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Eric Spierings - One of the best experts on this subject based on the ideXlab platform.
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minor Histocompatibility Antigens past present and future
Tissue Antigens, 2014Co-Authors: Eric SpieringsAbstract:Minor Histocompatibility (H) Antigens are key molecules driving allo-immune responses in botH graft-versus-Host-disease (GvHD) and in graft-versus-leukemia (GvL) reactivity in Human leukocyte Antigen (HLA)-matcHed Hematopoietic stem-cell transplantation (HSCT). Dissection of tHe dual function of minor H Antigens became evident tHrougH tHeir different modes of tissue and cell expression, i.e. Hematopoietic system-restricted or broad. Broadly expressed minor H Antigens can cause botH GvHD and GvL effects, wHile Hematopoietic system-restricted minor H Antigens are more prone to induce GvL responses. THis pHenomenon renders tHe latter group of minor H Antigens as curative tools for HSCT-based immunotHerapy of Hematological malignancies and disorders, in wHicH minor H Antigen-specific responses are enHanced in order to eradicate tHe malignant cells. THis article describes tHe immunogenetics of minor H Antigens and metHods tHat Have been developed to identify tHem. Moreover, it summarizes tHe clinical relevance of minor H Antigens in transplantation, witH special regards to allogeneic HSCT and solid-organ transplantation.
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pHenotype frequencies of autosomal minor Histocompatibility Antigens display significant differences among populations
PLOS Genetics, 2007Co-Authors: Eric Spierings, Matthijs Hendriks, L Absi, Angelica Canossi, Sonal U Chhaya, John Crowley, Harry Dolstra, Jean Francois Eliaou, Thomas M Ellis, Jurgen EnczmannAbstract:Minor Histocompatibility (H) Antigens are allogeneic target molecules Having significant roles in alloimmune responses after Human leukocyte Antigen-matcHed solid organ and stem cell transplantation (SCT). Minor H Antigens are instrumental in tHe processes of transplant rejection, graft-versus-Host disease, and in tHe curative graft-versus-tumor effect of SCT. THe latter cHaracteristic enabled tHe current application of selected minor H Antigens in clinical immunotHerapeutic SCT protocols. No information exists on tHe global pHenotypic distribution of tHe currently identified minor H Antigens. THerefore, an estimation of tHeir overall impact in Human leukocyte Antigen-matcHed solid organ and SCT in tHe major etHnic populations is still lacking. For tHe first time, a worldwide pHenotype frequency analysis of ten autosomal minor H Antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major etHnic populations. Significant differences in minor H Antigen frequencies were observed between tHe etHnic populations, some of wHicH appeared to be geograpHically correlated.
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a uniform genomic minor Histocompatibility Antigen typing metHodology and database designed to facilitate clinical applications
PLOS ONE, 2006Co-Authors: Eric Spierings, Jos J M Drabbels, Matthijs Hendriks, Jos Pool, Marijke J Spruytgerritse, Frans H J ClaasAbstract:Background. Minor Histocompatibility (H) Antigen mismatcHes significantly influence tHe outcome of HLA-matcHed allogeneic stem cell transplantation. THe molecular identification of Human H Antigens is increasing rapidly. In parallel, clinical application of minor H Antigen typing Has gained interest. So far, relevant and simple tools to analyze tHe minor H Antigens in a quick and reliable way are lacking. MetHodology and Findings. We developed a uniform PCR witH sequence-specific primers (PCR-SSP) for 10 different autosomal minor H Antigens and H-Y. THis genomic minor H Antigen typing metHodology allows easy incorporation in tHe routine HLA typing procedures. DNA from previously typed EBV-LCL was used to validate tHe metHodology. To facilitate easy interpretation for clinical purposes, a minor H database named dbMinor (Http://www.lumc.nl/ dbminor) was developed. Input of tHe minor H Antigen typing results subsequently provides all relevant information for a given patient/donor pair and additional information on tHe putative graft-versus-Host, graft-versus-tumor and Host-versus-graft reactivities. Significance. A simple, uniform and rapid metHodology was developed enabling determination of minor H Antigen genotypes of all currently identified minor H Antigens. A dbMinor database was developed to interpret tHe genomic typing for its potential clinical relevance. THe combination of tHe minor H Antigen genomic typing metHodology witH tHe online dbMinor database and applications facilitates tHe clinical application of minor H Antigens anti-tumor targets after stem cell transplantation.
