| MHC-incompatible allo-geneic BMT(bone marrow transplantation) has higher incidences of graft failure and post-transplant complications associated, of which GVHD(grft-versus-host disease)is the most severe problem contributing mainly to the cause of death in the setting of allo-BMT.Inhibition of the donor's T cells with non-specific immune inhibitive agents or deleption of T cells of the graft is usually employed to decrease GVHD obviously,though both approaches bring about a significant rise in failure of engraftment, replase of malignant diseases and infection post BMT.Therfor, keeping and modulating the donor's T cells of the graft to tolerate specially to the host's antigen counts much.Induction of anergy of T cells by blocking transduction of costimulatory signal is well known as a feasible and effective method.But it is impossible to achieve a complete cutoff and a desired result through this way because there are too many such pathways existing and funtioning.So it is optimal to regulate a variety of signal pathways simultaneously.Tju 103,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 and GVHD post allo-BMT.And CTLA4-Ig is one of the most powerful reagents for blocking costimulatory signals.So combination of Tju 103 and CTLA4-Ig,modulating both antigen andcostimulatory signals,may produce a more intensive immune inhibition to T cells.But it is unknown whether it can preserve the potential of CTLA4-Ig to induce a special tolerance.Under such background,we will try the combination of the two reagents in modulation of the double-signal pathways for activation of T cells and test its effects on expressions of phenotypes and function of the donor's T cells,and on GVHD,GVL and anti-infection post allo-BMT,in order to seek an effective access to induction of special tolerance in an allo-BMT setting with less GVHD and strong GVL effect and anti-infection capacity.Methods(1) Induction of anergy of the donor's T cells in allo-BMT and tests for their pheotypes and function: Selected the donor's(C57BL/6H-2b) T cells ,then modulated the double signals for activation of T cells by culturing them with CTLA4-Ig/Tjul03 in the presence of the recipients' antigens(MitC-handled macrophags from BALB/cH-2d or CB6FlH-2bd). At last,FCM was employed to check the phenotypes of the regulated donor's T cells, and methylcellulose colony-forming unit culture, MLR and MTT assays for effects on hematpoiesis, proliferation and cytotoxicity respectively.(2)Development of the mice models of EL9611 erythroleukemia: Developed two mice models of EL9611 erythroleukemia by tail vein injection of EL9611 cells to the recipients(BALB/c or CB6Fl),then verified the models.(3)Development of the mice models of GVHD post allo-BMT: BALB/c and CB6F1 mice were preconditioned with TBI of 60Co as recipients, then were transplanted in the modes of C57BL/6H-2b-BALB/cH-2dand C57BL/6H-2b-CB6FlH'2bA to build the mice GVHD models of allo-BMT,and at last were comfirmed for GVHD. (4) Mice allo-BMT assay: With C57BL/6 mice as donors and BALB/cor CB6F1 mice as recipients, full mismatched or haploidentical allo-BMT was carried out on the basis of the above mice models. After that, tests for effects of combination of CTLA4-Ig and Tjul03 on engraftment, GVHD, GVL effect, infection and skin transplantation post BMT were done.Results(1) Proliferative response and cytotoxicity of T cells: With stimulus for induction of specific tolerance, CTLA4-Ig and CTLA4-Ig/Tjul03 both inhibited significantly proliferative response of C57BL/6 mice T cells to encountered antigen(BALB/c or CB6Fl)(inhibitive rate: full disparate BMT by 77.67 + 0.58% and 87.67+1.16%; semi-compatible BMT by 80.76 + 2.68% and 89.54 + 3.15%), but preserved their normal response to unencountered and leukemic antigens(inhibitive rate: full mismatched BMT by 4.33 +0.58% and 4.67 + 1.16%;...
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