UTY gene codes for an HLA-B60-restricted human male-specific minor histocompatibility antigen involved in stem cell graft rejection: Characterization of the critical polymorphic amino acid residues for T-cell recognition

Departments of Hematology and Immunohematology and Bloodbank, Leiden University Medical Center, Leiden, The Netherlands.
Blood (Impact Factor: 10.45). 12/2000; 96(9):3126-32.
Source: PubMed

ABSTRACT Rejection of a graft after human leukocyte antigen (HLA)-identical stem cell transplantation (SCT) can be caused by recipient's immunocompetent T lymphocytes recognizing minor histocompatibility antigens on donor stem cells. During rejection of a male stem cell graft by a female recipient, 2 male (H-Y)-specific cytotoxic T lymphocyte (CTL) clones were isolated from peripheral blood. One CTL clone recognized an HLA-A2-restricted H-Y antigen, encoded by the SMCY gene. Another CTL clone recognized an HLA-B60-restricted H-Y antigen. In this study UTY was identified as the gene coding for the HLA-B60-restricted H-Y antigen. The UTY-derived H-Y antigen was characterized as a 10-amino acid residue peptide, RESEEESVSL. Although the epitope differed by 3 amino acids from its X-homologue, UTX, only 2 polymorphisms were essential for recognition by the CTL clone HLA-B60 HY. These results illustrate that CTLs against several H-Y antigens derived from different proteins can contribute simultaneously to graft rejection after HLA-identical, sex-mismatched SCT. Moreover, RESEEESVSL-specific T cells could be isolated from a female HLA-B60+ patient with myelodysplastic syndrome who has been treated with multiple blood transfusions, but not from control healthy HLA-B60+ female donors. This may indicate that RESEEESVSL-reactive T cells are more common in sensitized patients.

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    • "This important observation indicates that certain H–Y antigens should be able to elicit responses that target leukaemic cells in the absence of significant collateral damage. However, all H–Y antigens characterized so far as targets of T cell responses are ubiquitously expressed (Wang et al, 1995; Pierce et al, 1999; Vogt et al, 2000, 2002). Moreover, mapping of the Y chromosome did not reveal any antigens with a haematopoietic-restricted expression (Skaletsky et al, 2003). "
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    ABSTRACT: Immunotherapeutic approaches that target antigens that are differentially recognized on haematopoietic and non-haematopoietic cells may specifically enhance the graft-versus-leukaemia (GVL) effect of donor lymphocyte infusion. In this study, we have characterized a new HLA-B*5201-restricted epitope of the UTY gene. Unusually, presentation of this epitope was restricted to lymphoblasts. As a result, a T cell clone specific to this epitope recognized normal and malignant male B and T lymphoblasts, while showing little reactivity towards male HLA-B*5201+ fibroblasts. Transfer of its T cell receptor (TCR) into donor T cells led to the generation of large numbers of T cells, which acquired the specificity of the original clone, its avidity and the differential pattern of reactivity towards lymphoblasts and fibroblasts. Remarkably, the specific response of TCR-transferred T cells was significantly higher than that of the original clone. This is the first demonstration of the possibility to preserve the specific pattern of a T cell response to a differentially expressed antigen after TCR-transfer and to augment the amplitude of this response concomitantly. These results indicate that it may be feasible to enhance the GVL effect of donor lymphocyte infusions in lymphoproliferative malignancies by the transfer of TCRs specific to epitopes that are differentially recognized on lymphoblasts.
    British Journal of Haematology 06/2005; 129(3):392-402. DOI:10.1111/j.1365-2141.2005.05461.x · 4.71 Impact Factor
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    ABSTRACT: Stem cell transplantation (SCT) is an accepted treatment for patients with hematological malignancies. Stem cell donor-derived T cells mediate both beneficial Graft-versus-Leukemia (GvL) effects and detrimental Graft-versus-Host Disease (GvHD). Relapse of the original disease can be treated with infusions of donor lymphocytes (DLI). Like SCT, DLI elicits both GvHD and GvL. The risk of severe GvHD is especially high if the stem cell donor and patient are not fully matched for human leukocyte antigens (HLA). To minimize GvHD after HLA-mismatched SCT DLI should consist of pre-selected donor T cells that display reactivity restricted to the patient's residual leukemic or hematopoietic cells. This thesis focuses on exploring the alloHLA-A2 T cell repertoire and testing the feasibility of generating alloHLA-A2-restricted T cells specific for the hematopoietic system-restricted minor Histocompatibility antigens (mHags) HA-1 or HA-2. We describe several new methods of alloHLA-restricted antigen-specific T cell stimulation. However, we also show that alloHLA-recognition by T cells is inherently crossreactive. Unfortunately, currently available technologies can not readily distinguish between crossreactive and antigen-specific alloHLA-restricted T cells. We therefore conclude that generation of alloHLA-restricted antigen-specific T cells is as yet not feasibible in a clinical setting.
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