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Ex vivo inhibition of NF-kappaB signaling in alloreactive T-cells prevents graft-versus-host disease

O'Shaughnessy, M. J. and Vogtenhuber, C. and Sun, K. and Sitcheran, R. and Baldwin, A. S. and Murphy, W. J. and Dang, L. and Jaffee, B. and Palmer, E. and Serody, J. S. and Blazar, B. R.. (2009) Ex vivo inhibition of NF-kappaB signaling in alloreactive T-cells prevents graft-versus-host disease. American journal of transplantation : official journal of the American Society of Transplant Surgeons (ASTS) and the American Society of Transplantation (AST), Vol. 9. pp. 452-462.

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Official URL: http://edoc.unibas.ch/dok/A6006364

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Abstract

The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the graft-versus-host disease (GVHD) capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-kappaB pathway in alloreactive T-cells, which is critical for T-cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-kappaB activation, can induce T-cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control or PS1145-treated MLR cells in syngeneic Rag(-/-) recipients resulted in intact contact hypersensitivity (CHS) responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-kappaB pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early posttransplant GVHD lethality but that also permits donor T-cell responses to recover after a period of lymphopenic expansion.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Transplantation Immunology and Nephrology (Palmer/Steiger)
UniBasel Contributors:Palmer, Ed
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Munksgaard
ISSN:1600-6135
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:22
Deposited On:24 May 2013 09:02

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