B Cell Biology (Videos Available)

Monday July 02, 2018 from 08:30 to 09:30

Room: N-106

303.4 Acquired resistance to transplantation tolerance as a result of prior pregnancy requires B cells

Award Winner

Ashley N. Suah, United States has been granted the TTS Young Investigator Scientific Award

Ashley N. Suah, United States

General Surgery Resident
Department of Surgery
University of Chicago Medicine


Acquired Resistance to Transplantation Tolerance as a Result of Prior Pregnancy Requires B Cells

Ashley Suah1, Stella H Khiew1, James S Young1, Dengping Yin1, Qiang Wang1, Marisa Alegre2, Anita S Chong1.

1Department of Surgery, University of Chicago Medicine, Chicago, IL, United States; 2Department of Medicine, University of Chicago Medicine, Chicago, IL, United States

Introduction: Clinical data suggest allogeneic pregnancy is a sensitizing event; yet, recent data from mouse models indicates it induces fetal-specific regulatory T cell (Treg) expansion that mediates systemic, fetal-specific immune regulation post-partum (PP). In this study, we aimed to define the mechanism for acquired resistance to allograft tolerance after allogeneic pregnancy.
Methods: Virgin female wild-type (WT) B/6, µKO, or anti-HEL BCR-tg (MD4) mice were mated with male B/c-2W-OVA transgenic mice.  Fetus-specific IgG were monitored by flow cytometry, while donor-specific cellular responses were tracked using Kd+IEd+Ld tetramers for B cells, and 2W:I-Ab and OVA:Kb tetramers for CD4+ and CD8+ T cells, respectively.  At PP day 30–45, F1 (B/6 x B/c)-2W-OVA heart transplants (HTx) were performed and anti-CD154 (POD 0, 7, 14) and donor splenocytes (DST, POD 0) were used to induce tolerance.
Results: Fetus-specific IgG increased during and post-pregnancy to a 9-fold peak by PP day 21.  Prior donor-matched pregnancy, but not syngeneic pregnancy, prevented the induction of tolerance in 60% of PP-WT B/6 recipients, despite a significant increase in percentage of fetal-specific FOXP3+ cells and a modest reduction in number of fetal-specific conventional CD4+ T cells (Tconvs) examined at POD 21–189, compared to PP-WT B/6 untransplanted controls.  In contrast, ongoing donor-specific germinal center B cell responses were detected suggesting a B cell-mediated resistance to transplant tolerance. Strikingly, anti-CD154/DST successfully achieved long-term graft acceptance in PP-µKO B/6 and PP-MD4 (normal B cell numbers but ≤5% donor-specific B cells compared to WT) recipients.
Conclusion: Despite the sustained expansion of maternal FoxP3+ Tregs with fetal/allograft-specificity, allogeneic pregnancy results in subsequent resistance to transplant tolerance induced with anti-CD154/DST.  These studies provide new insights into the mechanism of pregnancy-induced sensitization by demonstrating a necessity for B cells in preventing subsequent induction of fetal/allograft-specific transplantation tolerance.

American Society of Transplant Surgeons .

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