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Inhibition of NF-B-Dependent T Cell Activation Abrogates Acute Allograft Rejection¹

Patricia W. Finn^*,, James R. Stone, Mark R. Boothby and David L. Perkins^2,*

^* Laboratory of Molecular Immunology, Pulmonary and Critical Care, Department of Medicine, and Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Vanderbilt University, Nashville, TN 37232

Using a heterotopic model of transplantation, we investigated the role of T cell activation in vivo during allograft rejection in I-B(N)-transgenic mice that express a transdominant inhibitor of NF-B in T cells. Our results show indefinite prolongation of graft survival in the I-B(N)-transgenic recipients. Interestingly, at the time of rejection of grafts in wild-type recipients, histology of grafts in the I-B(N)-transgenic recipients showed moderate rejection; nevertheless, grafts in the I-B(N) recipients survived >100 days. Analysis of acute phase cytokines, chemokine, chemokine receptors, and immune responses shows that the blockade of NF-B activation in T cells inhibits up-regulation of many of these parameters. Interestingly, our data also suggest that the T cell component of the immune response exerted positive feedback regulation on the expression of multiple chemokines that are produced predominantly by non-T cells. In conclusion, our studies indicate NF-B activation in T cells is necessary for acute allograft rejection.

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