| IntroductionOrgan transplantation has become a well-established modality for treatment of end stage disease. The development of new immunosuppressive agents and UW solution, as well as the refinement of surgical techniques have accounted for the remarkable improvement in 1-year and 5-years patient survival, even long-term patient survival. However, almost all of patients undergone organ transplantation should receive permanent and regular treatment of immunosuppressive agents. Otherwise, acute rejection or chronic rejection will still be the main cause of death in transplant recipients who survived a indefinite time. In fact, allograft rejection is mainly due to T cell activation. It is well known that T cell activation requires signals from two types of cell surface receptors. The first signal, confering the specificity of the response, is provided by the interaction between the T cell receptor (TCR)/CD3 complex and the peptide-major histocompatibility complex (MHC) complex on the antigen-presenting cell (APC). The ligation of costimulatory molecules CD28 and CD 154 on T cell with their ligands B7 or CD40 on the APC, which delivers the second signal, plays a critical role in full T cells activation. CTLA4 is rapidly upregulated after T cell activation. The binding of CTLA4 on T cell to B7 on APC delivers the negative signal for T cell activation and inhibits T cell response. Absence ofcostimulation may result in T cell unresponsiveness and suppression of IL-2 gene expression, as well as lymphoproliferative disorder, namely T cell tolerance to implanted grafts.In despite of a large number of evidence emphasize that CD28 molecule provide the predominant signal for initiating T cell response to antigens, not all the activation of T cell are dependent on CD28 pathway. Previous research has demonstrated that CD28-/- mice are able to reject skin allografts as wild-type mice. Blockade of CD40-CD154 ligation is insufficient to inhibit cardiac allograft rejection in some mouse strain combination. Recent report has confirmed that CD8+ T cell can be fully activated in absence of signal via CD28 or CD 154 molecules; therefore, other costimulatory receptors may be involved in the development of optimal T cell response.The 4-IBB receptor which belongs to TNFR superfamily is a type I membrane protein expressed on activated cytolytic and helper T cells, as well as NK cells. The ligand for 4-IBB receptor is 4-IBB ligand (4-1BBL), which is expressed on APCs including B cells, macrophages, and dendritic cells. Recent report indicates that under the condition of repeated Ag-stimulation, down-regulated expression of CD28 molecule on activated T cells leads to the activation-induced cell death (AICD), while 4-IBB molecules may supply sufficient costimulatory signals to sustain T cells activation, and inhibit AICD. Interaction of 4-IBB with 4-1BBL play an important role in sustaining T cells activation, amplifying cytotoxic T lymphocyte (CTL) response, as well as inducing IL-2 production in the complete absence of a signal through CD28 molecule. Study of using anti-4-lBB mAb infusion has demonstrated that 4-1BB/4-1BBL interactions can amplify the proliferation of CD8+ T cells, and augment GVHD-induced lethality and allogeneic BM rejection mediated by either CD4+ or CD8+ donor T cells. Collectively,these data imply that 4-1BB signal can have an important role in the cellular immune response after allo-transplantation.In contrast to CD28, 4-IBB is not constitutively expressed on T cells, therefore, whether 4-1BB/4-1BBL pathways was involved in allo-immune response to transplant antigen was worthy of further study. In the present research we investigated the gene expression of 4-IBB in transplanted heart in mice and its implication in allo-immune response by means of pathology, RT-PCR, Western-blot, EMSA, ELISA, direct immunofluorescence cytochemical staining and confocal microscopy, as well as flow cytometry. We also explored whether CsA and FK506 were able to inhibit the expression of costimulatory molecule...
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