Edus H Warren - One of the best experts on this subject based on the ideXlab platform.
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leukemia associated minor Histocompatibility Antigen discovery using t cell clones isolated by in vitro stimulation of naive cd8 t cells
Blood, 2010Co-Authors: Edus H Warren, Marie Bleakley, Tetsuya Nishida, Brith Otterud, Julia L Richardt, Audrey Mollerup, Michael Hudecek, Colette ChaneyAbstract:T-cell immunotHerapy tHat targets minor Histocompatibility (H) Antigens presented selectively by recipient Hematopoietic cells, including leukemia, could prevent and treat leukemic relapse after Hematopoietic cell transplantation witHout causing graft-versus-Host disease. To provide immunotHerapy tHat can be applied to a majority of transplantation recipients, it is necessary to identify leukemia-associated minor H Antigens tHat result from gene polymorpHisms tHat are balanced in tHe population and presented by common Human leukocyte Antigen alleles. Current approacHes for deriving minor H Antigen–specific T cells, wHicH provide essential reagents for tHe molecular identification and cHaracterization of tHe polymorpHic genes tHat encode tHe Antigens, rely on in vivo priming and are often unsuccessful. We sHow tHat minor H Antigen–specific cytotoxic T lympHocyte precursors are found predominantly in tHe naive CD8+ T-cell subset and provide an efficient strategy for in vitro priming of native T cells to generate T cells to a broad diversity of minor H Antigens presented witH common Human leukocyte Antigen alleles. We used tHis approacH to derive a panel of stable cytotoxic T lympHocyte clones for discovery of genes tHat encode minor H Antigens and identify a novel Antigen expressed on acute myeloid leukemia stem cells and minimally in graft-versus-Host disease target tissues.
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a polymorpHic oncofetal Antigen recognized by cd8 ctl from two patients experiencing regression of metastatic renal cell carcinoma after allogeneic Hct
Blood, 2005Co-Authors: Edus H Warren, Jeffrey K Mito, Scott S Tykodi, John A Thompson, Brenda M Sandmaier, R StorbAbstract:Regression of metatstatic renal cell carcinoma (RCC) Has been observed in 8–57% of patients undergoing nonmyeloablative allogeneic Hematopoietic cell transplant (HCT) from HLA-matcHed donors. Tumor regression in tHis setting typically occurs after complete donor T cell engraftment is establisHed, and is correlated witH tHe development of GVHD. We previously isolated from two patients experiencing regression of metastatic RCC after nonmyeloablative allogeneic HCT CD8 + CTL clones tHat recognized a RCC-associated minor Histocompatibility (H) Antigen presented by HLA-A*0201, and localized tHe gene encoding tHis Antigen to cHromosome 19q. To identify tHe gene tHat encodes tHis Antigen, a cDNA expression library made from a HLA-A*0201 + minor H Antigen-positive tumor cell line was screened using a transfection assay in COS-7 cells. After two rounds of screening, a 1.4 kb cDNA was identified tHat stimulated HLA-A*0201-dependent cytokine release from minor H Antigen-specific CTL. Sequencing sHowed tHat tHis cDNA was derived from tHe MGC13170 gene on cHromosome 19q, witHin tHe region of significant linkage. Sequencing of MGC13170 alleles in minor H Antigen-positive and minor H Antigen-negative cells revealed six single nucleotide polymorpHisms (SNPs), inHerited as a Haplotype and all previously identified, tHat determined susceptibility or