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11.
Samarth S. Durgam Maria-Luisa Alegre Anita S. Chong 《The Journal of experimental medicine》2022,219(5)
Pregnancy is recognized as a spontaneously acquired state of immunological tolerance by the mother to her semi-allogeneic fetus, but it is a major cause of allosensitization in candidates for organ transplantation. This sensitization, assessed by the presence of anti-HLA IgG, contributes to sex disparity in access to transplantation and increases the risk for rejection and graft loss. Understanding this dual tolerance/sensitization conundrum may lead to new strategies for equalizing access to transplantation among sexes and improving transplant outcomes in parous women. Here, we review the clinical evidence that pregnancy results in humoral sensitization and query whether T cell responses are sensitized. Furthermore, we summarize preclinical evidence on the effects of pregnancy on fetus-specific CD4+ conventional, regulatory, and CD8+ T cells, and humoral responses. We end with a discussion on the impact of the divergent effects that pregnancy has upon alloantigen re-encounter in the context of solid organ transplantation, and how these insights point to a therapeutic roadmap for controlling pregnancy-dependent allosensitization.IntroductionThe fact that multiple successive pregnancies with the same male partner can be brought to term successfully suggests that the immunological response to a semi-allogeneic fetus is diametrically opposite to the responses elicited by genetically comparable transplanted organs. Peter Medawar in 1953 (Medawar, 1953) discussed this “immunological paradox of pregnancy,” and since then, there have been extensive investigations into how the fetus avoids rejection. A plethora of immune regulatory mechanisms has been uncovered within the uterine environment, including enrichment in regulatory T cells (Tregs), natural killer cells, regulatory macrophages, entrapment of APCs, and chemokine gene silencing of decidual stromal cells (PrabhuDas et al., 2015). Systemic factors that prevent fetal rejection have also been identified, including immune modulation by pregnancy-related hormones and release of tolerogenic placental debris, which may contribute to the preferential systemic expansion of fetus-specific Tregs and acquired dysfunction by conventional T cells (Tconvs) and CD8+ T cells. Since the majority of these mechanisms either act locally or only during pregnancy, it was assumed that T cell tolerance would manifest itself only in the context of subsequent pregnancy, and that encounter with the same alloantigens in the context of a solid organ transplant, in the absence of local or systemic pregnancy-induced immunomodulation, would trigger allograft rejection.The emphasis on T cells as the major mediator of allograft rejection and on T cell tolerance as a means to achieve transplantation tolerance parallels the focus on the constraint of T cells in pregnancy. Thus, despite studies in the 1980s by Bell and Billington (Bell and Billington, 1981; Bell and Billington, 1983; Bell and Billington, 1986) that pregnancy can elicit paternal-reactive antibodies, how pregnancy sensitizes B cell responses while maintaining T cell tolerance to the semi-allogeneic fetus has remained an under-investigated topic in preclinical models (PrabhuDas et al., 2015). In contrast and driven by the ease in quantifying HLA-specific antibodies but difficulty in assessing HLA-specific T cell responses, clinical studies in solid organ transplantation have revealed that pregnancy is a highly sensitizing event that results in the production of fetus-reactive anti-HLA antibodies, and the presence of these antibodies limits access to transplantation and contributes to increased risk of transplant rejection. In this review, we focus on the contrasting effects of pregnancy on these two arms of the adaptive immune system, and on how these pregnancy-shaped responses are recalled by alloantigens that are shared between offspring and transplanted allograft.Clinical impact of pregnancy alloimmunization in organ transplantationHumoral sensitizationThe effect of pregnancy on the immune system was first reported by J.J. Rodd in 1959 when he described peripartum women experiencing an increased number of blood transfusion reactions (Van Rood