Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1

Abstract

Umbilical cord blood transplantation is applied as treatment for mainly pediatric patients with hematologic malignancies. The clinical results show a relatively low incidence of graft-versus-host disease and leukemia relapse. Since maternal cells traffic into the fetus during pregnancy, we questioned whether cord blood has the potential to generate cytotoxic T cells specific for the hematopoietic minor histocompatibility (H) antigen HA-1 that would support the graft-versus-leukemia effect. Here, we demonstrate the feasibil- IntroductionIn the last decade, umbilical cord blood transplantation (CBT) has been available as an alternative to human leukocyte antigen (HLA)-matched sibling or unrelated donor stem cell transplantation (SCT) for the treatment of hematologic malignancies. [1][2][3][4][5][6][7] The clinical outcome of transplanted CB grafts with 1 or 2 HLA antigen mismatches demonstrates a similar risk of developing graft-versushost disease (GvHD) as compared to HLA-matched unrelated SCT. 5,6 A significant lower incidence of acute and chronic GvHD was reported after HLA-identical CBT when compared to sibling SCT. 4 Collectively, these clinical results point to a decreased incidence of GvHD after CBT.GvHD is often associated with a curative graft-versus-leukemia (GvL) response. Minor H antigen disparities between donor and recipient play important roles in both the GvH and GvL reactivity after HLA-matched SCT as reviewed. 8 One of the well-described minor H antigens is HA-1. The immunodominant minor H antigen HA-1 is encoded by a diallelic gene with a single amino acid polymorphism. 9 The HA-1 "positive" allele (HA-1 pos ) contains a histidine at position 3 (HA-1 H ), whereas the HA-1 "negative" allele (HA-1 neg ) contains an arginine (HA-1 R ). The HA-1 H peptide is recognized by HLA-A2-restricted CD8 pos cytotoxic T cells from HA-1 neg donors. [10][11][12] The expression of HA-1 is restricted to the hematopoietic lineage and to epithelial carcinomas. 13,14 This restricted expression makes HA-1 an attractive target antigen for GvL and graft-versus-tumor responses. 15 Despite the lower incidence of GvHD after CBT, there is no indication of increased leukemia relapse rates when compared with sibling or unrelated donor SCT. [3][4][5] Comparable survival rates point to an as-yet-unexplored GvL potential of cord blood. Relatively little is known about the development of antigenspecific T-cell responses around birth. 16 Mature monocytederived neonatal dendritic cells (DCs) are able to efficiently prime antigen-specific cytotoxic T cells in vitro. 17 In bulk cultures, cord blood T cells proliferate in response to alloantigen. 18 Yet the development of functional alloreactive cytotoxic T cells is impaired. [18][19][20] Limiting dilution studies have, however, reported normal precursor frequencies of cytotoxic T cells specific for allo-HLA class I and class II in cord blood. [20][21][22] Thus, the capacity to develop allogeneic cytotoxic T cells is intact at birth, despite overall diminished magnitude of responses....

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

“…3,26,27 In this study, we questioned whether, For personal use only. on April 3, 2019. by guest www.bloodjournal.org From besides T CTL , also minor H antigen-specific CD8 ϩ T REG are generated and, if so, whether both populations can be demonstrated in adult donors.…”

Umbilical cord blood transplantation: Basic biology and clinical challenges to immune reconstitution

“…UCB HLA compatibility is also predictive of engraftment [15]. Minor histocompatibility disparity in unrelated allogeneic transplantation may contribute to graft rejection and to graftversus-leukemia effects [38][39][40][41]. HLA class I mismatching including HLA-C and NK epitope mismatching are associated with higher rates of graft rejection and severe acute GVHD after unrelated donor transplantation [42,43].…”

Consideration of noninherited maternal Ags as permissible HLA mismatches in cord blood donor selection

“…4 Tolerance toward these HLA mismatched NIMA is thought to be mediated by the suppression of alloreactive cell expansion via regulatory T cells and/or the lysis of NIMA-specific targets via NIMA-specific cytotoxic T cells. 5,6 This tolerance can be exploited in CBT if the donor-recipient HLA mismatch is a match to the CB NIMA. In patients with haematological malignancies, NIMA-matched grafts were associated with a lower transplant-related mortality and improved engraftment, leading to reduced overall mortality compared with HLA mismatched, non-NIMA-matched CBT.…”