Pregnancy-induced humoral sensitization overrides T cell tolerance to fetus-matched allografts in mice

Suah, Ashley; Tran, Dong-Kha V.; Khiew, Stella H.W.; Andrade, Michael S.; Pollard, Jared M.; Jain, Dharmendra; Young, James S.; Yin, Dengping; Chalasani, Geetha; Alegre, Maria‐Luisa; Chong, Anita S.

doi:10.1172/jci140715

Cited by 32 publications

(29 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A 2021 study from Chong's group found that pregnancy induces a tolerogenic cellular response to paternal‐derived fetal antigens but a sensitized humoral response in a mouse model of pregnancy allosensitization 54 . As shown previously, most allospecific T cells generated during pregnancy were regulatory, and the conventional T cells that did develop had an anergic phenotype and were incapable of IFNγ production 55,56 .…”

Section: Humoral Allosensitizationmentioning

confidence: 86%

Plasma cell biology: Foundations for targeted therapeutic development in transplantation

Rossi

Alloway

Hildeman

et al. 2021

Immunological Reviews

View full text Add to dashboard Cite

Solid organ transplantation is a life‐saving procedure for patients with end‐stage organ disease. Over the past 70 years, tremendous progress has been made in solid organ transplantation, particularly in T‐cell‐targeted immunosuppression and organ allocation systems. However, humoral alloimmune responses remain a major challenge to progress. Patients with preexisting antibodies to human leukocyte antigen (HLA) are at significant disadvantages in regard to receiving a well‐matched organ, moreover, those who develop anti‐HLA antibodies after transplantation face a significant foreshortening of renal allograft survival. Historical therapies to desensitize patients prior to transplantation or to treat posttransplant AMR have had limited effectiveness, likely because they do not significantly reduce antibody levels, as plasma cells, the source of antibody production, remain largely unaffected. Herein, we will discuss the significance of plasma cells in transplantation, aspects of their biology as potential therapeutic targets, clinical challenges in developing strategies to target plasma cells in transplantation, and lastly, novel approaches that have potential to advance the field.

show abstract

Section: Humoral Allosensitizationmentioning

confidence: 86%

Plasma cell biology: Foundations for targeted therapeutic development in transplantation

Rossi

Alloway

Hildeman

et al. 2021

Immunological Reviews

View full text Add to dashboard Cite

show abstract

“…The association between the presence and avidity of anti-HLA antibodies during pregnancy, and pregnancy complications including preeclampsia and spontaneous preterm delivery are also highlighted in recent studies (60,61), but with somewhat discordant impacts on maternal serological responsiveness to fetal antigen stimulation in subsequent pregnancies (62). While these results suggest pregnancy-induced humoral B cell sensitization works in opposition to T cell tolerance, with discordant impacts on fetal-matched tissue organ allografts, being able to stratify the relative roles of B and T cells also opens up the exciting possibility for targeting individual immune components for enforcing fetal tolerance (63).…”

Section: Maternal Innate and Adaptive Immune Cells With Fetal Specificitymentioning

confidence: 94%

Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory

et al. 2021

View full text Add to dashboard Cite

In the fifteen minutes it takes to read this short commentary, more than 400 babies will have been born too early, another 300 expecting mothers will develop preeclampsia, and 75 unborn third trimester fetuses will have died in utero (stillbirth). Given the lack of meaningful progress in understanding the physiological changes that occur to allow a healthy, full term pregnancy, it is perhaps not surprising that effective therapies against these great obstetrical syndromes that include prematurity, preeclampsia, and stillbirth remain elusive. Meanwhile, pregnancy complications remain the leading cause of infant and childhood mortality under age five. Does it have to be this way? What more can we collectively, as a biomedical community, or individually, as clinicians who care for women and newborn babies at high risk for pregnancy complications, do to protect individuals in these extremely vulnerable developmental windows? The problem of pregnancy complications and neonatal mortality is extraordinarily complex, with multiple unique, but complementary perspectives from scientific, epidemiological and public health viewpoints. Herein, we discuss the epidemiology of pregnancy complications, focusing on how the outcome of prior pregnancy impacts the risk of complication in the next pregnancy — and how the fundamental immunological principle of memory may promote this adaptive response.

show abstract

“…It is indeed now well established in both mice and humans that conceptus-derived cells, proteins, exosomes, RNA, and DNA disseminate broadly in the maternal circulation and can deposit in maternal tissues (31)(32)(33)(34)(35)(36). Importantly, disseminated protein antigens are detectable in the maternal spleen and other secondary lymphoid organs in mouse models of pregnancy ( 37) where these antigens can prime both maternal T cells (37)(38)(39)(40)(41)(42)(43)(44)(45) and B cells (46). Although fetal microchimerism clearly occurs, resulting in seeding of maternal tissues that may persist for decades, its impact on humoral immunity remains undefined (32,36).…”

Section: Overview Of the Anatomy Of Pregnancy Sensitization And The Availability Of Fetal Alloantigenmentioning

confidence: 99%

“…Some activated B cells do not enter the germinal center reaction and instead proliferate and differentiate via an extrafollicular pathway. Recent work utilizing a semiallogeneic mouse model of pregnancy suggests that the maternal B cell response to fetal antigens may proceed in a fashion independent of the germinal center, which may implicate the extrafollicular pathway in the development of maternal sensitization (46). In an excellent review, Elsner et al distinguish between canonical B cell responses, in which a brief extrafollicular phase precedes the germinal center response, and non-canonical ones, which have extended extrafollicular phases (86).…”

Section: Extrafollicular Responsesmentioning

confidence: 99%

“…Murine models of pregnancy and allotransplantation have been used to overcome some of these limitations, and mouse investigations have thus revealed several insights into the origins and functions of alloreactive B cells ( 46 , 115 ). Pertinent to this review, a recent study used peptide:MHC tetramers to examine alloreactive T and B cells concordantly in mice alloimmunized by either pregnancy or transplantation.…”

Section: Hla-reactive B Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Memory B Cells in Pregnancy Sensitization

2021

View full text Add to dashboard Cite

Memory B cells play an important role in immunity to pathogens as these cells are poised to rapidly differentiate into antibody-secreting cells upon antigen re-encounter. Memory B cells also develop over the course of HLA-sensitization during pregnancy and transplantation. In this review, we discuss the potential contribution of memory B cells to pregnancy sensitization as well as the impact of these cells on transplant candidacy and outcomes. We start by summarizing how B cell subsets are altered in pregnancy and discuss what is known about HLA-specific B cell responses given our current understanding of fetal antigen availability in maternal secondary lymphoid tissues. We then review the molecular mechanisms governing the generation and maintenance of memory B cells during infection – including the role of T follicular helper cells - and discuss the experimental evidence for the development of these cells during pregnancy. Finally, we discuss how memory B cells impact access to transplantation and transplant outcomes for a range of transplant recipients.

show abstract

Pregnancy-induced humoral sensitization overrides T cell tolerance to fetus-matched allografts in mice

Cited by 32 publications

References 63 publications

Plasma cell biology: Foundations for targeted therapeutic development in transplantation

Plasma cell biology: Foundations for targeted therapeutic development in transplantation

Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory

Memory B Cells in Pregnancy Sensitization

Contact Info

Product

Resources

About