Acute graft-versus-host disease after bone marrow transplantation with a single HLA-DPB1*1001 mismatch: involvement of different TCRBV subsets

Abstract

Summary:HLA-DP incompatibility is not considered as an exclusion criterion for bone marrow donors, because such incompatibility was not shown to affect significantly the risk for acute graft-versus-host disease (GVHD). In line with this clinical observation, it was proposed that in the context of bone marrow transplantation, HLA-DP determinants did not function as transplantation antigens in the same way as HLA-A, -B or -DR. In contrast to the above conclusion, we recently demonstrated the presence of HLA-DPB1*0501 specific T cell clones in a skin biopsy of a patient who developed aGVHD after receiving a bone marrow transplant (BMT) in which the only mismatched allele in the GVHD direction was HLA-DPB1*0501. At that time, this case was unique and occurred in a relatively uncommon graft setting where the patient received purified CD34 + BM cells from an unrelated donor. In the present study, we analyzed the immunological events associated with an aGVHD which occurred in the context of a 'regular' allogeneic BMT involving a single HLA-DPB1*1001 mismatch between donor and recipient in the GVHD direction. To this end, we analyzed several amplified T cell subsets present within a T cell line derived from a skin biopsy performed at the onset of GVHD. Our results demonstrated that T cell populations belonging to the TCRBV2, TCRB6.7, TCRBV14 and TCRBV17 subsets were specific for the HLA-DPB1*1001 mismatched allele. These data strengthen and generalize our first conclusion that a single HLA-DP mismatch between donor and recipient can activate a strong T cell response in vivo and consequently challenge the notion that HLA-DP incompatibility should not be taken into account in the choice of BM donors. Moreover, they also underline the idea that HLA-DP antigens may represent an interesting immune target for future therapeutic approaches. Keywords: transplantation; HLA-DP; GVH Allogeneic bone marrow transplantation (BMT) can be successfully used to treat patients with several hematologic malignancies or severe aplastic anaemia. The major complication of this procedure is graft-versus-host disease (GVHD) with a risk of 20-50% when donor and recipient are HLA-identical siblings. 1 When no HLA-identical sibling is available (which is the case for more than 60% of patients), matched or partially mismatched unrelated donors represent an alternative source of bone marrow. 2,3 Unfortunately, the rate of GVHD and rejection appears to increase with the extent of HLA mismatch. With respect to HLA disparities, the increased risk of aGVHD associated with HLA-A, -B, -DR mismatches between donor and recipient is well established. 2 In contrast, concerning HLA-DP incompatibility, conclusions drawn from clinical statistics or biological data are apparently conflicting: although severe GVHD following HLA-DP incompatible, but otherwise HLA-identical, BMT has been reported by several groups, recent analysis of a large series of patients did not confirm that HLA-DP antigens played a significant role in the incidence of severe acute GVHD (see Re...

The degree of matching at HLA-DPB1 predicts for acute graft-versus-host disease and disease relapse following haematopoietic stem cell transplantation

“…[13][14][15][16][17][18] HLA-DP-specific T-cells have been isolated from skin biopsies at the onset of graft-versushost-disease (GvHD) in HLA-DP mismatched transplants. 19 It has also been reported that most leukaemic blasts are accessible to direct lysis by allogeneic HLA-DPspecific T cells, suggesting that these cells may also be responsible for an antileukaemic effect. 20 Although it was previously reported that DPB1 had no impact on the incidence of transplant complications, such as acute GvHD, (aGvHD), 21,22 there has since emerged evidence that HLA-DPB1 does play a role in alloreactivity following HSCT.…”

Impact of HLA-DPB1 Matching in Unrelated Allogeneic Stem Cell Transplantation: Results of Two Centers From Turkey

“…In transplant setting allogeneic HLA-DP-specific T cells have been identified in both GVHD and GVL cases. [6][7][8][9] However, the importance of this locus, as a transplantation antigen remained poorly understood. One of the reasons that this antigen has received less attention is the weak linkage disequilibrium, dependent on a recombination hot spot between the HLA-DQ and DP loci.…”

Recognition of leukemic blasts by HLA-DPB1-specific cytotoxic T cell clones: a perspective for adjuvant immunotherapy post-bone marrow transplantation

“…The HLA-DPB1*1001-specific T cell clone CTLVB2 was derived from the skin biopsy of a patient with acute GVHD after an allogeneic BMT. 20 The B lymphoblastoid cell lines used …”

“…Although increased risk of GVHD due to HLA-DPB1 incompatibility is not statistically detectable, 15,16 HLA-DP-specific T cells can be isolated from skin biopsies at the onset of GVHD each time an HLA-DP mismatch is present. [17][18][19][20] If an HLA-DP mismatch can induce an allogeneic response in vivo, it should be able to trigger both a GVH and a GVL effect (as long as leukemic cells express HLA-DP antigens). We are currently considering the use of HLA-DPB1-specific T cell clones transfected with the viral HSv-tk gene and directed against an HLA-DPB1 mismatch allele in the GVH direction (to spare regenerating hematopoiesis) in order to generate an allogeneic GVH-GVL effect in the context of a T cell-depleted BMT.…”