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Els Goulmy - One of the best experts on this subject based on the ideXlab platform.
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The relevance of minor Histocompatibility Antigens in solid organ transplantation.
Current Opinion in Organ Transplantation, 2009Co-Authors: Miranda P. Dierselhuis, Els GoulmyAbstract:Purpose of reviewDisparities in minor Histocompatibility Antigens between HLA-matched organ and hematopoietic stem cell donors and recipients create the risks of graft failure and graft-versus-host disease (GvHD) respectively. A decade ago, technical advances combined with genomic information result
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Minor Histocompatibility Antigens: from transplantation problems to therapy of cancer.
Human Immunology, 2006Co-Authors: Els GoulmyAbstract:The idea of transferring healthy marrow for the therapeutic treatment of the various diseases of the blood and of the immune system made a significant contribution to controlling diseases and to advancing modern clinical sciences. The first series of bone marrow transplantations in the 1960s were confronted with severe complications. It became clear that matching for the human leukocyte antigen (HLA) system between donor and recipient significantly improved the clinical results. Nonetheless, an unacceptable percentage of severe complications remained that is mainly attributable to non-HLA Histocompatibility systems, i.e., minor Histocompatibility Antigens. Observations in the 1970s that minor Histocompatibility Antigens cause serious problems in human bone marrow transplantation laid the basis for their use as curative Antigens in stem cell transplantation to date. Thus, the allo-immune T cell activities caused by minor histocompatibililty antigen disparities between HLA-matched donor and recipient can now be applied for the benefit of the transplant patient.
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expanding the immunotherapeutic potential of minor Histocompatibility Antigens
Journal of Clinical Investigation, 2005Co-Authors: Eric Spierings, Els GoulmyAbstract:Minor Histocompatibility Antigens (mHAgs) selectively expressed by cells or cell subsets of the hematopoietic system are targets of the T cell–mediated graft-versus-leukemia response that develops following allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematological malignancies. This observation has served as the rationale for utilizing mHAg-specific immunotherapy for the treatment of particular patients. However, at present, only a select and small number of patients could potentially benefit from mHAg-based immunotherapy. A report from de Rijke et al. in this issue of the JCI describes a new hematopoietic lineage–specific HLA-B7–restricted mHAg associated with remission of chronic myeloid leukemia. This result represents another example of an mHAg-mediated graft-versus-leukemia response, thereby expanding the number of patients eligible for mHAg-based immunotherapy in the setting of HSCT.
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Immunotherapy of cancer through targeting of minor Histocompatibility Antigens.
Current Opinion in Immunology, 2005Co-Authors: Lothar Hambach, Els GoulmyAbstract:Minor Histocompatibility Antigens are allogeneic targets of T-cell mediated graft-versus-tumour effects following allogeneic stem cell transplantation. Recent research has identified several minor Histocompatibility Antigens as tumour proteins and has also disclosed their unique properties in both the induction and the effector phase of graft-versus-tumour effects. Targeting tumour-specific minor Histocompatibility Antigens by adoptive immunotherapy will battle against tumour tolerance and evoke allo-immune responses, thereby enhancing graft-versus-tumour effects against leukaemia and solid tumours. Recently acquired knowledge of the role of donor immunisation status, new techniques in the generation of minor Histocompatibility antigen-specific cytotoxic T lymphocytes in vitro, and innovative principles in vaccination will help to design clinical trials that exploit minor Histocompatibility Antigens in the immunotherapy of cancer.
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Minor Histocompatibility Antigens: allo target molecules for tumor-specific immunotherapy.
