Tao H R
Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Hokkaido Igaku Zasshi. 1998 May;73(3):227-37.
FK506 treatment markedly increased survival rates of [BALB/c-->C3H/He] bone marrow and spleen (BM/Spl) chimeras which had severe graft-versus-host disease (GVHD), marking 91% survival rates on day 60. In contrast, none of the vehicle-treated allogeneic BM/Spl chimeras survived more than 43 days after bone marrow transplantation (BMT). All the [BALB/c-->C3H/He] bone marrow (BM) chimeras survived more than 60 days after BMT, regardless of FK506 treatment. Alloreactive mixed lymphocyte reactions (MLRs) against alloantigens in donor, host, and third party on week 8 were markedly inhibited in the spleen cells from all the chimeras including [C3H/He-->C3H/He] (syngeneic) BM chimeras. On week 12, alloreactive MLRs were still low in FK506-treated allogeneic BM/Spl and BM chimeras although those against third party alloantigen in the spleen cells from vehicle-treated allogeneic BM chimeras and syngeneic BM chimeras gradually recovered. Somewhat nonspecific cytotoxic activities against these alloantigens were sometimes observed, especially in week 8. Mitogen-induced responses confirmed that the immunosuppressive activity of FK506 was directed to T cells, since concanavalin A (ConA)- and phytohemagglutinin (PHA)-induced responses were completely inhibited, but lipopolysaccharide (LPS)- and pokeweed mitogen (PWM)-induced responses were not. Reverse-transcription polymerase chain reaction (RT-PCR) method suggested that perforin and granzyme B gene expressions were basically unchanged or rather increased in the spleen cells from FK506-treated allogeneic BM/Spl and BM chimeras. These gene expressions suggested that FK506 exerted its immunosuppressive effect in murine allogeneic bone marrow chimeras without mediating perforin and granzyme B.
FK506治疗显著提高了患有严重移植物抗宿主病（GVHD）的[BALB/c→C3H/He]骨髓和脾脏（BM/Spl）嵌合体的存活率，在第60天时存活率达到91%。相比之下，接受赋形剂治疗的同种异体BM/Spl嵌合体在骨髓移植（BMT）后存活时间均未超过43天。所有[BALB/c→C3H/He]骨髓（BM）嵌合体在BMT后存活时间均超过60天，无论是否接受FK506治疗。在第8周时，包括[C3H/He→C3H/He]（同基因）BM嵌合体在内的所有嵌合体的脾细胞中，针对供体、宿主和第三方同种异体抗原的同种异体混合淋巴细胞反应（MLR）均受到显著抑制。在第12周时，接受FK506治疗的同种异体BM/Spl和BM嵌合体中的同种异体MLR仍然较低，尽管接受赋形剂治疗的同种异体BM嵌合体和同基因BM嵌合体脾细胞中针对第三方同种异体抗原的反应逐渐恢复。有时会观察到针对这些同种异体抗原的一些非特异性细胞毒性活性，尤其是在第8周时。丝裂原诱导反应证实FK506的免疫抑制活性针对T细胞，因为刀豆蛋白A（ConA）和植物血凝素（PHA）诱导的反应完全受到抑制，但脂多糖（LPS）和商陆丝裂原（PWM）诱导的反应未受抑制。逆转录聚合酶链反应（RT-PCR）方法表明，在接受FK506治疗的同种异体BM/Spl和BM嵌合体的脾细胞中，穿孔素和颗粒酶B基因表达基本未改变或反而增加。这些基因表达表明，FK506在小鼠同种异体骨髓嵌合体中发挥免疫抑制作用，而不介导穿孔素和颗粒酶B。
