The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform

Els Goulmy - One of the best experts on this subject based on the ideXlab platform.

Stanley R Riddell - One of the best experts on this subject based on the ideXlab platform.

  • A single minor Histocompatibility Antigen encoded by UGT2B17 and presented by human leukocyte Antigen-A*2902 and -B*4403.
    Transplantation, 2007
    Co-Authors: Seitaro Terakura, Makoto Murata, Edus H Warren, Alessandro Sette, John Sidney, Tomoki Naoe, Stanley R Riddell
    Abstract:

    T-cell responses to minor Histocompatibility Antigens are mediators of graft-versus-host disease and organ graft rejection. We previously identified a human minor Histocompatibility Antigen that is recognized by CD8 cytotoxic T lymphocytes (CTLs) and encoded by the UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17) gene, which is highly expressed in the liver, colon, and small intestine. The UGT2B17 is presented by human leukocyte Antigen (HLA)-A*2902, and the immunogenicity of this minor Histocompatibility Antigen results from differential protein expression in donor and recipient cells as a consequence of a UGT2B17 gene deletion. An HLA-B*4403-restricted CD8 CTL clone was isolated from the same hematopoietic stem cell transplant recipient that exhibited an HLA-A*2902-restricted UGT2B17-specific response. The minor Histocompatibility Antigen recognized by the HLA-B*4403-restricted clone was identified, and the ability of the peptide to be presented by HLA-B*4402 was examined. The HLA-B*4403-restricted CTL clone recognized a peptide encoded by UGT2B17, which is identical to the peptide presented by HLA-A*2902. Peptide binding assays revealed this UGT2B17 peptide binds with comparable affinity to HLA-B*4402 as to HLA-B*4403. This patient had acute graft-versus-host disease involving liver and gastrointestinal tract, suggesting the T-cell response directed against UGT2B17 is involved in graft-versus-host disease. A single peptide encoded by UGT2B17 can be presented by HLA-A*2902, B*4402 and B*4403, and may serve as an immunodominant minor Histocompatibility Antigen in individuals with these HLA alleles that undergo transplantation of stem cells or organ grafts from UGT2B17 disparate donors.

  • a single minor Histocompatibility Antigen encoded by ugt2b17 and presented by human leukocyte Antigen a 2902 and b 4403
    Transplantation, 2007
    Co-Authors: Seitaro Terakura, Makoto Murata, Edus H Warren, Alessandro Sette, John Sidney, Tomoki Naoe, Stanley R Riddell
    Abstract:

    Background. T-cell responses to minor Histocompatibility Antigens are mediators of graft-versus-host disease and organ graft rejection. We previously identified a human minor Histocompatibility Antigen that is recognized by CD8+ cytotoxic T lymphocytes (CTLs) and encoded by the UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17) gene, which is highly expressed in the liver, colon, and small intestine. The UGT2B17 is presented by human leukocyte Antigen (HLA)-A*2902, and the immunogenicity of this minor Histocompatibility Antigen results from differential protein expression in donor and recipient cells as a consequence of a UGT2B17 gene deletion. Methods. An HLA-B*4403-restricted CD8+ CTL clone was isolated from the same hematopoietic stem cell transplant recipient that exhibited an HLA-A*2902-restricted UGT2B17-specific response. The minor Histocompatibility Antigen recognized by the HLA-B*4403-restricted clone was identified, and the ability of the peptide to be presented by HLA-B*4402 was examined. Results. The HLA-B*4403-restricted CTL clone recognized a peptide encoded by UGT2B17, which is identical to the peptide presented by HLA-A*2902. Peptide binding assays revealed this UGT2B17 peptide binds with comparable affinity to HLA-B*4402 as to HLA-B*4403. This patient had acute graft-versus-host disease involving liver and gastrointestinal tract, suggesting the T-cell response directed against UGT2B17 is involved in graft-versus-host disease. Conclusions. A single peptide encoded by UGT2B17 can be presented by HLA-A*2902, B*4402 and B*4403, and may serve as an immunodominant minor Histocompatibility Antigen in individuals with these HLA alleles that undergo transplantation of stem cells or organ grafts from UGT2B17 disparate donors.