The Cancer Journal, 2004Co-Authors: Els GoulmyAbstract:Minor Histocompatibility Antigens have to be considered as key molecules in the stem cell-based immunotherapy of malignancies. Allogeneic stem cell transplantation (SCT) is a well-established and effective therapy for advanced hematologic malignancies. The apparent powerful graft-versus-leukemia effect of SCT led clinicians to apply SCT for the treatment of metastatic solid tumors. The SCT-based graft-versus-tumor reaction in the allogeneic human leukocyte antigen-matched SCT setting is mediated by allo-immune effector cells directed against tumor-related target Antigens. The target molecules involved in the allo-immune graft-versus-tumor reaction are tumor-specific Antigens, tumor-associated Antigens, and tissue- and cell-specific minor Histocompatibility Antigens. The power of the minor Histocompatibility Antigens in the human leukocyte antigen-identical, stem cell-based immunotherapy for malignancies is their "allo-ness." As opposed to tumor-associated self Antigens, the complexes of MHC and allo-target peptide are likely to be more immunogeneic than the major Histocompatibility complex and self-target peptide complexes. Moreover, minor Histocompatibility allo-Antigens are not subject to self tolerance. Earlier minor Histocompatibility Antigens were seen as alien entities, disturbing the success of the so ideally matched organ and SCT donor-recipient combinations. To date, minor Histocompatibility Antigens can be set in the favorable light of useful tools for immunotherapy for cancer. The first clinical application of the hematopoietic minor Histocompatibility Antigens HA-1 and HA-2 is currently being explored in a stem cell-based setting for hematologic malignancies. Because HA-1 is also expressed on carcinoma cells, a stem cell-based vaccination trial for patients with metastatic breast or renal cancer is about to start as well. The immunotherapeutic potential of minor Histocompatibility Antigens demands serious searches for new minor Histocompatibility Antigens and analyses of their phenotype frequency, tissue distribution, and functional membrane expression. The minor Histocompatibility Antigens meeting the prerequisites for specific immunotherapy for malignancies, such as membrane expression and tissue and/or cell specificity, may offer the curative tools for stem cell-based immunotherapy for various hematologic and nonhematologic malignancies.
Roel Willemze - One of the best experts on this subject based on the ideXlab platform.
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high throughput characterization of 10 new minor Histocompatibility Antigens by whole genome association scanning
Cancer Research, 2010Co-Authors: Cornelis A M Van Bergen, Roel Willemze, Caroline E Rutten, Edith D Van Der Meijden, Simone A P Van Luxemburgheijs, Ellie Lurvink, Jeanine J Houwingduistermaat, Michel G D Kester, Arend Mulder, J Frederik H FalkenburgAbstract:In this study, efficient T-cell selection was combined with SNP genotyping to discover a significant number of new minor Histocompatibility Antigens that can be targeted by cellular immunotherapy of cancer.
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Minor Histocompatibility Antigens as targets of cellular immunotherapy in leukaemia.
Best Practice & Research Clinical Haematology, 2004Co-Authors: J.h.f. Falkenburg, Roel WillemzeAbstract:Allogeneic human-leukocyte-antigen-matched stem cell transplantation is associated with a lower risk of relapse of leukaemia than autologous transplantation due to a T-cell-mediated graft-vs.-leukaemia effect. Replacement of patient haematopoiesis by donor haematopoiesis allows the application of donor-derived specifically targeted cellular immunotherapy for the treatment of leukaemia. Following allogeneic transplantation, donor-derived T cells recognizing minor Histocompatibility Antigens expressed on haematopoietic cells from the patient may result in eradication of all haematopoietic cells of recipient origin. Since after transplantation, normal haematopoiesis is of donor origin, these T-cell responses may result in establishment of full donor chimerism associated with elimination of the haematological malignancy. By targeting the immune response to minor Histocompatibility Antigens that are not expressed on non-haematopoietic tissues, graft-vs.-host reactions may be limited. Several methods can be used for in vitro selection of T-cell responses with high specificity for malignant cells, and in vitro manipulation of donor T cells including transfer of antigen-specific T-cell receptors may greatly enhance specificity and efficacy of donor-derived cellular immunotherapy of haematological malignancies.