et al., 1958). It was this observation that allowed for the discovery of anti-HLA antibodies from the sera of pregnant women (Van Rood et al., 1958). Anti-HLA antibodies are produced during the first trimester of a pregnancy and increase in titer over the gestational course and with multiple pregnancies (Lee et al., 2011). During the postpartum phase, antibody levels rise in the first 90 d and gradually disappear in 50% of postpartum women over a 1–2 yr period (Cecka, 2010; Masson et al., 2013). Anti-HLA antibody titers following kidney transplantation increase more robustly in patients having had prior pregnancies than in those having received previous transplantation or transfusion, suggestive of robust pregnancy-induced memory B cells (Higgins et al., 2015). Notably, although pregnancy-induced alloantibodies can diminish with time, alloreactive memory T and B cells can persist (Senn et al., 2021). Thus, anti-HLA antibodies and memory B cells induced by semi-allogeneic pregnancies play a pivotal role prior to and after transplantation, especially for multiparous women.Historically, anti-HLA antibody titers were measured by the panel-reactive antibody (PRA) technique through a complement-dependent cytotoxicity assay; however, the major limitation of this method is its inconsistency and lack of HLA specificity. In 2009, the United Network for Organ Sharing implemented measuring sensitization using single HLA-coated beads, an assay that precisely identifies specific HLA antigen targets (Cecka, 2010). A computer algorithm generates a calculated PRA (cPRA) according to the HLA frequencies derived from the donor population with the goal of providing consistently accurate results on the extent of sensitization of transplant candidates and the chances for a highly sensitized candidate to find a compatible organ donor. Around 30% of pregnant women are sensitized when measured via complement-dependent cytotoxicity assay, whereas 50–75% of women were found to be sensitized by pregnancy when the single HLA bead assay was used (Bromberger et al., 2017). Furthermore, a retrospective analysis of the United Network for Organ Sharing registry’s waitlist pool showed that individuals with a cPRA >98% were over-represented by women by ~60% (Redfield et al., 2016). Cumulatively, these data reveal the detrimental impact of pregnancy in women in need of a transplant and the disparity it creates toward identifying a suitable donor organ and having a successful post-transplantation course.Living donor kidney transplantation has better outcomes compared to kidney transplantation from deceased donors (Roodnat et al., 2003). However, 30% fewer women received living donor kidney transplantation as compared with men despite comparable referrals (Bromberger et al., 2017; Roodnat et al., 2003). Pregnancy was identified as a major contributor to this disparity, as postpartum women were increasingly incompatible with their spouse and offspring compared with men (Bromberger et al., 2017). Furthermore, parous women are at a higher risk of being sensitized to unrelated donors sharing an allele of the partner or offspring (Gibney et al., 2006; Vaidya et al., 2006). Child-specific sensitization measured by single-HLA bead assay was detected at the HLA-A/B/C/DR loci in 28–38% of 301 multiparous women analyzed (Honger et al., 2013), with child-specific HLA-B loci being the most sensitizing followed by HLA-A > HLA-DRB1 > HLA-C (Dankers et al., 2003; Honger et al., 2013). Furthermore, by quantifying mother/child mismatches by the number of mismatched HLA eplets, where an eplet is defined as the cluster of amino acids representing the smallest functional unit of structural epitopes on the HLA molecule targeted by B cell receptor and antibodies, the rate of child-specific sensitization increased with the presence of ≥20 mismatched eplets (Honger et al., 2013). These observations are reminiscent of eplet-load mismatch between the organ donor and the recipient predicting de novo anti-HLA antibody production by the host and reduced graft survival, and thus underscories the detrimental effects of pregnancy-induced humoral sensitization (Philogene et al., 2020; Sapir-Pichhadze et al., 2020).T cell sensitizationIn contrast to the abundant evidence that fetus-specific B cell responses are induced during pregnancy and the barrier