title: Costimulatory blockade with monoclonal antibodies to induce alloanergy in donor lymphocytes.
abstract: Alloreactive donor T cells are central to the pathogenesis of Graft-versus-Host Disease (GvHD). Non-specific T cell depletion of donor grafts reduces GvHD, but increases infection and disease relapse. Several strategies are, therefore, in development to selectively remove alloreactive donor T cells prior to transplant while retaining beneficial donor T cells. An alternative approach is ex vivo alloanergization of donor T cells via allostimulation and blockade of costimulatory signals with fusion proteins or monoclonal antibodies. This strategy, which selectively inactivates alloreactive donor T cells, has been tested with some success in previous clinical trials of HLA-mismatched bone marrow transplantation. To build on the findings of these early trials, the strategy is now being tested in a multi-center clinical study of alloanergized donor lymphocyte infusion after HLA-mismatched stem cell transplantation. Recent advances in the understanding of alloanergization include the recognition of the central role played by CD4(+) regulatory T cells and new applications include the combination of alloanergization with T cell redirection to maximize anti-tumor activity. This mini-review will give an overview of the immunological basis for alloanergization, the previous and current clinical applications, and how new pre-clinical data have helped to create exciting new avenues of translational research in this area.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA. j.k.davies@qmul.ac.uk.|Centre for Haemato-Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. j.k.davies@qmul.ac.uk.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Davies
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000918:Antibody Specificity; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002986:Clinical Trials as Topic; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D006680:HLA Antigens / Q000032:analysis; D006402:Hematologic Diseases / Q000276:immunology / Q000628:therapy*; D006801:Humans; D066298:In Vitro Techniques; D008212:Lymphocyte Depletion / Q000009:adverse effects; D009894:Opportunistic Infections / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D037182:T-Cell Antigen Receptor Specificity / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D011993:Recombinant Fusion Proteins