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minor Histocompatibility Antigens in human stem cell transplantation
Experimental Hematology, 2003Co-Authors: J Frederik H Falkenburg, Lisette Van De Corput, Erik W A Marijt, Roel WillemzeAbstract:Minor Histocompatibility Antigens (mHags) play a major role in graft rejection, the induction of detrimental graft-vs-host disease (GVHD), and the development of the beneficial graft-vs-leukemia (GVL) effect after allogeneic stem cell transplantation (SCT). mHags can be defined as amino acid polymorphisms in cellular proteins that can lead to differential presentation of antigenic peptides in HLA molecules and therefore to differential recognition by T cells. The tissue distribution of the mHags and the HLA molecules by which they can be presented play a significant role in the clinical outcome of T-cell responses against these Antigens. In part, differential recognition by T cells of mHags specifically expressed in hematopoietic cells, including the malignant cells from the recipient may result in GVL reactivity without concurrent GVHD. Furthermore, T-cell responses against proteins solely expressed in hematopoietic cell lineages from which the malignancy is derived may be appropriate mediators of GVL reactivity without GVHD induction. Characterization of clinical immune responses in patients treated for relapsed leukemia after allogeneic SCT with donor lymphocyte infusion in the absence of GVHD may lead to the characterization of new mHags that can be exploited to generate tumor-specific immune responses. By in vitro generation of T-cell responses against defined mHags, the efficacy and specificity of cellular immunotherapy against hematologic malignancies in the context of allogeneic transplantation may be improved.
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Minor Histocompatibility Antigens as targets of graft-versus-leukemia reactions.
Current Opinion in Hematology, 2002Co-Authors: J.h.f. Falkenburg, W.a.f. Marijt, M.h.m. Heemskerk, Roel WillemzeAbstract:The main advantage of allogeneic stem cell transplantation over autologous stem cell transplantation for hematologic malignancies is the ability to perform cellular immunotherapy using donor-derived immune effector cells after transplantation. In HLA-matched allogeneic stem cell transplantation, the beneficial graft-versus-leukemia effect of donor lymphocytes appears to be caused mainly by alloreactive T cells that are capable of recognizing minor Histocompatibility Antigens on the malignant cell population from the patient. The tissue distribution of minor Histocompatibility Antigens probably determines the clinical result of T-cell responses against these Antigens. Whereas T cells recognizing broadly expressed Antigens cause not only graft-versus-leukemia but also graft-versus-host disease, T cells recognizing minor Histocompatibility Antigens specifically expressed on hematopoietic cells may mainly eliminate hematopoietic cells from the recipient, including the malignant cells, without affecting donor hematopoiesis or normal nonhematopoietic tissues. Graft-versus-host disease may still occur because of the induction of inflammatory responses against hematopoietic cells in the tissues. Vaccination of patients after transplantation or vaccination of stem cell donors before transplantation using minor Histocompatibility antigen-specific peptides, ex vivo production of minor Histocompatibility antigen-specific T cells, and redirection of T-cell specificity by gene transfer of T-cell receptors may be strategies to eradicate specifically the malignant cells after allogeneic stem cell transplantation.
J Frederik H Falkenburg - One of the best experts on this subject based on the ideXlab platform.
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high throughput characterization of 10 new minor Histocompatibility Antigens by whole genome association scanning
Cancer Research, 2010Co-Authors: Cornelis A M Van Bergen, Roel Willemze, Caroline E Rutten, Edith D Van Der Meijden, Simone A P Van Luxemburgheijs, Ellie Lurvink, Jeanine J Houwingduistermaat, Michel G D Kester, Arend Mulder, J Frederik H FalkenburgAbstract:In this study, efficient T-cell selection was combined with SNP genotyping to discover a significant number of new minor Histocompatibility Antigens that can be targeted by cellular immunotherapy of cancer.
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minor Histocompatibility Antigens in human stem cell transplantation
Experimental Hematology, 2003Co-Authors: J Frederik H Falkenburg, Lisette Van De Corput, Erik W A Marijt, Roel WillemzeAbstract:Minor Histocompatibility Antigens (mHags) play a major role in graft rejection, the induction of detrimental graft-vs-host disease (GVHD), and the development of the beneficial graft-vs-leukemia (GVL) effect after allogeneic stem cell transplantation (SCT). mHags can be defined as amino acid polymorphisms in cellular proteins that can lead to differential presentation of antigenic peptides in HLA molecules and therefore to differential recognition by T cells. The tissue distribution of the mHags and the HLA molecules by which they can be presented play a significant role in the clinical outcome of T-cell responses against these Antigens. In part, differential recognition by T cells of mHags specifically expressed in hematopoietic cells, including the malignant cells from the recipient may result in GVL reactivity without concurrent GVHD. Furthermore, T-cell responses against proteins solely expressed in hematopoietic cell lineages from which the malignancy is derived may be appropriate mediators of GVL reactivity without GVHD induction. Characterization of clinical immune responses in patients treated for relapsed leukemia after allogeneic SCT with donor lymphocyte infusion in the absence of GVHD may lead to the characterization of new mHags that can be exploited to generate tumor-specific immune responses. By in vitro generation of T-cell responses against defined mHags, the efficacy and specificity of cellular immunotherapy against hematologic malignancies in the context of allogeneic transplantation may be improved.
