Type 1 diabetes is characterized by T-cell infiltration of the islets of Langerhans and abundant HLA class II molecule expression on islet endothelial cells (ECs).The specificity of infiltrating T-cells for islet autoantigens has been amply demonstrated in animal models, and is implicit in human diabetes, but the processes regulating endothelial transmigration of islet autoantigen-specific T-cells into islets are not known. We examined the ability of ECs expressing HLA class II molecules to process and present the islet autoantigen GAD65 and examined the effects of presentation on transmigration of GAD65-specific T-cells. Primary cultures of human vascular ECs expressing the DRB1*0401 (VEC1) and DRB1*0301 (VEC2) genotypes were established and de novo expression of HLA class II molecules induced with interferon-␥. Under these conditions, VEC1 efficiently processed and presented whole GAD65 to the HLA-DR4 -restricted murine T-cell hybridoma T33.1 that recognizes the 274-286 epitope of GAD65. Using a transwell system, we examined the effect of GAD65 presentation on migration of GAD65-specific T-cells across EC monolayers. Migration of T33.1 hybridoma cells and of the human T-cell clone, PM1#11 (recognizes GAD65 epitope 339-352 presented by HLA-DR3) across VEC1 and VEC2, respectively, were greatly enhanced in the presence of GAD65, commencing more rapidly and achieving a higher peak migration at 3 h. Migrated PM1#11 cells retained full proliferative capacity. These results support the hypothesis that presentation of autoantigens by islet endothelium in vivo could promote transmigration of circulating islet autoantigen-specific T-cells primed in regional lymph nodes against islet autoantigens. Diabetes 52:717-725, 2003
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....
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