they pose to transplantation, the effects of pregnancy-induced effector T cell responses on subsequent transplantation are more opaque. Specifically, although it is clear that maternal T cells acquire tolerance to the semi-allogeneic fetus, it is uncertain whether this T cell tolerance extends to subsequent organ allografts sharing antigens with the fetus. Early observations that fetal-derived stem cells can persist in low numbers in the mother’s circulation for as long as 27 yr, a phenomenon termed peripheral fetal microchimerism (Nelson, 1998), prompted the hypothesis that this microchimerism mediates long-term fetus-specific tolerance in mothers and promotes the acceptance of grafts from their offspring (Starzl et al., 1993). However, several studies testing the correlation between donor/recipient kinship and allograft fate have reported comparable outcomes between groups receiving grafts from offspring versus non-offspring (Cohen et al., 2018; Ghafari, 2008; Mahanty et al., 2001). A recent retrospective analysis performed using the Organ Procurement and Transplant Network living donor liver transplant database revealed that 1-, 5- and 10-yr allografts and patient survival was poorer among mothers who received the organ from their offspring as compared with unrelated living donors (Dagan et al., 2020). A major caveat of such studies is the potential pro-rejection effects of pregnancy-sensitized B cells even when pregnancy-induced antibodies have diminished; as a result, the contribution of pregnancy-primed T cells, either pro-rejection or pro-tolerogenic, may be obscured. Indeed, Senn et al. (2021) reported that women with prior pregnancies receiving kidneys from their husband consistently had a higher rate of antibody-mediated rejection compared with women with prior pregnancies receiving kidneys from other living or deceased donors.A limited number of studies have attempted to directly quantify ex vivo donor-specific T cell responses arising during normal human pregnancy using proliferation, cytokine production, or cellular cytotoxicity as readouts. When IL-4 and IFNγ ELISPOT assays were used to quantify PBMC responses from non-pregnant versus pregnant women to paternal or pooled alloantigens, Mjosberg et al. (2007) reported that pregnancy did not result in increased paternal-specific IL-4 or IFNγ responses. Furthermore, removal of Tregs resulted in non-specific increases in IFNγ responses and paternal-specific augmentation in IL-4 production. Collectively, their study suggested an absence of pregnancy-specific sensitization of T cells, while also hinting at postpartum Tregs controlling fetus-specific IL-4 responses and broadly controlling IFNγ responses. Notably, reduced frequencies of circulating FoxP3+ Tregs were observed with spontaneous preterm birth, preeclampsia, and recurrent spontaneous miscarriages compared to healthy pregnancies suggesting a more systemic effect of Tregs (Dimova et al., 2011; Inada et al., 2015; Inada et al., 2013; Kisielewicz et al., 2010; Koucky et al., 2014; Mjosberg et al., 2010; Nadkarni et al., 2016; Schober et al., 2012; Tilburgs et al., 2008; Tsuda et al., 2018).Pregnancy-induced Tregs are critical for promoting both primary and secondary pregnancies by suppressing T cell proliferation and cytokine production not only in secondary lymphoid organs but also in the placenta (Salvany-Celades et al., 2019). Expansion of Tregs in the decidual tissue has been prostulated to suppress fetus-specific responses locally (Tilburgs et al., 2008; Erlebacher, 2013). Notably, three different Treg populations have been identified at the maternal–fetal interface: CD25HIFOXP3+, PD1HIFOXP3−IL-10+, and TIGIT+FOXP3dim Tregs. Decidual CD25HIFOXP3+ Tregs were able to suppress the proliferation and IFNγ and TNFα production by CD4+ and effector CD8+ T cells in vitro, whereas decidual PD1HI Tregs and TIGIT+ Tregs inhibited CD4+ but not effector CD8+ T cells. However, whether pregnancy-induced Tregs are most potent in the decidua or whether they can also dominantly suppress T cell responses to offspring-matched allografts in secondary lymphoid organs is currently unknown.CD8+ T cell responses to fetus-specific minor antigens have been more consistently reported to develop during pregnancy compared to CD4+ T cell responses (Linscheid and Petroff, 2013). Lissauer et