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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: 10.1097/01.tp.0000520347.55444.0e
125.5
Free

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.

FIGURE 1

FIGURE 1

References:

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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