? The rejection of solid organ allografts in fully mismatched recipients is dependent on T cell activation, and blockade of specific costimulatory receptors on T cells leads to the acceptance of certain allogeneic tissues. However, the biochemical signaling pathways necessary in T cells for promoting allograft rejection or tolerance, are not fully understood. T cell stimulation leads to the nuclear translocation of several transcription factors, including nuclear factor of activated T cells (NFAT), activating protein 1 (AP-1), and nuclear factor-kB (NF-kB). Of these transcription factors, NF-kB is a lead candidate for regulating transcription of genes central to the allogeneic immune response, as its activation has been linked to cell survival, differentiation, and cytokine production in different systems, mRNA expression levels of the different NF-kB subunits are upregulated in allogeneic grafts during acute rejection episodes. Furthermore, graft survival is prolonged following treatment with decoy NF-kB oligonucleotides, and cardiac allografts are permanently accepted in mice with impaired NF-kB activation in T cells. Using mice expressing a mutant IkBa superrepressor transgene restricted to the T cell lineage that reduces NF-kB activation in T cells (IkBaDN-Tg mice), we have observed effective rejection of fully mismatched skin allografts but permanent acceptance of cardiac allografts. Furthermore, exposure of these mice to cardiac allografts resulted in acceptance of subsequent donor skin allografts. Our central hypothesis is that exposure to alloantigens presented by some but not all tissues during impaired NF-kB activation in T cells leads to donor-specific tolerance. This hypothesis will be tested in the context of the following specific aims.
Aim 1. To determine how donor-specific tolerance following exposure to cardiac allografts is promoted in mice with impaired T cell-intrinsic NF-kB activation.
Aim 2. To determine the factors leading to greater immunogenicity of skin than cardiac allografts in mice with impaired NF-kB activation in T cells.
Aim 3. To determine the tissue requirements for achieving donor-specific tolerance in the context of impaired NF-kB activation and the applicability of this strategy to wildtype recipients. ? ? ?
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