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Induction of Sensitization and Resistance to Transplant Tolerance by Allogeneic Pregnancy

Suah, Ashley N.1; Young, James S.1; Khiew, Stella Hsu-Wei1; Wang, Qiang1; Yin, Denping1; Alegre, Maria-Luisa2; Chong, Anita S.1

doi: 10.1097/

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

Introduction: Clinical data suggest allogeneic pregnancy is a sensitizing event[1][2]; yet, recent data from mouse models suggest it induces fetal-specific regulatory T cell (Treg) expansion and differentiation into memory Tregs that mediate systemic, fetal-specific immune regulation post-partum (PP)[3][4]. In this study, we sought to define the immunological consequences of allogeneic pregnancy for the induction of allograft tolerance in mice.

Methods: Virgin female B/6 mice were mated with male B/c-2 W-OVA transgenic mice and conception date was confirmed with visualization of a copulation plug. Fetal-specific CD4+ and CD8+ T cell responses were tracked PP using 2 W:I-Ab and OVA:Kb tetramers, and fetal-specific antibodies were monitored using B/c targets and flow cytometry. At PP day 30–45, F1 (B/6 x B/c)-2 W-OVA heart transplants were performed and recipients were treated with anti-CD154 (POD 0, 7, 14) and donor-specific splenocytes (POD 0) to induce tolerance. Graft rejection was determined by direct palpation.

Results: PP females demonstrated a fifteen-fold increase in total number of fetal-specific Tregs and seven-fold increase in number of fetal-specific conventional CD4+ and CD8+ T cells (Tconvs) at PP day 30–45, compared to virgin controls. 2 W:IAb CD4+ Tconvs showed modestly increased expression of markers of anergy (CD44+FR4+CD73+: 20% PP vs 6% V) and OVA:Kb CD8+ Tconvs markers of exhaustion (PD-1: 10% PP vs 0% V). Fetal-specific antibodies increased throughout pregnancy to a peak three-fold increase by PP day 30–45. 7 of 10 PP mice rejected their heart graft by day 21–28 post-transplant, while all virgin mice (N = 25) accepted their grafts for > 60 days (Fig 1).

Conclusion: Despite sustained expansion of maternal FoxP3+ Tregs with fetal/allograft-specificity and acquisition of Tconvs with an anergic/exhausted phenotype, allogeneic pregnancy induced fetal-specific antibodies and a resistance to transplant tolerance.




1. Redfield RR, Scalea JR, Zens TJ, et al. The mode of sensitization and its influence on allograft outcomes in highly sensitized kidney transplant recipients. Nephrol Dial Transplant. 2016; 31(10):1746-53.

2. Porrett P, Bromberger B, Hashmi S, Morrison A, Sawinski D. Pregnancy excludes women from successful living donor transplantation. Am J Transplant. 2016; 16 (suppl 3).

3. Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature. 2012; 490(7418):102-106.

4. Kalekar LA, Schmiel SE, Nandiwada SL et al. CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nature. 2016; 17(3): 304-15.

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