Minor histocompatibility antigen H-Y is expressed on human hematopoietic progenitor cells.

Voogt, P. J.; Goulmy, Els; Fibbe, W. E.; Veenhof, W. F. J.; Brand, Anneke; Falkenburg, J. H. F.

doi:10.1172/jci113697

Cited by 35 publications

(22 citation statements)

References 30 publications

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“…Since the specific lysis of these targets was low in the 54Cr release assay these results confirm the high sensitivity of the clonogenic assay as a tool for the study of cellularly defined antigens on HPC's (31). Clone S, the CD4+ CTL clone that recognizes in vitro transformed EBV-LCL from DR2 positive individuals and some (EBV negative) AML samples did not show specific growth inhibition of the leukemic-HPC and HPC's from both patients in the clonogenic assay.…”

Section: Discussionsupporting

confidence: 65%

“…The cells were washed and further cultured in RPMI plus 10% FCS (GIBCO BRL, Gaithersburg, MD). Cell-mediated inhibition of clonogenic (leukemic) progenitor cell growth (31). To determine specific reactivity of the anti-mH CTL clones with clonogenic leukemic progenitor cells (leukemic-HPC), remission bone marrow progenitor cells (remission-HPC) and donor bone marrow progenitor cells (donor-HPC) 3.l04 target cells (leukemic cells or bone marrow cells) in 0.1 ml medium consisting of Iscove's Modified Dulbecco's Medium (IMDM) plus 15% human AB serum was mixed with irradiated ( l5Gy) CTL at effector/target (E/T) ratio 1:1.…”

Section: Methodsmentioning

confidence: 99%

“…In vitro, we have demonstrated that CD8+ mH antigen specific cytotoxic T lymphocyte (CTL) clones generated from patients with GVHD after allogeneic BMT, are capable of antigen-specific lysis of freshly obtained leukemic cells, and of antigen specific growth inhibition of the clonogenic leukemic precursor cells (leukemic-HPC) from unrelated patients (21, 22). Furthermore, we have shown that CD8+ mH antigen specific CTL clones can recognize mH antigens on hematopoietic progenitor cells (HPC) (23)(24)(25). Recently, we have demonstrated that mH antigen specific CD4+ CTL clones could be generated from a patient with chronic myeloid leukemia (CML) with acute GVHD grade HI-IV after allogeneic BMT (Faber, L.M., S.A.P.…”

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Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes.

Faber¹,

Hoeven²,

Goulmy³

et al. 1995

J. Clin. Invest.

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IntroductionWe investigated whether minor histocompatibility (mH) Allogeneic bone marrow transplantation (BMT)' has been associated with an immune-mediated anti-leukemic effect, the graftversus-leukemia (GVL) effect. T lymphocytes from the donor marrow graft may be responsible for this GVL effect since T cell depletion of the graft is correlated with an increased risk of leukemic relapse after BMT (1-6). Since a correlation has been found between the occurrence of GVHD with a decreased risk of leukemic relapse after BMT (2, 4, 7-12) it is hypothesized that the donor-derived T lymphocytes that cause GVHD may also be the mediators of the GVL reactivity. More recently, direct clinical evidence for a GVL effect has been demonstrated by several investigators (13-15). Hematological and cytogenetic remissions after leukocyte transfusion from the original marrow donor for Philadelphia-positive patients with chronic myeloid leukemia (CML) who relapsed after allogeneic BMT have been reported. In the etiology of both GVL and GVHD minor histocompatibility (mH) antigens may play an important role (16-20). In vitro, we have demonstrated that CD8+ mH antigen specific cytotoxic T lymphocyte (CTL) clones generated from patients with GVHD after allogeneic BMT, are capable of antigen-specific lysis of freshly obtained leukemic cells, and of antigen specific growth inhibition of the clonogenic leukemic precursor cells (leukemic-HPC) from unrelated patients (21, 22). Furthermore, we have shown that CD8+ mH antigen specific CTL clones can recognize mH antigens on hematopoietic progenitor cells (HPC) (23)(24)(25). Recently, we have demonstrated that mH antigen specific CD4+ CTL clones could be generated from a patient with chronic myeloid leukemia (CML) with acute GVHD grade HI-IV after allogeneic BMT (Faber, L.M., S.A.P. van Luxemburg-Heijs, W.F.J. Veenhof, R. Willemze, and J.H.F. Falkenburg, manuscript submitted for publication). As previously illustrated, some mH-specific CTL clones recognize both hematopoietic and non-hematopoietic cells, whereas other reactivities appear to be restricted to cell types of hematopoietic origin (26). In this study we investigated whether mH antigen specific CD8+ or CD4+ CTL clones generated from patients with GVHD differentially recognize leukemic-HPC from patients with AML or CML and normal HPC from their HLA genotypically identical sibling donor. Furthermore, we evaluated whether these mH specific CTL clones can discriminate between leukemic-HPC and the remission progenitor bone marrow cells (remission-HPC), within the same patient with AML. We demonstrate that although in general these CD8+ and CD4+ mH antigen specific CTL clones do not differentially recognize leukemic-HPC and normal HPC, differences in susceptibility to lysis of malignant versus normal cells can be observed suggesting that in some patients this may result in a specific GVL effect.Recognition of Leukemic and Normal Cells by mH-specific T Cells 877 J. Clin. Invest.