resistance to lysis by minor H Antigen-specific CTL. Analysis of 5′ and 3′ truncation constructs derived from tHe MGC13170 cDNA identified an interval encoding a 48-residue open reading frame tHat contained tHe epitope and spanned one of tHe six SNPs (dbSNP rs3745526) tHat Had been sHown to correlate witH CTL recognition. FurtHer analysis of minigenes spanning tHis nonsynonymous T↔A SNP identified an interval containing T at tHe polymorpHic position and encoding a predicted 11-residue peptide tHat stimulated maximal HLA-A2-dependent cytokine release from minor H Antigen-specific CTL. THe T↔A SNP is predicted to create a Ser↔THr polymorpHism in tHe encoded peptide. A syntHetic 11-mer peptide containing Ser at tHe polymorpHic residue, but not tHe Homologous peptide containing THr at tHis position, was recognized by minor H Antigen-specific CTL wHen pulsed onto minor H Antigen-negative HLA-A*0201 + cells, tHus demonstrating tHat tHe T allele of MGC13170 encodes tHe minor H Antigenic peptide. THe function of MGC13170 is unknown, but a previous study (ZHou et al ., Ai ZHeng21:341–345, 2002) suggested a role in resistance of tumor cells to cHemotHerapeutic agents. THe range of tissues in wHicH tHe epitope-encoding MGC13170 sequence is expressed was evaluated in silico by probing tHe translated Human EST database witH tHe predicted sequence of tHe 48-residue polypeptide encoded by tHe epitope-containing ORF. Of tHe several Hundred ESTs identified tHat encoded tHe Ser- or THr-containing peptide sequence, 72% were derived from tumor cells or cell lines (including RCC), 5% from embryonic or fetal tissues, 9% from embryonic stem cells, and 11% from normal tissues. THus, MGC13170 encodes a novel HLA-A*0201-restricted minor H Antigen tHat is expressed in a wide variety of neoplastic, embryonic, and fetal cells. FurtHer studies of MGC13170 as a possible target for antitumor immune responses after allogeneic HCT are underway.
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a Human minor Histocompatibility Antigen resulting from differential expression due to a gene deletion
Journal of Experimental Medicine, 2003Co-Authors: Makoto Murata, Edus H Warren, Stanley R RiddellAbstract:Minor Histocompatibility Antigens (minor H Antigens) are targets of graft-versus-Host disease and graft-versus-leukemia responses after allogeneic Human leukocyte Antigen identical Hematopoietic stem cell transplantation. Only a few Human minor H Antigens Have been molecularly cHaracterized and in all cases, amino acid differences between Homologous donor and recipient proteins due to nucleotide polymorpHisms in tHe respective genes were responsible for immunogenicity. Here, we Have used cDNA expression cloning to identify a novel Human minor H Antigen encoded by UGT2B17, an autosomal gene in tHe multigene UDP-glycosyltransferase 2 family tHat is selectively expressed in liver, intestine, and Antigen-presenting cells. In contrast to previously defined Human minor H Antigens, UGT2B17 is immunogenic because of differential expression of tHe protein in donor and recipient cells as a consequence of a Homozygous gene deletion in tHe donor. Deletion of individual members of large gene families is a common form of genetic variation in tHe population and our results provide tHe first evidence tHat differential protein expression as a consequence of gene deletion is a mecHanism for generating minor H Antigens in Humans.
Jos Pool - One of the best experts on this subject based on the ideXlab platform.
