Prevention and treatment of GVHD mediated by herpes simplex virus-semi random 39 thymidine kinase-ganciclovir/acydovir after murine ailo-bone marrow transplantation

Abstract

Obiective To study whether herpes simplex virus-semi random 39 thymidine kinase-ganciclovir/acyclovir (HSV-sr39TK-GCV/ACV) could prevent and treat graft-versus-host disease (GVHD) after murine allo-bone marrow transplantation (alIo-BMT). Methods Donor spleniclyrnphocytes were infected by lentiviral vectors carrying HSV-sr39TK. With donor bone marrow cells,they were both transplanted into recipient mice irradiated by 60>Coγ ray. C57BL/6 mice were used as the donor mice. Balb/c mice were used as the recipient mice. GCV/ACV was administered for 7 daysby intraperitoneal injection after transplantation. The recipient mice were divided into 6 groups: (1)GCV groups. These mice were transplanted with bone marrow cells and sr39TK+T lymphocytes.Ten mice were administered with GCV 0. 5 rng/d between 0 day and 6 day after transplantation. Ten were administered with GCV 0. 5 mg/d between 7 day and 13 day after transplantation. And the others were administered with GCV between 12 day and 18 day after transplantation; (2) ACV groups. These mice were transplanted with bone marrow cells and sr39TK+T lymphocytes. Ten micewere administered with ACV 0. 5 mg/d between 0 day and 6 day after transplantation. Ten were administered with ACV 0. 5 mg/d between 7 day and 13 day after transplantation. And the otherswere administered with ACV between 12 day and 18 day after transplantation; (3) Transplantation control group. These mice were only transplanted with bone marrow cells; (4) Splenic lymphocytes control group. These mice were transplanted bone marrow cells and splenic lymphocytes; (5) GCV control group. These mice were transplanted with bone marrow cells and splenic lymphocytes, andadministered with GCV 0.5 mg/d between 7 day and 13 day after transplantation; (6) sr39TK controlgroup. These mice were transplanted with bone marrow cells and sr39TK+T lymphocytes. The sur-vival time, incidence of GVHD, T lymphocytes immunity reconstruction and the ratio of allogeneicchimeras were detected after allo-BMT. Results The mice in control groups were all dead no morethan 19 days after transplantation. The average survival time in GCV groups was (36.70±5.20),(40.30±4.69) and (27.10±4.85) days, respectively. The average survival time in ACV groups was(36.50±5.26), (46.20±3.61) and (30.90±5.21 ) days, respectively. The average survival time inGCV groups and ACV groups were all longer than in control groups. The survival time in GCV groupand ACV group was significantly longer than 4 control groups (P<0.01). The survival time waslonger and 50-day survival rate was higher in GCV group and ACV administered with GCV or ACV0.5 mg/d between 7 day and 13 day after transplantation than in other groups (P<0.05). Theincidence of Ⅲ-Ⅳ GVHD after allo-BMT in control group was 100%. The dead mice in experimentalgroups had pathological changes of Ⅱ-Ⅳ GVHD. Long-term survival mice only exhibited pathologicalchanges of Ⅰ-Ⅱ GVHD. Conclusion HSV-sr39TK-GCV/ACV had a certain effect in preventing andtreating GVHD after allo-BMT; The ACV's effect to control GVHD was better than GCV' s. Theeffect of ACV administration 7 days after allo-BMT to control GVHD was best. Key words: Genes, transgenic, suicide;  Graft vs host disease;  Bone marrow transplantation; Simplexvirus;  Thymidine, kinase