  • human minor Histocompatibility Antigen specific cd8 t cells are found predominantly in the cd45ra cd62l naive t cell subset
    Blood, 2005
    Co-Authors: Marie Bleakley, Audrey Mollerup, Colette Chaney, Michele Brown, Stanley R Riddell
    Abstract:

    Graft versus host disease (GVHD) after allogeneic stem cell transplant (SCT) is initiated by the activation of alloreactive T cells by host dendritic cells (DC) in lymphoid tissue. Studies in murine models have demonstrated that selective depletion of naive T cells abrogates GVHD in major and minor Histocompatibility Antigen (miH) mismatched SCT and provides for rapid reconstitution of memory T cell responses to pathogens. This suggests the memory subset may lack a sufficient repertoire of alloreactive T cells or fail to localize to sites where GVHD is initiated. If such a strategy were effective in humans, morbidity from GVHD would be reduced, but the graft versus leukemia (GVL) effect might be compromised. To explore the potential of this approach in humans, we developed a novel limiting dilution assay using DC as stimulator cells in vitro to analyze the frequency and repertoire of human miH reactive T cells in highly purified naive and memory T cell subsets obtained from HLA identical volunteer donor pairs. For each pair, mature DC were derived by differentiation of CD14+ monocytes in vitro from one volunteer, and pure (>97%) populations of naive (CD62L+, CD45 RA+, CD45RO-) and memory (CD45RO+) CD8 T cells were obtained by FACS sorting of CD8 enriched PBMC from the respective HLA identical sibling. Memory and naive T cells were cultured for 12 days in 96 well plates at a range of concentrations with DC at a 30:1 ratio and IL12 (10 ng/ml), and IL15 (10 ng/ml) was added on day 7. On day 12, the wells were screened against target cells from each volunteer in a chromium release assay (CRA) to quantitative T cells with reactivity against miH. All wells with reactivity in this screening assay were subsequently expanded using anti CD3 antibody and IL2 and retested by CRA to validate the results of the screening assay. In multiple experiments using different HLA matched pairs, T cells with specific and reproducible cytotoxic activity (>15% lysis) against target cells from the DC donor but not autologous targets were only isolated from wells plated with naive CD8 T cells, and there was no reproducible cytotoxicity from wells plated with memory T cells. This data demonstrates that miH specific CD8 T cells are found predominantly, and possibly exclusively, in the naive T cell subset in humans. This data is consistent with a dramatically reduced repertoire of miH alloreactive T cells in the memory T cell pool and supports the development of protocols to prevent GVHD by selective depletion of CD45RA+ CD8+ T cells from the hematopoietic cell graft. However, T cells specific for miH also contribute to the GVL effect and CD45RA depletion would be expected to compromise antileukemic activity. Using the above approach for isolating miH specific CTL from naive CD8 T cells, we have found a diverse repertoire of alloreactivity in most cultures and identified a subset of T cell lines and clones specific for miH presented selectively on hematopoietic cells. These T cells recognize primary ALL and AML samples that express the restricting HLA allele in vitro. MiH specific T cell clones can be reliably generated by this method using DC derived from monocytes of patients with advanced leukemia. Thus, it may be feasible to utilize this approach to isolate T cells specific for hematopoietic restricted miH for adoptive therapy as an adjunct to CD45RA depletion to preserve the GVL effect and allow separation of GVL from GVHD.

