Tracing donor-MHC class II reactive B cells in mouse cardiac transplantation: Delayed CTLA4-Ig treatment prevents memory alloreactive B-cell generation

Jinghui Yang, Jianjun Chen, James S. Young, Qiang Wang, Dengping Yin, Roger Sciammas, Anita S. Chong

Research output: Contribution to journalArticle

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Abstract

Background. The dual role of B cells as drivers and suppressors of the immune responses have underscored the need to trace the fate of B cells recognizing donormajor histocompatibility complex class I and class II after allograft transplantation.Methods. In this study, we used donor class II tetramers to trace the fate of I-Ed-specific B cells after immunization with BALB/c spleen cells or cardiac transplantation, in naive or sensitized C57BL/6 recipients. We combined this approach with genetic lineage tracing of memory B cells in activation-induced cytidine deaminase regulated Cre transgenic mice crossed to the ROSA26-enhanced yellow fluorescent protein reporter mice to track endogenous I-Ed-specific memory B cell generation. Results. Immunization with BALB/c splenocytes or heart transplantation induced an expansion and differentiation of I-Ed-specific B cells into germinal center B cells, whereas BALB/c heart transplantation into sensitized recipients induced the preferential differentiation into antibody-secreting cells. A 10.8-fold increase in the frequency of I-Ed-specific memory B cells was observed by day 42 postimmunization. Treatment with CTLA4-Ig starting on day 0 or day 7 postimmunization abrogated I-Ed-specificmemory B cell generation and sensitized humoral responses, but not if treatment commenced on day 14. Conclusions. The majority of donorspecificmemory B cells are generated between days 7 and 14 postimmunization, thus revealing a flexible timeframewhereby delayed CTLA4-Ig administration can inhibit sensitization and the generation of memory graft-reactive B cells.

Original languageEnglish (US)
Pages (from-to)1683-1691
Number of pages9
JournalTransplantation
Volume100
Issue number8
DOIs
StatePublished - Jul 26 2016
Externally publishedYes

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Heart Transplantation
B-Lymphocytes
Therapeutics
Immunization
Abatacept
Antibody-Producing Cells
Germinal Center
Cell Transplantation
Major Histocompatibility Complex
Transgenic Mice
Allografts
Spleen
Transplantation
Transplants

ASJC Scopus subject areas

  • Transplantation

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Tracing donor-MHC class II reactive B cells in mouse cardiac transplantation : Delayed CTLA4-Ig treatment prevents memory alloreactive B-cell generation. / Yang, Jinghui; Chen, Jianjun; Young, James S.; Wang, Qiang; Yin, Dengping; Sciammas, Roger; Chong, Anita S.

In: Transplantation, Vol. 100, No. 8, 26.07.2016, p. 1683-1691.

Research output: Contribution to journalArticle

Yang, Jinghui ; Chen, Jianjun ; Young, James S. ; Wang, Qiang ; Yin, Dengping ; Sciammas, Roger ; Chong, Anita S. / Tracing donor-MHC class II reactive B cells in mouse cardiac transplantation : Delayed CTLA4-Ig treatment prevents memory alloreactive B-cell generation. In: Transplantation. 2016 ; Vol. 100, No. 8. pp. 1683-1691.
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N2 - Background. The dual role of B cells as drivers and suppressors of the immune responses have underscored the need to trace the fate of B cells recognizing donormajor histocompatibility complex class I and class II after allograft transplantation.Methods. In this study, we used donor class II tetramers to trace the fate of I-Ed-specific B cells after immunization with BALB/c spleen cells or cardiac transplantation, in naive or sensitized C57BL/6 recipients. We combined this approach with genetic lineage tracing of memory B cells in activation-induced cytidine deaminase regulated Cre transgenic mice crossed to the ROSA26-enhanced yellow fluorescent protein reporter mice to track endogenous I-Ed-specific memory B cell generation. Results. Immunization with BALB/c splenocytes or heart transplantation induced an expansion and differentiation of I-Ed-specific B cells into germinal center B cells, whereas BALB/c heart transplantation into sensitized recipients induced the preferential differentiation into antibody-secreting cells. A 10.8-fold increase in the frequency of I-Ed-specific memory B cells was observed by day 42 postimmunization. Treatment with CTLA4-Ig starting on day 0 or day 7 postimmunization abrogated I-Ed-specificmemory B cell generation and sensitized humoral responses, but not if treatment commenced on day 14. Conclusions. The majority of donorspecificmemory B cells are generated between days 7 and 14 postimmunization, thus revealing a flexible timeframewhereby delayed CTLA4-Ig administration can inhibit sensitization and the generation of memory graft-reactive B cells.

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