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TRANSPLANTATION Brief report Pregnancy induces minor Histocompatibility Antigen–specific cytotoxic T cells: implications for stem cell transplantation and immunotHerapy
2016Co-Authors: Robert M Verdijk, Jos Pool, Tuna Mutis, Astrid G S Van Halteren, Antoinette Kloosterman, Maarten Van De Keur, Albert Naipal, Els GoulmyAbstract:Recipients of HLA-identical stem cell trans-plants Have a poorer transplant outcome if tHe donor is female ratHer tHan male. We analyzed wHetHer pregnancy primes for mi-nor Histocompatibility (H) Antigens. PeripH-eral blood mononuclear cells (PBMCs) from HealtHy multiparous female blood donors were depleted for CD4, CD14, CD16, and CD19 cells, stained witH minor H Antigen– specific HLA-A2 tetramers, sorted by fluo-rescence-activated cell sorting, and tested for cytotoxic activity. Minor H Antigens HY-, HA-1–, and HA-2–specific cytotoxic T cells (CD8, CD45RA) were present in PBMCs from 4 of 7 female donors up to 22 years after tHe last delivery. Interestingly, in 2 of tHe 4 cases microcHimerism of tHe putative immunizing minor H Antigen was observed. THus, pregnancy can lead to alloimmune responses against tHe infant’s paternal mi-nor H Antigens. THe minor H Antigen immuni-zation status of female donors raises impor-tant questions for tHe clinical practice of stem cell transplantation. (Blood. 2004;103
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naturally acquired tolerance and sensitization to minor Histocompatibility Antigens in HealtHy family members
Blood, 2009Co-Authors: Astrid G S Van Halteren, Jos Pool, Anneke Brand, Ewa Jankowskagan, William J Burlingham, Antoinette M Joosten, E Blokland, Els GoulmyAbstract:Bidirectional cell transfer during pregnancy frequently leads to postpartum persistence of allogeneic cells and alloimmune responses in botH tHe motHer and in Her offspring. THe life-long consequences of naturally acquired alloimmune reactivity are probably of importance for tHe outcome of allogeneic stem cell transplantation. We investigated tHe presence of CD8pos minor Histocompatibility (H) Antigen–specific cytotoxic T lympHocytes (TCTL) and CD8pos minor H Antigen–specific T regulator cells (TREG) in peripHeral blood cells obtained from 17 minor H Antigen–disparate motHer-offspring pairs. Absence of minor H Antigen–specific TREG, as marked by tHe feasibility to expand TCTL from isolated tetramerpos populations, was observed in 6 motHers and 1 son. THe presence of minor H alloAntigen–specific TREG was observed in 4 motHers and 5 sons. THese TREG were detected witHin isolated tetramerdim staining fractions and functioned in a CTLA-4–dependent fasHion. Our study indicates tHat botH TCTL and TREG mediated alloimmunity against minor H Antigens may be present in HealtHy female and male Hematopoietic stem cell donors, potentially influencing graft-versus-Host reactivity in different ways.
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a uniform genomic minor Histocompatibility Antigen typing metHodology and database designed to facilitate clinical applications
PLOS ONE, 2006Co-Authors: Eric Spierings, Jos J M Drabbels, Matthijs Hendriks, Jos Pool, Marijke J Spruytgerritse, Frans H J ClaasAbstract:Background. Minor Histocompatibility (H) Antigen mismatcHes significantly influence tHe outcome of HLA-matcHed allogeneic stem cell transplantation. THe molecular identification of Human H Antigens is increasing rapidly. In parallel, clinical application of minor H Antigen typing Has gained interest. So far, relevant and simple tools to analyze tHe minor H Antigens in a quick and reliable way are lacking. MetHodology and Findings. We developed a uniform PCR witH sequence-specific primers (PCR-SSP) for 10 different autosomal minor H Antigens and H-Y. THis genomic minor H Antigen typing metHodology allows easy incorporation in tHe routine HLA typing procedures. DNA from previously typed EBV-LCL was used to validate tHe metHodology. To facilitate easy interpretation for clinical purposes, a minor H database named dbMinor (Http://www.lumc.nl/ dbminor) was developed. Input of tHe minor H Antigen typing results subsequently provides all relevant information for a given patient/donor pair and additional information on tHe putative graft-versus-Host, graft-versus-tumor and Host-versus-graft reactivities. Significance. A simple, uniform and rapid metHodology was developed enabling determination of minor H Antigen genotypes of all currently identified minor H Antigens. A dbMinor database was developed to interpret tHe genomic typing for its potential clinical relevance. THe combination of tHe minor H Antigen genomic typing metHodology witH tHe online dbMinor database and applications facilitates tHe clinical application of minor H Antigens anti-tumor targets after stem cell transplantation.
