基质金属蛋白酶抑制剂对小鼠急性移植物抗宿主病的预防作用

Prophylactic effect of matrix metalloproteinase inhibitor on acute graft-versus-host disease in a murine model

目的探讨基质金属蛋白酶抑制剂（TIMP）对小鼠异基因造血干细胞移植（allo—HSCT）后急性移植物抗宿主病（aGVHD）的预防作用。方法用主要组织相容性复合物完全不相合的纯种近交系小鼠[供鼠为雌性C57BIf6（H-2^b）鼠；受鼠为雄性BALB／c（H-2^d）鼠]建立allo—HSCT后aGVHD动物模型。将小鼠随机分3组，给予TIMP（A组）、环孢菌素A（CsA）（B组）作为GVHD的预防方案。结果移植小鼠出现典型的aGVHD症状，未用aGVHD预防方案的移植小鼠（C组）死亡高峰在移植后第5天～第7天，全部死亡。用aGVHD预防方案的A组和B组小鼠aGVHD症状明显减轻，平均生存时间较C组显著延长[分别延长（4．8±1．4）d和（4．3±0．9）d，P〈0．05]。不同aGVHD预防方案的移植小鼠之间，移植后外周血常规变化差异无统计学意义。应用预防方案后，移植小鼠aGVHD病理表现减轻。结论TIMP能有效预防小鼠allo—HSCT后aGVHD，减轻其症状和病理损害程度，显著延长平均生存时间。TIMP对造血干细胞植入和造血恢复无显著影响。

Objective To explore the prophylactic effect of tissue inhibitor of martrix metalloproteinase （TIMP） on acute graft-versus-host disease （aGVHD） after allogeneic hematopoietic stem cell transplantation （allo-HSCT） in a murine model. Methods The murine model of aGVHD after allo-HSCT was established by using female C57BL/b （ H-2^b ） mouse as the donor, and male BALB/c （ H-2^d ） as the recipient. After allo-HSCT, recipient mice were divided into 3 groups. For aGVHD prophylaxis group A was given TIMP （2 mg/d） , group B CsA （5 mg·kg^-1·d^-1 ） was given, and group C nothing. Physical signs, mean survival time （MST）, peripheral blood counts and aGVHD histopathology were observed. Results Mice in group C developed typical aGVHD and 100% of mortality, with a MST of 8 days, and those in group A and B had longer survival, the MST being （ 4.8 ± 1.4） d and （ 4.3 ±0.9 ） d respectively, with no statistical difference in peripheral blood count between these two groups. Mice in group A showed less severe signs. Conclusions TIMP markedly prolongs MST of allo-HSCT recipients, delays the onset of aGVHD signs, and has no adverse effect on hematopoiesis reconstitution.