Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Minor histocompatibility antigens (mHags) can induce T-cell reactivities with important consequences for the graft-versus-leukemia effect and the development of graft-versus-host disease in HLA-matched stem cell transplantation settings. Recently, mHag-specific T cells were also demonstrated in multiparous woman and in solid organ transplant recipients. Microchimeric cells have been detected in the latter settings. To study whether microchimerism is instrumental in the induction and/or maintenance of mHag T cells, we developed an HA-1 allele-specific nested polymerase chain reaction. To optimize and validate the reliability of this method at different levels of microchimerism, serial dilutions of HA-1(H) cells titrated into HA-1(R) cells were tested. We demonstrated that the HA-1(H) allele can be reliably and consistently detected at concentrations as low as 1:10(5) without losing specificity. The developed HA-1-specific nested polymerase chain reaction is an important tool that facilitates the detection of HA-1 microchimerism in various clinical specimens and that promotes investigation of the effects of microchimerism on induction of mHag-specific T cells in the various settings of immunization.
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PMID:Detection of microchimerism by minor histocompatibility antigen HA-1 allele-specific nested polymerase chain reaction. 1584 87

Cytotoxic T lymphocyte (CTL) lines specific for allogeneic antigens were generated by in vitro stimulation of donor-derived peripheral blood mononuclear cells obtained from patients who received human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplantation (HSCT). One of the allogeneic antigen-specific CD4+ CTL lines, CTL-A, generated from a patient with T cell acute lymphoblastic leukaemia, recognised HLA-DPB1*0501-positive Epstein-Barr virus-immortalised human B cell line (EBV-B cells), phytohaemagglutinin blasts and leukaemia cells, but not interferon-gamma (IFN-gamma) treated HLA-DPB1*0501-positive fibroblasts, indicating that this CD4+ T-cell line recognised a minor histocompatibility antigen (mHa) that is preferentially expressed in haematopoietic cells in an HLA-DPB1*0501-restricted manner. The other CD4+ CTL line, CTL-B, generated from a patient with chronic myeloid leukaemia, recognised mismatched HLA-DQB1*0303 on EBV-B cells and phytohaemagglutinin (PHA) blasts. Interestingly, this CTL line did not recognise IFN-gamma-treated recipient's skin fibroblasts, as HLA-DQ was merely upregulated even after IFN-gamma stimulation in non-haematopoietic cells including fibroblasts, endothelial cells and hepatocytes. These results suggest that these CD4 positive CTLs, specific for mismatch HLA-DQ and mHa that are preferentially expressed on haematopoietic cells, may play an important role in induction of selective graft-versus-leukaemia effect without development of graft-versus-host disease after allogeneic HSCT.
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PMID:Possible involvement of allogeneic antigens recognised by donor-derived CD4 cytotoxic T cells in selective GVL effects after stem cell transplantation of patients with haematological malignancy. 1637 Oct 20

Characterization of the antigens recognized by tumor-reactive T cells isolated from patients successfully treated with allogeneic HLA-matched hematopoietic stem cell transplantation (SCT) can lead to the identification of clinically relevant target molecules. We isolated tumor-reactive cytotoxic CD8(+) T-cell (CTL) clones from a patient successfully treated with donor lymphocyte infusion for relapsed multiple myeloma after allogeneic HLA-matched SCT. Using cDNA expression cloning, the target molecule of an HLA-B7-restricted CTL clone was identified. The CTL clone recognized a minor histocompatibility antigen produced by a single nucleotide polymorphism (SNP) in the angiogenic endothelial-cell growth factor-1 (ECGF1) gene also known as thymidine phosphorylase. The SNP leads to an Arg-to-His substitution in an alternatively translated peptide that is recognized by the CTL. The ECGF1 gene is predominantly expressed in hematopoietic cells, although low expression can also be detected in other tissues. The patient from whom this CTL clone was isolated had mild graft-versus-host disease despite high numbers of circulating ECGF-1-specific T cells as detected by tetramer staining. Because solid tumors expressing ECGF-1 could also be lysed by the CTL, ECGF-1 is an interesting target for immunotherapy of both hematologic and solid tumors.
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PMID:Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer. 1649 72