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Section: Discussionsupporting

confidence: 65%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes.

Faber¹,

Hoeven²,

Goulmy³

et al. 1995

J. Clin. Invest.

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“…40,41 A small subset of ϳ 15 Y chromosome-specific genes, however, are expressed both within the testis and in a broad range of other tissues, 42 including both normal hematopoietic progenitor cells, 43 mature blood cells, and malignant blood cells. When expressed outside the immunologic sanctuary of the testis, the products of several of these genes are potently immunogenic and can elicit both CD8 ؉ and CD4 ؉ male-specific T-cell responses in MHC-matched but sex-mismatched donor/recipient pairs.…”

Section: H-y-specific Immune Responses In Sex-mismatched Hctmentioning

confidence: 99%

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT

Warren

Zhang

et al. 2012

Blood

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The outcome of allogeneic hematopoietic cell transplantation is influenced by donor/recipient genetic disparity at loci both inside and outside the MHC on chromosome 6p. Although disparity at loci within the MHC is the most important risk factor for the development of severe GVHD, disparity at loci outside the MHC that encode minor histocompatibility (H) antigens can elicit GVHD and GVL activity in donor/recipient pairs who are otherwise genetically identical across the MHC. Minor H antigens are created by sequence and structural variations within the genome. The enormous variation that characterizes the human genome suggests that the total number of minor H loci is probably large and ensures that all donor/ recipient pairs, despite selection for identity at the MHC, will be mismatched for many minor H antigens. In addition to mismatch at minor H loci, unrelated donor/ recipient pairs exhibit genetic disparity at numerous loci within the MHC, particularly HLA-DP, despite selection for identity at HLA-A, -B, -C, and -DRB1. Disparity at HLA-DP exists in 80% of unrelated pairs and clearly influences the outcome of unrelated hematopoietic cell transplantation; the magnitude of this effect probably exceeds that associated with disparity at any locus outside the MHC. (Blood. 2012;120(14):2796-2806) IntroductionGenetic nonidentity between donor and recipient is the key to the therapeutic efficacy of allogeneic hematopoietic cell transplantation (HCT) for malignant disease, but it is also the root of GVHD, its primary limitation. Pioneering studies in the late 1960s and early 1970s led to the critical discovery that donor/recipient genetic nonidentity at the MHC on chromosome 6p is the single most important risk factor for the development of severe GVHD. 1 The subsequent implementation of donor selection procedures according to donor/recipient MHC matching established with serologic assays and mixed lymphocyte culture revolutionized the nascent field of allogeneic marrow transplantation and enabled rapid growth during the subsequent decade in the annual number of transplantations performed, as well as considerable improvement in the likelihood of a successful transplantation outcome. Nonetheless, clinically significant GVHD still developed in a sizeable fraction of recipients of bone marrow grafts from sibling donors with whom they were genotypically identical throughout the MHC region on both copies of chromosome 6p. This observation suggested that genetic loci outside the MHC, encoding putative histocompatibility determinants that were collectively referred to as minor histocompatibility (H) antigens, could also influence a recipient's likelihood of developing GVHD or benefitting from GVL activity. 1,2 The intervening years have witnessed steady progress in elucidating the nature of minor H antigens and the genes that encode them and have seen the identification and characterization of other complex genetic loci that also influence histocompatibility in the allogeneic HCT setting. Here, we review the manner in which g...

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“…As RBCs are anucleate cells, one would not predict Smcy or Uty to be present in RBCs; indeed, the male antigens have not been detected in mature RBCs. 32,33 We used this system to assess whether the extent of leukoreduction was sufficient to prevent BMT rejection to an mHA present on leukocytes but not RBCs.…”

Section: Leukoreduction Prevents Bmt Rejection Induced By Hy Mha-mismmentioning

confidence: 99%

Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model

Desmarets

Cadwell

Peterson

et al. 2009

Blood

111

173

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When successful, human leukocyte antigen (HLA)-matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex-matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8 ؉ T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion.

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Minor histocompatibility antigen H-Y is expressed on human hematopoietic progenitor cells.

Abstract: Polymorphic minor transplantation antigens probably play an

Cited by 35 publications

References 30 publications

Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes.

Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes.

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT

Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model

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