  • CD8+ minor Histocompatibility Antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia stem cells
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Dominique Bonnet, Edus H Warren, Philip D. Greenberg, John E. Dick, Stanley R Riddell
    Abstract:

    Effective immunotherapy for human leukemia based on infusions of T lymphocytes requires the identification of effector T cells that target the leukemic stem cell. The transplantation of human acute myeloid leukemia into nonobese diabetic/severe combined immune deficient (SCID) mice has identified a rare leukemic progenitor termed the SCID leukemia-initiating cell, which is present in low frequency in the leukemic population and is essential for establishing leukemic hematopoiesis. Thus, this transplant model may be ideally suited to identify effector T cells with antileukemic activity. We report that CD8+ cytotoxic T lymphocyte (CTL) clones specific for minor Histocompatibility Antigens inhibit the engraftment of human acute myeloid leukemia cells in nonobese diabetic/SCID mice and demonstrate that this inhibition is mediated by direct CTL recognition of SCID leukemia-initiating cells. These results indicate that CD8+ minor Histocompatibility Antigen-specific CTL may be mediators of the graft-versus-leukemia effect associated with allogeneic hematopoietic cell transplantation and provide an experimental model to identify and select T cell clones for immunotherapy to prevent or treat relapse after allogeneic hematopoietic cell transplantation.

Gerd Schmitz - One of the best experts on this subject based on the ideXlab platform.

  • genomic organization of the human cholesterol responsive abc transporter abca7 tandem linkage with the minor Histocompatibility Antigen ha 1 gene
    Biochemical and Biophysical Research Communications, 2000
    Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd Schmitz
    Abstract:

    Abstract We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of ∼32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3′ gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5′ end of the coding region of the recently identified human minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of ∼48 kb size on chromosome 19p13.3.

  • Genomic organization of the human cholesterol-responsive ABC transporter ABCA7: tandem linkage with the minor Histocompatibility Antigen HA-1 gene.
    Biochemical and biophysical research communications, 2000
    Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd Schmitz
    Abstract:

    We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of approximately 32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3' gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5' end of the coding region of the recently identified human minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of approximately 48 kb size on chromosome 19p13.3.

Wolfgang E Kaminski - One of the best experts on this subject based on the ideXlab platform.

  • Homozygosity for the 168His variant of the minor Histocompatibility Antigen HA‐1 is associated with reduced risk of primary Sjögren's syndrome
    European Journal of Immunology, 2004
    Co-Authors: Mariann Harangi, Evelyn Orso, Emese Kiss, Erika Zilahi, Jörg Marienhagen, Wolfgang E Kaminski, Margit Zeher, Martin Fleck, Zoltan Szekanecz, Charalampos Aslanidis
    Abstract:

    The genes for the human ATP-binding cassette (ABC) transporter ABCA7 and the minor Histocompatibility Antigen HA-1 are juxtaposed in close proximity on chromosome 19p13.3. The multispan transmembrane protein ABCA7 contains an extracellular domain that is recognized by antisera from patients with Sjogren's syndrome (“Sjogren-epitope”). Recent work from our laboratory demonstrating the involvement of ABCA7 in cellular ceramide and phosphatidylserine export suggests a role for this transporter in programmed cell death. In HA-1, a protein of unknown function, a His/Arg polymorphism (His168Arg), which constitutes the immunologic target for HA-1-specific cytotoxic T cells, has been causatively linked to graft-versus-host disease after allogeneic stem cell transplantation. Because these findings suggest a potential implication of ABCA7 and HA-1 in immune processes, we tested the hypothesis that allelic variants in both genes are associated with autoimmune disorders. We identified a total of 31 exonic single-nucleotide polymorphisms (SNP) in the ABCA7/HA-1 gene complex, nine of which represent non-synonymous nucleotide alterations. Genotypes of ABCA7 and HA-1 SNP were determined in three distinct Caucasian populations of patients with primary Sjogren's syndrome and ethnically matched controls. Comparison of allele frequencies between these groups revealed that the incidence of the HA-1 168His allele is significantly lower in Sjogren's syndrome patients than in controls (p

  • genomic organization of the human cholesterol responsive abc transporter abca7 tandem linkage with the minor Histocompatibility Antigen ha 1 gene
    Biochemical and Biophysical Research Communications, 2000
    Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd Schmitz
    Abstract:

    Abstract We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of ∼32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3′ gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5′ end of the coding region of the recently identified human minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of ∼48 kb size on chromosome 19p13.3.