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mismatches of minor Histocompatibility Antigens between hla identical donors and recipients and the development of graft versus host disease after bone marrow transplantation
The New England Journal of Medicine, 1996Co-Authors: Els Goulmy, Alois Gratwohl, R F Schipper, Jos Pool, E Blokland, J Frederik H Falkenburg, J M Vossen, Georgia Boyce Vogelsang, Hans C Van Houwelingen, Jon J Van RoodAbstract:Background Graft-versus-host disease (GVHD) can be a major complication of allogeneic bone marrow transplantation even when the donor and recipient are siblings and share identical major Histocompatibility Antigens. The explanation may be a mismatch of minor Histocompatibility Antigens. We previously characterized five minor Histocompatibility Antigens, HA-1, 2, 3, 4, and 5, that are recognized by T cells in association with the major Histocompatibility Antigens HLA-A1 and A2. Methods We collected peripheral-blood leukocytes from 148 bone marrow recipients and their sibling donors, who were genotypically HLA identical. Fifty pairs were positive for HLA-A1, 117 were positive for HLA-A2, and 19 were positive for both. The pairs were typed with cytotoxic-T-cell clones specific for minor Histocompatibility Antigens HA-1, 2, 3, 4, and 5. Results Mismatches of HA-3 were equally distributed among recipients in whom GVHD developed and those in whom it did not. By contrast, a mismatch of only HA-1 was significantl...
Anthony G Brickner - One of the best experts on this subject based on the ideXlab platform.
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targeting minor Histocompatibility Antigens in graft versus tumor or graft versus leukemia responses
Trends in Immunology, 2008Co-Authors: Xin Feng, Kwokmin Hui, Hashem Younes, Anthony G BricknerAbstract:Allogeneic hematopoietic cell transplantation (alloHCT) represents the only curative therapy for several hematologic malignancies, and shows promise as a nascent treatment modality for select solid tumors. Although the original goal of alloHCT was hematopoietic reconstitution after sub-lethal chemoradiotherapy, recognition of a profound donor lymphocyte-mediated graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect has shifted the paradigm from pre-transplant cytoreduction to tumor control via donor lymphocytes. In human leukocyte antigen (HLA)-compatible alloHCT, GVL and GVT reactions are induced primarily by donor T-cell recognition of minor Histocompatibility Antigens (mHAgs). Here we review the literature regarding mHAg-specific T cells in GVL and GVT reactions, and discuss the prospects of exploiting mHAgs as immunotherapeutic targets.
Nilabh Shastri - One of the best experts on this subject based on the ideXlab platform.
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differences that matter major cytotoxic t cell stimulating minor Histocompatibility Antigens
Immunity, 2000Co-Authors: Subramaniam Malarkannan, Derry C. Roopenian, Tiffany Horng, Peter A Eden, Federico Gonzalez, Patty P Shih, Nathalie Brouwenstijn, Heiko Klinge, Greg J Christianson, Nilabh ShastriAbstract:Abstract Despite thousands of genetic polymorphisms among MHC matched mouse strains, a few unknown Histocompatibility Antigens are targeted by the cytotoxic T cells specific for tissue grafts. We isolated the cDNA of a novel BALB.B antigen gene that defines the polymorphic H28 locus on chromosome 3 and yields the naturally processed ILENFPRL (IFL8) peptide for presentation by K b MHC to C57Bl/6 CTL. The CTL specific for the IFL8/K b and our previously identified H60/K b complexes represent a major fraction of the B6 anti-BALB.B immune response. The immunodominance of these Antigens can be explained by their differential transcription in the donor versus the host strains and their expression in professional donor antigen-presenting cells.