International Journal of Hematology

DOI: 10.1007/s12185-011-0819-6 Pages: 594-601

Costimulatory blockade with monoclonal antibodies to induce alloanergy in donor lymphocytes

1. Dana-Farber Cancer Institute, Department of Medical Oncology

2. Queen Mary University of London, Centre for Haemato-Oncology, Barts Cancer Institute, John Vane Science Centre

Correspondence to:
Jeffrey K. Davies
Tel: +44-20-78823815
Fax: +44-20-78823891
Email: j.k.davies@qmul.ac.uk

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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.

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