Background-Posttransplant chronic allograft deterioration associated with development of transplant arteriosclerosis (TA) remains an unresolved problem. Recent studies suggest that the smooth muscle cells (SMCs) constituting the neointima are derived from recipient hematopoietic stem cells (HSCs). However, the underlying mechanisms of the process are not yet fully elucidated. Methods and Results-We examined the genes expressed in allografts at different stages of TA development using a mice aortic transplantation model. Genes were analyzed by a differential mRNA display technique. We show that stromal cell-derived factor-1␣ (SDF-1␣) is a critical molecular target for the treatment of TA. During the course of TA, intragraft SDF-1␣ expression was upregulated with time, and the circulating HSCs expressing its counterreceptor CXCR4 increased in the recipients receiving allografts. CXCR4-positive HSCs, derived from transplant recipients, migrated into allografts via microvessels in the adventitia and then toward the luminal side. The HSCs differentiated into SMC-like cells, contributing to the in situ formation of the neointima. In support of a functional role for these molecules, in vivo neutralization of SDF-1␣ inhibited HSC mobilization and significantly attenuated neointimal formation. Conclusions-Interaction between SDF-1␣ and CXCR4 plays a key role in TA development. Blockade of SDF-1␣ may become a new therapeutic modality for TA.
Transcriptional expression of a gene or genes is absolutely required for induction of glucocorticoid-induced thymocyte apoptosis. We have previously shown that expression of T cell death-associated gene 8 (TDAG8) is quickly induced exclusively in the thymus after dexamethasone (DEX) treatment. Here, we present data that TDAG8 expression is induced prior to induction of DEX-mediated apoptosis. In contrast, TDAG8 expression in thymocytes was not induced in the process of gamma-irradiation-mediated apoptosis. TDAG8 expression accelerated only DEX-induced, but not TCR-mediated or gamma-irradiation-induced, thymocyte apoptosis in transgenic mice overexpressing TDAG8. Interestingly, these effects were specifically detected in CD4(+)CD8(+) double-positive thymocytes. Moreover, activation of caspase-3, -8 and -9 was enhanced in thymocytes of TDAG8 transgenic mice after DEX stimulation. In conclusion, TDAG8 expression is involved in glucocorticoid-induced signals to activate caspase-9, -8 and -3 for subsequent apoptosis induction in CD4(+)CD8(+) double-positive thymocytes.
In psoriasis, CD28/B7 costimulatory molecules are well characterized. Here, using the severe combined immunodeficient (SCID) mouse-psoriasis xenograft model, we report therapeutic efficacy of a humanized anti-CD28 monoclonal antibody (FR255734; Astellas Pharmaceuticals Inc., Tokyo, Japan). Transplanted psoriasis plaques on the SCID mouse were treated weekly for 4 weeks with intraperitoneal injections of FR255734 at 10, 3, and 1-mg kg(-1) doses. Groups treated with doses of 10 and 3 mg kg(-1) had significant thinning of the epidermis and reduced HLA-DR-positive lymphocytic infiltrates. The length of the rete pegs changed from 415.2+/-59.6 to 231.4+/-40.4 microm (P<0.005) in the 10-mg kg(-1) group, and from 323.4+/-69.6 to 237.5+/-73.6 microm in the 3-mg kg(-1) group (P=0.002). Positive controls treated with CTLA4-Ig and cyclosporine had significant histological improvement, whereas plaques treated with saline and isotype controls (human and mouse IgG2) remained unchanged. In vitro studies have shown that FR255734 effectively blocked T-cell proliferation and proinflammatory cytokine production. These observations warrant studies to evaluate the efficacy of FR255734 in human autoimmune diseases.
FK734 is a partial agonist of CD28 signaling that can reduce human T cell alloresponses in the presence of strong costimulation by B7 molecules in vitro and can reduce T cell-mediated skin allograft rejection in vivo.
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