Iwata H, Kitagawa S, Sato S, Kosugi A, Hirose H, Hamaoka T, Shearer G M, Fujiwara H
Biomedical Research Center, Osaka University Medical School, Japan.
Transplantation. 1993 Jul;56(1):173-80. doi: 10.1097/00007890-199307000-00032.
C57BL/6 (B6) mice were injected i.v. with class I H-2-disparate B10.QBR spleen cells (10(7)/mouse). This regimen, termed "donor alloantigen-specific i.v. presensitization" (DSP), induced almost complete elimination of anti-B10.QBR mixed lymphocyte reaction/IL-2 production but did not affect the generation of CTL responses. Repeated (5 or 11 times) administration in vivo (over 7 or 18 days) of FK506 at suboptimal doses (0.75-1.0 mg/kg/day) failed to eliminate the capacities to exhibit MLR/IL-2 production and to generate CTL responses. Prolongation of skin graft survival was not induced by either of a single DSP or FK treatment (0.75-1.0 mg/kg/day, 11 times during 18 days) alone, but by the combination of these. Such combined treatment also resulted in almost complete reduction of CTL responses before (5 rounds of FK injection) or after (11 rounds of FK injection) recipients were engrafted with B10.QBR skin grafts. Under conditions in which lymphoid cells from mice receiving both treatments failed to generate CTL responses, the addition of recombinant IL-2 to cultures restored the CTL generation, suggesting that CTL precursors themselves are not attenuated by the combined treatment. Both prolongation of graft survival and suppression of CTL responses were obtained when the administration of FK506 was started before but not after DSP. Prolongation of graft survival could also be obtained in class I and II MHC-disparate combinations when the combined treatment was performed in a particular protocol. These results indicate that (1) DSP alone fails to prolong graft survival in class I and class I and II MHC-disparate combinations; (2) such failure is ascribed to the induction of CTL responses by CTL precursors and CTL helpers, both of which are DSP-resistant; (3) the administration of suboptimal doses of FK506 is not sufficient for the suppression of CTL responses, but is effective selectively for suppressing DSP-resistant CTL helpers; and (4) the combination of DSP with FK506 treatment in an appropriate protocol can thus prolong graft survival through the suppression of CTL-involved as well as CTL-independent graft rejection pathways.
将I类H-2不相合的B10.QBR脾细胞（10⁷/只小鼠）经静脉注射到C57BL/6（B6）小鼠体内。这种方案被称为“供体同种异体抗原特异性静脉预致敏”（DSP），它几乎完全消除了抗B10.QBR混合淋巴细胞反应/IL-2的产生，但不影响CTL反应的产生。以次优剂量（0.75 - 1.0毫克/千克/天）在体内重复（5次或11次）给予FK506（在7天或18天内）未能消除表现出MLR/IL-2产生和产生CTL反应的能力。单独的一次DSP或FK治疗（0.75 - 1.0毫克/千克/天，在18天内11次）均未诱导皮肤移植存活期延长，但二者联合则可。这种联合治疗还导致在受体植入B10.QBR皮肤移植前（5轮FK注射）或后（11轮FK注射）CTL反应几乎完全降低。在接受两种治疗的小鼠的淋巴细胞无法产生CTL反应的条件下，向培养物中添加重组IL-2可恢复CTL的产生，这表明CTL前体细胞本身并未因联合治疗而减弱。当在DSP之前而非之后开始给予FK506时，可获得移植存活期延长以及CTL反应的抑制。当按照特定方案进行联合治疗时，在I类和II类MHC不相合的组合中也可获得移植存活期延长。这些结果表明：（1）单独的DSP在I类以及I类和II类MHC不相合的组合中无法延长移植存活期；（2）这种失败归因于CTL前体细胞和CTL辅助细胞诱导的CTL反应，二者均对DSP有抗性；（3）给予次优剂量的FK506不足以抑制CTL反应，但对选择性抑制抗DSP的CTL辅助细胞有效；（4）因此，按照适当方案将DSP与FK506治疗联合，可通过抑制涉及CTL的以及不依赖CTL的移植排斥途径来延长移植存活期。