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minor H Antigen Ha 1 specific regulator and effector cd8 t cells and Ha 1 microcHimerism in allograft tolerance
Journal of Experimental Medicine, 2004Co-Authors: Ewa Jankowskagan, Jos Pool, Tuna Mutis, Richard Derks, Els Goulmy, William J BurlinghamAbstract:THe role of tHe Hematopoietic lineage-restricted minor Histocompatibility (H) Antigen HA-1 in renal allograft tolerance was explored. We obtained peripHeral blood samples from tHree recipients of Histocompatibility leukocyte Antigen (HLA)–matcHed, HA-1–mismatcHed renal transplants, one of wHicH Had discontinued immunosuppression >30 yr ago wHile sustaining normal kidney function. PeripHeral blood mononuclear cells (PBMCs) were injected into tHe footpads of severe combined immunodeficiency mice to measure Human delayed type Hypersensitivity (DTH) responses. All tHree patients manifested regulated DTH responses to HA-1H peptide. By differential tetramer staining intensities, we observed two distinct minor H Antigen HA-1–specific CD8+ T cell subsets. THe one tHat stained dimly Had tHe cHaracteristics of a T regulatory (TR) cell and produced interleukin (IL) 10 and/or transforming growtH factor (TGF) β. THese HA-1–specific TR cells coexisted witH brigHt tetramer-binding CD8+ T effector (TE) cells. THe CD8+ TE cells mediated HA-1–specific DTH and produced interferon-γ. Suppression of tHese TE functions by TR cells was TGFβ, IL-10, and cytotoxic T lympHocyte–associated Antigen 4 dependent. In addition, HA-1 microcHimerism was detected in two recipients, primarily in tHe dendritic cell fraction of tHe PBMCs. THis is tHe first demonstration of coexisting CD8+ memory TR and TE cells, botH specific for tHe same HA-1 Antigen, in tHe context of renal allograft tolerance.
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pregnancy induces minor Histocompatibility Antigen specific cytotoxic t cells implications for stem cell transplantation and immunotHerapy
Blood, 2004Co-Authors: Robert M Verdijk, Jos Pool, Tuna Mutis, Astrid G S Van Halteren, Anneke Brand, Antoinette Kloosterman, Maarten Van De Keur, Albert Naipal, Els GoulmyAbstract:Recipients of HLA-identical stem cell transplants Have a poorer transplant outcome if tHe donor is female ratHer tHan male. We analyzed wHetHer pregnancy primes for minor Histocompatibility (H) Antigens. PeripHeral blood mononuclear cells (PBMCs) from HealtHy multiparous female blood donors were depleted for CD4+, CD14+, CD16+, and CD19+ cells, stained witH minor H Antigen-specific HLA-A2 tetramers, sorted by fluorescence-activated cell sorting, and tested for cytotoxic activity. Minor H Antigens HY-, HA-1-, and HA-2-specific cytotoxic T cells (CD8+, CD45RA-) were present in PBMCs from 4 of 7 female donors up to 22 years after tHe last delivery. Interestingly, in 2 of tHe 4 cases microcHimerism of tHe putative immunizing minor H Antigen was observed. THus, pregnancy can lead to alloimmune responses against tHe infant's paternal minor H Antigens. THe minor H Antigen immunization status of female donors raises important questions for tHe clinical practice of stem cell transplantation.
Derry C Roopenian - One of the best experts on this subject based on the ideXlab platform.
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tHe immunogenomics of minor Histocompatibility Antigens
Immunological Reviews, 2002Co-Authors: Derry C Roopenian, Evan Young Choi, Aaron C BrownAbstract:Minor Histocompatibility (H) Antigens are a diverse assemblage of major Histocompatibility complex (MHC)-bound peptides witH tHe unifying property of acting as alloAntigens tHat induce allogeneic tissue rejection. THey are a consequence of any form of accumulated genetic variation tHat translates to differential MHC-presented peptide epitopes, tHe most common form of wHicH is simple sequence polymorpHisms. THe universe of potential minor H Antigens is large wHen transplantation is performed between genetically unrelated, MHC-matcHed individuals, especially considering tHe remarkable discriminative sensitivity of T cells. However, tHe pHenomenon of immunodominance greatly simplifies immune responses tHat ensue. One mouse minor H Antigen, H60, stands out in tHat tHe preponderance of tHe CD8 T cell response elicited in a complex alloAntigenic setting is directed against tHis single minor H Antigen epitope. Its immunodominance is because mice lacking H60 develop an unusually robust T cell repertoire dedicated to tHis single minor H Antigen. THe now well-cHaracterized mouse minor H Antigen system sHould provide a veHicle to assess tHe degree to wHicH immunodominant alloAntigens contribute to transplant rejection.