  • Genomic organization of the human cholesterol-responsive ABC transporter ABCA7: tandem linkage with the minor Histocompatibility Antigen HA-1 gene.
    Biochemical and biophysical research communications, 2000
    Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd Schmitz
    Abstract:

    We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of approximately 32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3' gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5' end of the coding region of the recently identified human minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of approximately 48 kb size on chromosome 19p13.3.

Robert Korngold - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of the immunoproteasome subunit lmp7 with onx 0914 ameliorates graft versus host disease in an mhc matched minor Histocompatibility Antigen disparate murine model
    Biology of Blood and Marrow Transplantation, 2015
    Co-Authors: Jenny Zilberberg, Jennifer Matos, Eugenia Dziopa, Leah Dziopa, Zheng Yang, Christopher J Kirk, Shahin Assefnia, Robert Korngold
    Abstract:

    Abstract In the current study we evaluated the effects of immunoproteasome inhibition using ONX 0914 (formerly PR-957) to ameliorate graft-versus-host disease (GVHD). ONX 0914, an LMP7-selective epoxyketone inhibitor of the immunoproteasome, has been shown to reduce cytokine production in activated monocytes and T cells and attenuate disease progression in mouse models of rheumatoid arthritis, colitis, systemic lupus erythematosus, and, more recently, encephalomyelitis. Inhibition of LMP7 with ONX 0914 in the B10.BR→CBA MHC-matched/minor Histocompatibility Antigen (miHA)-disparate murine blood and marrow transplant (BMT) model caused a modest but significant improvement in the survival of mice experiencing GVHD. Concomitant with these results, in vitro mixed lymphocyte cultures revealed that stimulator splenocytes, but not responder T cells, treated with ONX 0914 resulted in decreased IFN-γ production by allogeneic T cells in both MHC-disparate (B10.BR anti-B6) and miHA-mismatched (B10.BR anti-CBA) settings. In addition, a reduction in the expression of the MHC class I–restricted SIINFEKL peptide was observed in splenocytes from transgenic C57BL/6-Tg(CAG-OVA)916Jen/J mice exposed to ONX 0914. Taken together, these data support that LMP7 inhibition in the context of BMT modulates allogeneic responses by decreasing endogenous miHA presentation and that the consequential reduction in allogeneic stimulation and cytokine production reduces GVHD development.

  • a cd8 de loop peptide analog prevents graft versus host disease in a multiple minor Histocompatibility Antigen mismatched bone marrow transplantation model
    Biology of Blood and Marrow Transplantation, 2004
    Co-Authors: Swati Choksi, George F. Murphy, Thea M. Friedman, Judith C Kim, Diana Whitakermenezes, Robert Korngold
    Abstract:

    Abstract Donor CD8 + T cells can be potent mediators of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation to either major Histocompatibility complex (MHC) class I-or multiple minor Histocompatibility Antigen-mismatched recipients. To develop small molecular inhibitors of CD8 + T-cell activity, theoretical structural analysis of the human CD8α molecule was previously used to identify potential functional surface epitopes that interact with the MHC class I molecule. The DE loop (p71–78) was identified as such a target region, and a panel of synthetic cyclized peptide mimics of this region were tested for their inhibitory effects on cytotoxic T lymphocyte activity in human cell-mediated lympholysis assays. Peptide 1109 (CKRLGDTFVC) was most effective at inhibiting specific target cell lysis. Accordingly, studies were conducted to determine whether there was sufficient cross-species homology in the DE loop region and its nonpolymorphic interactive site on the β 2 -microglobulin domain of the MHC class I molecule to allow similar inhibition of murine CD8 + cytotoxic T lymphocyte activity. On the basis of strong in vitro inhibitory activity of 1109 in the murine system, the capacity of the peptide to inhibit in vivo CD8 + T-cell effector functions in skin and hematopoietic stem cell transplantation models was examined. In the C57BL/6 anti-bm1 skin allograft rejection model, across an MHC class I barrier, a single injection of 1109 at the time of transplantation significantly prolonged graft survival. Moreover, 1109 administered at the time of transplantation in the multiple minor Histocompatibility Antigen-disparate B10.BR→CBA GVHD model significantly prolonged the survival of lethally irradiated mice that underwent transplantation with donor bone marrow cells and CD8 + T cells. Histopathologic analysis confirmed that mice treated with the synthetic peptide exhibited diminution of epithelial target cell injury. Specificity of the peptide effect was evidenced by draining lymph node cells from B10.BR mice that had been challenged with CBA lymphocytes and simultaneously treated with 1109. These cells could not generate secondary proliferative responses in vitro upon stimulation with CBA splenocytes but could respond to third-party C57BL/6 stimulation. Thus, the 1109 peptide has potential application in the prevention of CD8-mediated GVHD development.

