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Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia.

ABSTRACT: Minor histocompatibility (H) antigens are major targets of a graft-versus-leukemia (GVL) effect mediated by donor CD8(+) and CD4(+) T cells following allogeneic hematopoietic cell transplantation (HCT) between human leukocyte antigen identical individuals. In the 15 years since the first molecular characterization of human minor H antigens, significant strides in minor H antigen discovery have been made as a consequence of advances in cellular, genetic and molecular techniques. Much has been learned about the mechanisms of minor H antigen immunogenicity, their expression on normal and malignant cells, and their role in GVL responses. T cells specific for minor H antigens expressed on leukemic cells, including leukemic stem cells, can be isolated and expanded in vitro and infused into allogeneic HCT recipients to augment the GVL effect to prevent and treat relapse. The first report of the adoptive transfer of minor H antigen-specific T-cell clones to patients with leukemic relapse in 2010 illustrates the potential for the manipulation of alloreactivity for therapeutic benefit. This review describes the recent developments in T-cell recognition of human minor H antigens, and efforts to translate these discoveries to reduce leukemia relapse after allogeneic HCT.

SUBMITTER: Bleakley M

PROVIDER: S-EPMC3061548 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia.

Bleakley Marie M Riddell Stanley R SR

Immunology and cell biology 20110208 3

Minor histocompatibility (H) antigens are major targets of a graft-versus-leukemia (GVL) effect mediated by donor CD8(+) and CD4(+) T cells following allogeneic hematopoietic cell transplantation (HCT) between human leukocyte antigen identical individuals. In the 15 years since the first molecular characterization of human minor H antigens, significant strides in minor H antigen discovery have been made as a consequence of advances in cellular, genetic and molecular techniques. Much has been lea ...[more]

PMID: 21301477

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Project description:Minor Histocompatibility (H) antigens are major histocompatibility complex (MHC)/Human Leukocyte Antigen (HLA)-bound peptides that differ between allogeneic hematopoietic stem cell transplantation (HCT) recipients and their donors as a result of genetic polymorphisms. Some minor H antigens can be used as therapeutic T cell targets to augment the graft-vs.-leukemia (GVL) effect in order to prevent or manage leukemia relapse after HCT. Graft engineering and post-HCT immunotherapies are being developed to optimize delivery of T cells specific for selected minor H antigens. These strategies have the potential to reduce relapse risk and thereby permit implementation of HCT approaches that are associated with less toxicity and fewer late effects, which is particularly important in the growing and developing pediatric patient. Most minor H antigens are expressed ubiquitously, including on epithelial tissues, and can be recognized by donor T cells following HCT, leading to graft-vs.-host disease (GVHD) as well as GVL. However, those minor H antigens that are expressed predominantly on hematopoietic cells can be targeted for selective GVL. Once full donor hematopoietic chimerism is achieved after HCT, hematopoietic-restricted minor H antigens are present only on residual recipient malignant hematopoietic cells, and these minor H antigens serve as tumor-specific antigens for donor T cells. Minor H antigen-specific T cells that are delivered as part of the donor hematopoietic stem cell graft at the time of HCT contribute to relapse prevention. However, in some cases the minor H antigen-specific T cells delivered with the graft may be quantitatively insufficient or become functionally impaired over time, leading to leukemia relapse. Following HCT, adoptive T cell immunotherapy can be used to treat or prevent relapse by delivering large numbers of donor T cells targeting hematopoietic-restricted minor H antigens. In this review, we discuss minor H antigens as T cell targets for augmenting the GVL effect in engineered HCT grafts and for post-HCT immunotherapy. We will highlight the importance of these developments for pediatric HCT.

Dataset Information

Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia.

Publications

Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia.

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