Journal
BLOOD
Volume 109, Issue 2, Pages 819-826Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-03-008219
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Funding
- NIAID NIH HHS [R01 AI017672, AI-42669, AI-17672, AI-46629, P01 AI046629, R37 AI017672] Funding Source: Medline
- NIAMS NIH HHS [R01 AR035506, AR-35506] Funding Source: Medline
- NIDDK NIH HHS [DK52530] Funding Source: Medline
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Allograft transplantation requires chronic immunosuppression, but there is no effective strategy to evaluate the long-term maintenance of immunosuppression other than assessment of graft function. The ability to monitor naive alloreactive T cells would provide an alternative guide for drug therapy at early, preclinical stages of graft rejection and for evaluating tolerance-inducing protocols. To detect and quantify naive alloreactive T cells directly ex vivo, we used the unique ability of naive T cells to rapidly produce TNF-alpha but not IFN-gamma. Naive alloreactive T cells were identified by the production of TNF-alpha after a 5-hour in vitro stimulation with alloantigen and were distinguished from effector/memory alloreactive T cells by the inability to produce IFN-gamma. Moreover, naive alloreactive T cells were not detected in mice tolerized against specific alloantigens. The frequency of TNF-alpha-producing cells was predictive for rejection in an in vivo cytotoxicity assay and correlated with skin allograft rejection. Naive alloreactive T cells were also detected in humans, suggesting clinical relevance. We conclude that rapid production of TNF-alpha can be used to quantify naive alloreactive T cells, that it is abrogated after the induction of tolerance, and that it is a potential tool to predict allograft rejection. (c) 2007 by The American Society of Hematology
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