Date: Monday, June 4, 2018
Session Time: 4:30pm-6:00pm
Presentation Time: 4:54pm-5:06pm
Location: Room 606/607
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, [micro]KO, 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-[micro]KO 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.
CITATION INFORMATION: Suah A., Khiew S., Young J., Yin D., Wang Q., Alegre M., Chong A. Acquired Resistance to Transplantation Tolerance as a Result of Prior Pregnancy Requires B Cells Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Suah A, Khiew S, Young J, Yin D, Wang Q, Alegre M, Chong A. Acquired Resistance to Transplantation Tolerance as a Result of Prior Pregnancy Requires B Cells [abstract]. https://atcmeetingabstracts.com/abstract/acquired-resistance-to-transplantation-tolerance-as-a-result-of-prior-pregnancy-requires-b-cells/. Accessed August 7, 2020.
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