Minor histocompatibility antigens (mHAg) induce major histocompatibility complex-restricted, T cell-mediated immune responses that may contribute to increased risk of graft-versus-host disease and graft-versus-leukemia effects. Unlike human leukocyte antigen genes, mHAg are encoded by genetically and functionally unrelated genes located throughout the chromosome. The role of mHAg in stem cell transplantation and the population frequencies of mHAg alleles remain unknown due in part to the lack of suitable high throughput methods for genotyping these diverse genes. Here we describe the development and utility of a multiplexed Luminex assay for genotyping human mHAg, including HA-1, HA-2, HA-3, HA-8, HB-1, CD31(125), and CD31(563). The assay uses a multiplexed, allele-independent, gated amplification of mHAg genes followed by differential detection of allele-specific primer extension products using the MultiCode PLx system (EraGen Biosciences, Madison, WI). The alleles are interrogated using a multiplex allele-specific primer extension reaction using primers tagged with EraCodes. The products are hybridized to Luminex beads and the hybridization duplexes are detected using streptavidin-phycoerythrin. The assay resolved the mHAg genotypes of 259 Caucasian donors and provided population estimates of mHAg gene and phenotypic frequencies. All mHAg alleles evaluated in this study exhibited Hardy-Weinberg equilibrium, although some mHAg phenotypes were present in large majority of individuals tested (HA-2, HB-1). This assay will provide a valuable tool for determining mHAg frequencies in other ethnic populations, as well as for establishing the clinical importance of mHAg disparities in stem cell transplantation.
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PMID:Multiplex genotyping of human minor histocompatibility antigens. 1657 18

Enhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen-mismatched alloHSCT (DBA/2-->BALB/c: H-2(d)) recipients, alloMHC gene (H-2K(b)) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2K(b) gene transfer provides only a limited antitumor effect after syngeneic (BALB/c-->BALB/c) HSCT. By contrast, the H-2K(b) gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2K(b) gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.
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PMID:Allogeneic MHC gene transfer enhances antitumor activity of allogeneic hematopoietic stem cell transplantation without exacerbating graft-versus-host disease. 1660 36

The graft-versus-leukemia effect of allogeneic stem-cell transplantation is believed to be mediated by T-cell recognition of minor histocompatibility antigens on recipient cells. For minor histocompatibility antigens HA-1 and HA-2, normal cell expression is restricted to hemopoietic cells, and boosting the immune response to these antigens may potentiate graft-versus-leukemia effect without accompanying graft-versus-host disease. To increase efficacy, expansion of HA-1- or HA-2-specific CTL before transplantation is desirable. However, primary HA-1- or HA-2-specific CTL expanded in vitro are often of low avidity. An alternative approach is to prime specific CTL responses in vivo by vaccination. Clearly, donor vaccination must be safe and specific. We have developed DNA fusion vaccines able to induce high levels of epitope-specific CTL using linked CD4(+) T-cell help. The vaccines incorporate a domain of tetanus toxin (DOM) fused to a sequence encoding a candidate MHC class I binding peptide. This design generates antitumor CD8(+) T-cell responses and protective immunity in preclinical models. For clinical application, we constructed vaccines encoding HLA-A*0201-restricted peptides from human HA-1 and HA-2, which were fused to DOM, and tested their performance in HLA-A*0201-transgenic mice. Priming induced epitope-specific, IFNgamma-producing CD8(+) T cells with cytotoxic function boosted to high levels with electroporation. Strikingly, these mouse T cells efficiently killed human lymphoblastoid cell lines expressing endogenous HA-1 or HA-2. High avidity is indicated by the independence of cytolysis from CD8/MHC class I interaction. These safe epitope-specific vaccines offer a potential strategy to prime HA-1- or HA-2-specific CTL in transplant donors before adoptive transfer.
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PMID:DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens. 1670 72

Reduced intensity conditioning (RIC) prior to allogeneic hematopoietic cell transplantation (HCT) has shown promise in lowering the incidence of post-transplant complications including infection and graft-versus-host disease. T-cell-mediated graft rejection, however, remains a crucial factor in determining how 'mild' a level of immunosuppression can be administered. Understanding the kinetics of resistance responses as well as the role of CD4+ and CD8+ T cells underlies the development of protocols to circumvent resistance and support hematopoietic engraftment. In these studies, a major histocompatibility complex (MHC)-matched/minor histocompatibility antigen (MiHA) disparate RIC HCT model was developed in which resistance against donor hematopoietic progenitors as well as mature peripheral blood cells could be assessed. Interestingly, resistance was diminished in the absence of either host CD4+ or CD8+ T cells. However, its impairment was more severe in CD4-/- mice where resistance was not detected. Host CD4+ T cells were required for optimal expansion of specific (H60) T-cell receptor (TCR) expressing host anti-donor MiHA reactive CD8+ T cells following HCT. These observations demonstrate a critical role for host CD4+ T cells in resistance against MiHA disparate HCT. This RIC HCT resistance model will be useful for the analysis of the barrier to engraftment mediated by host T cells and the development of strategies to support engraftment.
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PMID:MiHA reactive CD4 and CD8 T-cells effect resistance to hematopoietic engraftment following reduced intensity conditioning. 1679 24