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immunodominance of H60 is caused by an abnormally HigH precursor t cell pool directed against its unique minor Histocompatibility Antigen peptide
Immunity, 2002Co-Authors: Gregory J Christianson, Thomas J Sproule, Nadja Jung, Yoshitaka Yoshimura, Sebastian Joyce, Derry C RoopenianAbstract:THe H60 minor Histocompatibility (H) Antigen peptide is derived from a glycoprotein tHat serves as a ligand for tHe stimulatory NKG2D receptor. We sHow tHat tHis peptide is remarkably immunodominant in tHat it competes effectively witH MHC alloAntigens, is efficiently crosspresented by Host Antigen-presenting cells (APCs), and readily elicits naive CD8 T cell responses in vitro. H60 immunodominance is neitHer a consequence of NKG2D engagement nor competition among minor H Antigens on APCs. Instead, H60 immunodominance is a consequence of an abnormally HigH naive precursor frequency of H60 peptide reactive CD8 T cells. Understanding wHy tHe H60 peptide is so immunogenic Has important implications in tissue transplantation and vaccine design.
Stanley R Riddell - One of the best experts on this subject based on the ideXlab platform.
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a ugt2b17 positive donor is a risk factor for HigHer transplant related mortality and lower survival after bone marrow transplantation
British Journal of Haematology, 2005Co-Authors: Seitaro Terakura, Makoto Murata, Stanley R Riddell, Tetsuya Nishida, Nobuhiko Emi, Yoshiki Akatsuka, Yasuo Morishima, Yoshihisa Kodera, Tomoki NaoeAbstract:We recently identified a Human minor Histocompatibility (H) Antigen, encoded by UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17), wHose immunogenicity results from differential expression in donor and recipient cells as a consequence of a Homozygous deletion of tHe UGT2B17 gene. UGT2B17 is HigHly expressed in tHe liver and colon, wHicH are major targets for graft-versus-Host disease (GVHD). To assess tHe significance of Homozygous UGT2B17 gene deletion in allogeneic Haematopoietic stem cell transplantation (HSCT), we analysed DNA from 435 stem cell transplant recipients witH a Haematological malignancy and tHeir Human leucocyte Antigen-identical unrelated bone marrow donors using sequence-specific primer polymerase cHain reaction. Homozygous deletion of tHe UGT2B17 gene was observed in 85% of normal donors and in 82% of patients. THe analysis sHowed no significant association between UGT2B17 mismatcH in tHe GVHD direction and tHe incidence of acute GVHD, cHronic GVHD, relapse, or survival. However, tHe use of a UGT2B17-positive donor was an independent risk factor for HigHer transplant-related mortality and lower survival after transplantation. UGT2B17 is a metabolic enzyme for Hormones, drugs, and potentially toxic exogenous compounds and is expressed in subsets of Haematopoietic cells. THus, tHe enzyme function of UGT2B17 in donor cells may affect tHe outcome of allogeneic HSCT.
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a Human minor Histocompatibility Antigen resulting from differential expression due to a gene deletion
Journal of Experimental Medicine, 2003Co-Authors: Makoto Murata, Edus H Warren, Stanley R RiddellAbstract:Minor Histocompatibility Antigens (minor H Antigens) are targets of graft-versus-Host disease and graft-versus-leukemia responses after allogeneic Human leukocyte Antigen identical Hematopoietic stem cell transplantation. Only a few Human minor H Antigens Have been molecularly cHaracterized and in all cases, amino acid differences between Homologous donor and recipient proteins due to nucleotide polymorpHisms in tHe respective genes were responsible for immunogenicity. Here, we Have used cDNA expression cloning to identify a novel Human minor H Antigen encoded by UGT2B17, an autosomal gene in tHe multigene UDP-glycosyltransferase 2 family tHat is selectively expressed in liver, intestine, and Antigen-presenting cells. In contrast to previously defined Human minor H Antigens, UGT2B17 is immunogenic because of differential expression of tHe protein in donor and recipient cells as a consequence of a Homozygous gene deletion in tHe donor. Deletion of individual members of large gene families is a common form of genetic variation in tHe population and our results provide tHe first evidence tHat differential protein expression as a consequence of gene deletion is a mecHanism for generating minor H Antigens in Humans.