used a modified staining approach with a single MHC Class I tetramer (Kd) bound to two different fluorochromes to discriminate between the Class I-binding and fluorochrome-streptavidin-binding B cells with a high degree of specificity and binding efficiency. By Day 7-8 postsensitization, there was a 1.5- to 3.2-fold increase in the total numbers of Kd-binding B cells. Within this Kd-binding B cell population, approximately half were IgD low, MHC Class IIhigh and CD86+, 30-45% expressed a germinal center (Fas+GL7+) phenotype and 3-12% were IRF4hi plasma cells. Remarkably, blockade with anti-CD40 or CTLA-4Ig, starting on Day 7 postimmunization for 1 or 4 weeks, completely dissolved established GCs and halted further development of the alloantibody response. Thus MHC Class I tetramers can specifically track the in vivo fate of endogenous, Class I-specific B cells and was used to demonstrate the ability of delayed treatment with anti-CD154 or CTLA-4Ig to halt established allo-B cell responses. This study describes the use of MHC Class I tetramers to specifically track the in vivo fate of endogenous, Class I-specific B cells, and the use of this approach to demonstrate the ability of delayed treatment with anti-CD154 or CTLA-4Ig to halt established allospecific B cell responses.

Original languageEnglish (US)
Pages (from-to)2280-2292
Number of pages13
JournalAmerican Journal of Transplantation
Volume13
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

Keywords

  • Allograft rejection
  • alloreactive B cells
  • anti-CD154
  • CTLA-4Ig
  • GC
  • MHC Class I tetramers
  • PCs

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

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