We determined the alleles of five polymorphic molecules including HA-1 and four adhesion molecules for 106 patients transplanted with HLA-identical stem cell grafts and investigated the association of mismatches as correlates of relapse and graft-versus-host disease (GVHD). All 106 recipients underwent stem cell transplantation (SCT) after myeloablative conditioning between 1985 and 2002. Risk status of disease at SCT was standard (n=63) and high (n=42). After SCT, 36, 49 and 33 developed acute GVHD, chronic GVHD and relapsed, respectively. Our patients relapsed at rates of 16.7 and 38.6% with one or more and without incompatibilities (P=0.013). The relapse rates of patients with CD62L, CD31 codon 563, CD31 codon 125, HA-1 and CD49b incompatibilities were 5.9, 11.8, 15.4, 16.0 and 33.3%, respectively. The frequency of acute GVHD did not differ regardless of incompatibilities. In standard-risk group, the accumulated relapse rates of 19 and 44 patients with and without minor histocompatibility antigen incompatibility were 22% and unexpectedly 66%, respectively (P=0.02). The probability of 12-year survival was 88% in the former and 66% in the latter patients (P=0.03). Our data suggest that incompatibility of CD62L, CD31 codon 563 and CD31 codon 125 contributes to a graft-versus-leukemia effect rather than to GVHD, resulting in prolonged survival after HLA-identical SCT.
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PMID:Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. 1698 Sep 88

Graft-versus-host disease (GvHD) is the main complication after haematopoietic stem cells transplantation (HSCT) and acute forms (aGvHD) occur in 20-40% of cases even after donor (D) and recipient (R) HLA matching, apparently because of D/R minor histocompatibility antigen (mHA) mismatches and cytokine polymorphisms. The genotype of cytokines and mHA of 77 haematological R following HSCT from HLA identical siblings were determined to detect genetic polymorphisms correlated with GvHD. We analysed TNFA (-863 C/A, -857 C/T and G/A at positions -574, -376, -308, -244, -238), IL-10 (-1082 G/A, -819 C/A, -592 C/T), IL-1B (T/C +3953), IL-1RA (VNTR), HA-1 (H/R allele) and CD-31 (C/G at codon 125, A/G at codon 563). Allele frequencies were in Hardy-Weinberg equilibrium and similar to those of 77 healthy controls. We observed positive correlations between a lower risk of clinically significant aGvHD and both the presence of -1082G -819C -592C IL-10 haplotype when both R and D are considered together and the absence of R IL-1RA allele 2. Furthermore, we observed an association between the absence of TNF-A -238 A allele and the risk of extensive chronic GvHD. mHA and cytokines genotyping would thus seem a valid source of information for the prior identification of recipients with a higher risk of aGvHD.
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PMID:Role of non-HLA genetic polymorphisms in graft-versus-host disease after haematopoietic stem cell transplantation. 1698 83

The immune environment present after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to the control of leukemia. Our laboratory has demonstrated in a murine model that vaccination of recipients after transplantation with recipient tumor vaccines does not exacerbate graft-versus-host disease but does induce meaningful graft-versus-tumor effects. We previously demonstrated that part of the reason for the lack of graft-versus-host disease from post-transplantation vaccination is due to gradual acquisition of tolerance or unresponsiveness to recipient immunodominant minor histocompatibility antigens that are ubiquitously expressed in the recipient. However, our prior studies have not critically addressed the question of whether a similar process of acquisition of unresponsiveness to or tolerance of antigens present on minimal residual disease also occurs. The present study tested the hypothesis that unresponsiveness to antigens present on minimal residual disease present at the time of HSCT would also occur. The answer to this question would have a significant effect on the potential efficacy of post-transplantation tumor vaccines. In a murine model of major histocompatibility complex matched, minor histocompatibility antigen mismatched HSCT (C3.SW female donors and C57BL/6 female recipients), we tested whether transplant recipients would acquire unresponsiveness to antigens present on small numbers of residual leukemia/lymphoma cells. We employed a male C57BL/6 lymphoid malignancy with an immunoglobulin/c-myc oncogene in these studies using as a model of tumor-restricted antigen the well-characterized male (HY) antigen system present only on the tumor but not present as ubiquitous minor antigens in the recipient. After HSCT, recipients did not mount immune responses to the ubiquitously distributed immunodominant recipient strain H7 minor histocompatibility antigen, but did retain the capacity to mount significant T cell responses to HY antigens present on small numbers of HY+ tumor cells present at transplantation. Additional studies using small numbers of nonmalignant recipient male B cells or dendritic cells as models of minimal residual disease also demonstrated that the transplant recipients retained their capacity to mount anti-HY T cell responses. After HSCT, recipients may retain the capacity to mount effective T cell responses to antigens present on minimal residual disease and still acquire relative tolerance to ubiquitously distributed immunodominant minor antigens that are related to graft-versus-host disease.
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PMID:Hematopoietic stem cell recipients do not develop post-transplantation immune tolerance to antigens present on minimal residual disease. 1722 51


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