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Am J Transplant. 2013 Sep;13(9):2280-92. doi: 10.1111/ajt.12350. Epub 2013 Jul 15.

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

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1
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.

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 (K(d)) 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 K(d) -binding B cells. Within this K(d) -binding B cell population, approximately half were IgD(low) , MHC Class II(high) and CD86(+), 30-45% expressed a germinal center (Fas(+) GL7(+)) phenotype and 3-12% were IRF4(hi) 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.

KEYWORDS:

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

PMID:
23855587
PMCID:
PMC3797532
DOI:
10.1111/ajt.12350
[Indexed for MEDLINE]
Free PMC Article
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