Deconstructing the allo-specific memory B cell response Allo-specific B cells and their antibody products are strongly predict with acute and chronic allograft rejection, especially in sensitized transplant recipients with pre-existing donr-specific antibodies (DSA). The source of antibody in the sensitized recipients derives from two distinct cellular pools: constitutive production of allo-specific antibody from the long lived plasa cell and de novo production from reactivated memory B cells in the recall response. While the long lived plasma cells can be viewed as a static population that produces a finite amount of antibody (life time times secretion rate), memory B cells represent a highly dynamic population that re- cycle indefinitely to produce bursts of antibody and to reseed the long lived plasma cell and memory B cell pools. Thus, we posit that understanding the roles of memory B cells under circumstances of transplantation, especially the mechanisms that regulate the dynamic behavior of allo-specific memory B cells, will ultimately prove to be important for controlling transplant rejection. Our work has uncovered a central regulator of B cell differentiation that controls the identity of differentiated B cells as a function of antigen affinity/avidity of the B cell antigen receptor (BCR). The Irf4 transcription factor controls the generation of plasma cells (PC) and Germinal Center B (GC B) cells by activating the expression of the rate limiting transcription factors important for those cell fates, Blimp-1 and Bcl6, respectively. We hypothesize that Irf4 plays a similarly critical role in controlling the generation of memory B cells as well as in controlling the dynamics of memory B cell reactivation. Furthermore, we have optimized a strategy to follow the fate of individual allogeneic MHC-specific B cells responding to transplants in mice. This technology has enabled us to quantify the proportions of PC, GC B, and memory B cells after primary and secondary immunizations. Therefore we propose to define the life cycle of allo-antigen specific memory B cells and how that may be altered by costimulation blockade, to identify the conditions with which memory B cells reactivate, and to determine the impact of memory B cells on mechanisms of humoral rejection.

Public Health Relevance

Memory B cells are a dynamic cell type that recycles indefinitely into future immune responses to produce bursts of high affinity antibody and to reseed the long lived plasma cell and memory B cell pool. In this proposal, we combine single cell tracking technology with novel genetic tools to better understand the life cycle of allogeneic MHC-specific memory B cells and how that may be perturbed by costimulation blockade as well as the rules by which memory B cells reactivate during new immune responses. These studies will provide new insight into the associations of alloantibody and increased incidence of transplant rejection as well as into new immunosuppressive strategies to control B cells and their antibody products.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI110513-03
Application #
9210559
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Rice, Jeffrey S
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2016-02-01
Budget End
2016-07-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Chong, Anita S; Ansari, M Javeed (2018) Heterogeneity of memory B cells. Am J Transplant 18:779-784
Young, James S; McIntosh, Christine; Alegre, Maria-Luisa et al. (2017) Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans. Transplantation 101:2671-2681
Chong, A S; Khiew, S H (2017) Transplantation tolerance: don't forget about the B cells. Clin Exp Immunol 189:171-180
Chong, Anita S (2017) Alone Again, Naturally: B Cells Encountering Antigen Without T cells. Transplantation 101:1956-1958
Young, J S; Chen, J; Miller, M L et al. (2016) Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection. Am J Transplant 16:2312-23
Yang, Jinghui; Chen, Jianjun; Young, James S et al. (2016) Tracing Donor-MHC Class II Reactive B cells in Mouse Cardiac Transplantation: Delayed CTLA4-Ig Treatment Prevents Memory Alloreactive B-Cell Generation. Transplantation 100:1683-91
Chong, Anita S (2016) From Pipe Dream to Donor-Specific PC Elimination: Novel Ways to Target Alloantibodies. Transplantation 100:2238-2239
Chen, Jianjun; Wang, Qiang; Yin, Dengping et al. (2015) Cutting Edge: CTLA-4Ig Inhibits Memory B Cell Responses and Promotes Allograft Survival in Sensitized Recipients. J Immunol 195:4069-73
Chong, Anita S; Sciammas, Roger (2015) Memory B cells in transplantation. Transplantation 99:21-8
Chong, Anita S; Perkins, David L (2014) Transplantation: molecular phenotyping of T-cell-mediated rejection. Nat Rev Nephrol 10:678-80