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 journalArticle

35 Citations (Scopus)

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

Fingerprint

B-Lymphocytes
Isoantibodies
Fluorescent Dyes
Immunoglobulin D
Germinal Center
Streptavidin
Plasma Cells
Antibody Formation
Allografts
Spleen
Transplantation
Lymph Nodes
Staining and Labeling
Phenotype
Antibodies
Population

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)

Cite this

Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig. / Chen, J.; Yin, H.; Xu, J.; Wang, Q.; Edelblum, K. L.; Sciammas, Roger; Chong, A. S.

In: American Journal of Transplantation, Vol. 13, No. 9, 09.2013, p. 2280-2292.

Research output: Contribution to journalArticle

Chen, J. ; Yin, H. ; Xu, J. ; Wang, Q. ; Edelblum, K. L. ; Sciammas, Roger ; Chong, A. S. / Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig. In: American Journal of Transplantation. 2013 ; Vol. 13, No. 9. pp. 2280-2292.
@article{783b5c604b854f19b3761befc2ad8a1b,
title = "Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig",
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.",
keywords = "Allograft rejection, alloreactive B cells, anti-CD154, CTLA-4Ig, GC, MHC Class I tetramers, PCs",
author = "J. Chen and H. Yin and J. Xu and Q. Wang and Edelblum, {K. L.} and Roger Sciammas and Chong, {A. S.}",
year = "2013",
month = "9",
doi = "10.1111/ajt.12350",
language = "English (US)",
volume = "13",
pages = "2280--2292",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell",
number = "9",

}

TY - JOUR

T1 - Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig

AU - Chen, J.

AU - Yin, H.

AU - Xu, J.

AU - Wang, Q.

AU - Edelblum, K. L.

AU - Sciammas, Roger

AU - Chong, A. S.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Allograft rejection

KW - alloreactive B cells

KW - anti-CD154

KW - CTLA-4Ig

KW - GC

KW - MHC Class I tetramers

KW - PCs

UR - http://www.scopus.com/inward/record.url?scp=84883453086&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883453086&partnerID=8YFLogxK

U2 - 10.1111/ajt.12350

DO - 10.1111/ajt.12350

M3 - Article

C2 - 23855587

AN - SCOPUS:84883453086

VL - 13

SP - 2280

EP - 2292

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

IS - 9

ER -