| Allo-geneic bone marrow transplantation(allo-BMT) has been accepted as the most effective treatment for many hematologic malignancies,aplastic anemia and inherited disease.But HLA-identical donors are difficult to obtain,HLA haploidentical transplantations are treatment options.Compared with HLA-identical transplants, HLA haploidentical transplantations are complicated by higher rates of Graft-versus-host disease(GVHD) causing early post-transplant mortality.GVHD is a pathophysiological process caused by alloreactive donor T-cell which culminates in multi-organ system dysfunction and destruction. In the past,preclinical and clinical studies involving ex vivo T-cell depletion of the donor BM inoculum and the use of immunosuppressive drugs have shown to be effective approaches to reduce the incidence of GVHD.However,these approaches may result in several adverse consequences,including the increased incidence of leukemia relapse, opportunistic infection and graft rejection.Rather than attempt to suppress donor T-cell responses in the host post-transplantation,approaches to tolerize donor T cells to recipient alloantigens prior to infusion would have several advantages. Importantly,tolerance induction is more likely to be specifically directed against host alloantigens than leukemia or viral antigens which may reach critical antigenic threshold levels during the course of tolerance induction. This would preserve the functional capacity of the remaining T cells to respond to infectious agents and residual leukemia cells.In regard to blocking positive costimulatory signals,the most well-studied interaction involves that of B7/CD28. CD40/CD40L.Direct evidence exists to show that blockade of CD28:B7 interactions by CTLA4-Ig can inhibit T-cell activation and prolong survival.It is well known as a feasible and effective method,but it is insufficient to modulate the immune tolerance of HLA haploidenticaltransplantations.It is necessary to explore new methods or combinations for the induction of tolerance.The immune activation of T cells requires two signals from antigen presenting cells(APC).One of these signals is delivered to the T-cell receptor(TCR) by an immunogenic peptide displayed in the context of the major histocompatibility complex. The other,a "costimulatory"signal,is generated by the interaction of certain cell-surface proteins on APCs and T cells.Without a costimulatory signal,signaling by the peptide TCR complex does not result in T-cell immunity,but rather in a state of anergy,in which T cell are rendered specifically incapable of responding the antigen that was presented to them in the absence of a costimulatory signals.So it is optimal to regulate a variety of signal pathways simultaneously.TJU103,a small non-peptide organic compound,which was created recently,by binding to the site of CD4, through which CD4 links to MHC- II ,can regulate the antigen signal transduction and cause a marked decline in rejection post allo-skin transplantation.So B7:CD28-based tolerance induction stratrgies may be further augmented by combining CTLA4-Ig blockade with TJU 103.In this research,we try to explore the feasibility and the efficiency of combining TJU 103 with CTLA4-Ig to induce the donor T-cell tolerance,in order to seek an effective access for mitigating the pathogenic effects of GVHD,and conserve the GVL effect in HLA-haploidentical BMT.l.Dose response inhibition of donor T-cell proliferation in the presence of various concentrations of TJU103 or CTLA4-Ig aloneMTT assays were used to evaluate donor T-cell proliferation in MLC.Peripheral blood mononuclear cells(PBMCs) were obtained from heparinized peripheral blood from HLA haploidentical healthy donors(parents 15 cases,children 3 cases,sibling 2 cases) and acute leukemia patients in complete regression(CR).PBMCs were isolated by Histopaque density separation (1.077 g/ml density gradient).The isolated and washedPBMCs were harvested and nucleated cells counted using a hemocytometer and expressed at concentration lx109cells/L. PBMCs from donors were u... |
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