Importance Of ICOS-B7RP-1 Costimulation In Acute And Chronic Allograft Rejection Of Rat Heart Transplantation

Background Allograft rejection will still be the main cause of death in transplant recipients who survived a indefinite time. In fact,allograft rejectionis 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) 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 o f CTLA4 on T cell to B7 on APC delivers the negative signal for T cell activation and inhibits T cell response.Absence of costimulation 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.It is known that the CD28 family plays a key role in regulating T-cell activation; costimulation of a T cell through CD28 is critical for generating antigen-specific immune responses, including an increase of CD4 T-cell proliferation to enhance the production of cytokines, which induce the maturation of the CD8 effector T cell and promote T-cell survival. In contrast, costimulation via CTLA4 downregulates the immune responses by inhibiting T-cell proliferation, cytokine production, and cell cycle progression.Recent studies discovered that other members of the B7/CD28 family also participate in the regulation of cellular and humoral immune responses. One of these is an inducible costimulator (ICOS) that is also called an activation-inducible lymphocyte immunomediatory molecule. Unlike CD28, an ICOS is not constitutively expressed on T cells, but is induced after T-cell activation. Despite the structural homology of an ICOS with CD28 and CTLA4 (19% and 13% similarity of amino-acid sequence of an ICOS to CD28 and CTLA4 in rat, the ICOS differs in mechanisms of action from the others; it does not interact with ligands for CD28 and CTLA4 (B7.1 and B7.2). A novel member of the B7 family called B7 h , B7RP-1, GL50, or ICOSL has been identified as a ligand for ICOS. An ICOS may enhance basic T-cell responses to a foreign antigen, including cell proliferation, secretion of lymphokines, up-regulation of molecules that mediate cell-cell interaction, effective help for antibody secretion by B cells, and maintenance or modulation of memory...