al. (2012) assayed fetal-specific CD8+ cytotoxic responses using MHC-peptide dextramer multimers bearing a HY-immunodominant peptide in women pregnant with a male fetus. These CD8+ T cells expanded during pregnancy and persisted in the post-natal period in 50–62% of pregnant women. Furthermore, the fetal-specific CD8+ T cells retained their ability to proliferate, secrete IFNγ, and lyse target cells. These observations corroborated previous studies (Bouma et al., 1996; James et al., 2003; Mommaas et al., 2002; Piper et al., 2007; Verdijk et al., 2004) and suggested that fetal-specific CD8+ T cells expand during pregnancy and persist postpartum. It is tempting to speculate that preservation of fetus-CD8+ T cell responses during pregnancy, especially in the decidua, may have been evolutionarily selected to ensure the development of protective immunity for the developing fetus against viral infections, given that the fetus is haplo-identical to the mother, and thus maternal HLA-restricted CD8+ responses will recognize virally infected fetal cells (Tilburgs and Strominger, 2013; van Egmond et al., 2016). Indeed, observations that the decidua contains a higher percentage of CD8+ T cells and a lower percentage of CD4+ T cells compared with the peripheral blood is consistent with this possibility (Tilburgs et al., 2009; van Egmond et al., 2016).Potentially divergent fates of fetus-specific T cell subsets, together with a paucity of studies examining fetus-specific T cell responses in the extended postpartum period, make it difficult to definitively conclude if pregnancy-primed T cells are functionally tolerant or sensitized to fetal antigens presented in the context of a solid organ transplant. The ex vivo quantification of fetus-specific T cell responses is technically challenging and complicated by the increased frequency of pregnancy-induced Tregs (Salvany-Celades et al., 2019). Furthermore, ex vivo observations may not necessarily predict how these cells will behave in vivo after transplantation with organs sharing HLA antigens with the fetus. In vivo studies in postpartum recipients suggest that poorer outcomes are complicated by pregnancy-induced humoral sensitization (Author No. of transplants Outcome Terasaki et al. (1995) Husband-to-mother: n = 368 Comparable allograft survival between spousal donor and unrelated living donor. Pregnancy is a risk factor for loss of allograft Child-to-mother: n = 1,411 Mahanty et al. (2001) Offspring-to-mother: n = 874 Fetal tolerance did not translate to a superior allograft survival from offspring donors. Multiple pregnancy trended towards poor allograft survival Unrelated living donor to mother: n = 310 Cohen et al. (2003) Offspring-to-parent: n = 3,370 Comparable death censored 5-yr allograft survival in offspring-to-parent compared to unrelated living donor Unrelated living donor: n = 8,351 Deceased donor: n = 44,792 Miles et al. (2008) Offspring to mother: n = 3,124 Comparable and poor allograft survival in offspring-to-parent and parent-to-offspring transplants Parent to offspring: n = 6,076 Ghafari (2008) Offspring-to-mother: n = 12 Unrelated living donor allografts survival was significantly higher compared to offspring and husband donor allografts Husband-to-mother: n = 9 Unrelated living donor: n = 150 Choi et al. (2012) Offspring-to-mother: n = 49 Comparable 5- and 10-yr kidney graft survival between offspring-to-mother and offspring-to-father transplant. Mother-to-child had worse outcome Parent-to-offspring: n = 146 Redfield et al. (2016) Highly sensitized: n = 7,145 Increased graft loss by 23% among women with a history of pregnancy and transfusion compared to non-sensitized Non-sensitized: n = 100,147 Cohen et al. (2018) Offspring-to-mother: n = 1,332 Comparable allograft survival between offspring and unrelated living donor transplant to mother Unrelated living donor: n = 1,435 Dagan et al. (2020) Offspring-to-mother: n = 148 Offspring donor allograft survival lower compared to unrelated living donor Unrelated living donor: n = 93 Male offspring donor resulted in poorer survival compared to female offspring donor Senn et al. (2021) Husband-to-mother: n = 25 Poor allograft survival among mothers who received allograft from spouse compared to unrelated living donor or deceased donor Unrelated living donor: n = 52 Deceased donor: n = 120