  • Importance of minor Histocompatibility Antigen expression by nonhematopoietic tissues in a CD4+ T cell–mediated graft-versus-host disease model
    The Journal of clinical investigation, 2003
    Co-Authors: Stephen C. Jones, George F. Murphy, Thea M. Friedman, Robert Korngold
    Abstract:

    Minor Histocompatibility Antigens with expression restricted to the recipient hematopoietic compartment represent prospective immunological targets for graft-versus-leukemia therapy. It remains unclear, however, whether donor T cell recognition of these hematopoietically derived minor Histocompatibility Antigens will induce significant graft-versus-host disease (GVHD). Using established bone marrow irradiation chimeras across the multiple minor Histocompatibility Antigen-disparate, C57BL/6-->BALB.B combination, we studied the occurrence of lethal GVHD mediated by CD4+ T cells in recipient mice expressing only hematopoietically derived alloAntigens. Even substantial dosages of donor C57BL/6 CD4+ T cells were unable to elicit lethal GVHD when transplanted into [BALB.B-->C57BL/6] chimeras. Instead, chimeric mice displayed transient cachexia with reduced target-tissue injury over time, reflecting an early, limited, graft-versus-host response. On the other hand, the importance of minor Histocompatibility Antigens derived from nonhematopoietic tissues was demonstrated by the finding that [C57BL/6-->BALB.B] chimeric mice succumbed to C57BL/6 CD4+ T cell-mediated GVHD. These data suggest that severe acute CD4+ T cell-mediated GVHD across this minor Histocompatibility Antigen barrier depends on the expression of nonhematopoietically rather than hematopoietically derived alloAntigens for maximal target-tissue infiltration and injury.

  • importance of minor Histocompatibility Antigen expression by nonhematopoietic tissues in a cd4 t cell mediated graft versus host disease model
    Journal of Clinical Investigation, 2003
    Co-Authors: Stephen C. Jones, George F. Murphy, Thea M. Friedman, Robert Korngold
    Abstract:

    Minor Histocompatibility Antigens with expression restricted to the recipient hematopoietic compartment represent prospective immunological targets for graft-versus-leukemia therapy. It remains unclear, however, whether donor T cell recognition of these hematopoietically derived minor Histocompatibility Antigens will induce significant graft-versus-host disease (GVHD). Using established bone marrow irradiation chimeras across the multiple minor Histocompatibility Antigen–disparate, C57BL/6→BALB.B combination, we studied the occurrence of lethal GVHD mediated by CD4+ T cells in recipient mice expressing only hematopoietically derived alloAntigens. Even substantial dosages of donor C57BL/6 CD4+ T cells were unable to elicit lethal GVHD when transplanted into [BALB.B→C57BL/6] chimeras. Instead, chimeric mice displayed transient cachexia with reduced target-tissue injury over time, reflecting an early, limited, graft-versus-host response. On the other hand, the importance of minor Histocompatibility Antigens derived from nonhematopoietic tissues was demonstrated by the finding that [C57BL/6→BALB.B] chimeric mice succumbed to C57BL/6 CD4+ T cell–mediated GVHD. These data suggest that severe acute CD4+ T cell–mediated GVHD across this minor Histocompatibility Antigen barrier depends on the expression of nonhematopoietically rather than hematopoietically derived alloAntigens for maximal target-tissue infiltration and injury.