Tju103和CTLA4-Ig联合诱导主要组织相容复合物半相合小鼠骨髓移植耐受

Induction of tolerance in MHC haploidentical bone marrow transplantation in mice by combination of Tju103 and CTLA4-Ig

目的 观察吲哚亚甲基异烟腙 (Tju1 0 3)和细胞毒性T淋巴细胞相关性抗原 4免疫球蛋白 (CTLA4 Ig)联合应用 ,对主要组织相容复合物 (MHC)半相合小鼠骨髓移植的植入以及移植后移植物抗宿主病 (GVHD)、移植物抗白血病 (GVL)和抗感染的影响 ;探索一条既能降低GVHD又能保留GVL和抗感染能力的移植途径。方法 体外以受者 (正常CB6F1鼠 ,H 2 bd)抗原为特异性免疫耐受诱导原 ,MHC半相合的供者 (C5 7BL/ 6鼠 ,H 2 b)T淋巴细胞经和Tju1 0 3、CTLA4 Ig共育后 ,与供者骨髓细胞混合输入经预处理的受者体内。观察Tju1 0 3和CTLA4 Ig联合作用对移植后造血重建、GVHD、GVL和抗感染的影响。结果 单纯照射组 (A组 ) :全部 (1 0只 )白血病小鼠于照射后 1 1d内死于造血功能衰竭 ,大部分 (8只 )死于照射后 4～ 7d。环磷酰胺 (CTX)治疗组 (B组 ) :全部 (1 0只 )小鼠于接种白血病细胞后 1 6～ 2 3d(移植后 1 1～ 1 8d)死于白血病 ,但CTX治疗延长了白血病小鼠存活期。单纯移植组 (C组 ) :全部 (1 0只 )小鼠于移植后 2 1d内死亡 ,均死于GVHD。CsA预防组 (D组 ) :4只小鼠于移植后 8～ 2 2d内死亡 ,其中 1只死于白血病 ,2只死于感染 ,1只死于GVHD ;6只存活超过30d。Tju1 0 3处理组 (E组 ) :4只小鼠于移植后 9～ 2 6d内死亡 ,?

Objective To observe the effect of combination of Tju103 and CTLA4-Ig on engraftment, graft versus host disease (GVHD), graft versus leukemia (GVL) and anti-infection post major histocompatibility complex (MHC) haploidentical bone marrow transplantation in mice in order to seek an effective access to transplantation with less GVHD and more potential GVL and anti-infection.Methods In the presence of the recipient's antigen (normal CB6F1, H-2 bd) as a stimulus for induction of specific immune tolerance, T cells from the MHC haploidentical donors (C57BL/6, H-2 b) were first in vitro cultured with Tju103 and CTLA4-Ig, then were transfused with the donors' bone marrow cells into the preconditioned recipients. At last, the effect of combination of Tju103 and CTLA4-Ig on hematopoietic rebuilding, GVHD, GVL and anti-infection was observed in compared with CsA, Tju103 and CTLA4-Ig as controls.Results The only irradiated group (group A): All the mice (10 mice) died of failure of hematopoiesis within 11 days post irradiation, of which most (8 mice) died within 4～7 days post transplantation. The CTX-treated leukemia group (group B): All the mice (10 mice) died of leukemia within 16～23 days post leukemia cells infusion (11～18 days post BMT). CTX treatment prolonged the survival time. The only transplanted group (group C): The mice began to die from day 16 post transplantation, and all (10 mice) died of GVHD within 3 weeks. The CsA prophylaxis group (group D): 4 mice died within 8～22 days after transplantation, of which one died of leukemia, two died of infection and one died of GVHD, and the remaining 6 survived over 30 days post transplantation. The Tju103 treated group (group E): 4 mice died within 9～26 days post transplantation, of which one died of leukemia, one died of infection and two died of GVHD, and the remaining 6 mice survived over 30 days post transplantation. The CTLA4-Ig treated group (group F): 3 mice died within 14～23 days after transplantation, of which one died of infection and two died of GVHD, and the remaining 7 survived over 30 days post transplantation. The Tju103/CTLA4-Ig treated group (group G): one died of GVHD on day 19 after transplantation, and the remaining 9 mice survived over 30 days post transplantation. Conclusions CsA, Tju103 or CTLA4-Ig alone could prolong survival time and reduce incidence and degree of GVHD severity. But CTLA4-Ig could spare much ability of GVL and anti-infection while Tju103, just like CsA, couldn't. Combination of both was the most favorable way for transplantation with the most remarkable efficiency on prolongation of survival time and reduction of GVHD.