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....
High expression levels of the calcium-binding proteins S100A8 and S100A9 in myeloid cells in kidney transplant rejections are associated with a favorable outcome. Here we investigated the myeloid cell subset expressing these molecules, and their function in inflammatory reactions. Different monocyte subsets were sorted from buffy coats of healthy donors and investigated for S100A8 and S100A9 expression. To characterize S100A9high and S100A9low subsets within the CD14+ classical monocyte subset, intracellular S100A9 staining was combined with flow cytometry (FACS) and qPCR profiling. Furthermore, S100A8 and S100A9 were overexpressed by transfection in primary monocyte-derived macrophages and the THP-1 macrophage cell line to investigate the functional relevance. Expression of S100A8 and S100A9 was primarily found in classical monocytes and to a much lower extent in intermediate and non-classical monocytes. All S100A9+ cells expressed human leukocyte antigen—antigen D related (HLA-DR) on their surface. A small population (<3%) of CD14+ CD11b+ CD33+ HLA-DR− cells, characterized as myeloid derived suppressor cells (MDSCs), also expressed S100A9 to high extent. Overexpression of S100A8 and S00A9 in macrophages led to enhanced extracellular reactive oxygen species (ROS) production, as well as elevated mRNA expression of anti-inflammatory IL-10. The results suggest that the calcium-binding proteins S100A8 and S100A9 in myeloid cells have an immune regulatory effect.
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