SUPPRESSION OF ALLOGRAFT RESPONSES BY COMBINING DONOR ALLOANTIGEN-SPECIFIC INTRAVENOUS PRESENSITIZATION WITH SUBOPTIMAL DOSES OF FK506

C57BL/6 (B6) mice were injected i.v. with class I H-2-disparate B10.QB R spleen cells (10(7)/mouse). This regimen, termed ''donor alloantigen -specific i.v. presensitization'' (DSP), induced almost complete elimi nation of anti-B10.QBR mixed lymphocyte reaction/IL-2 production but d id not affect the generation of CTL responses. Repeated (5 or 11 times ) administration in vivo (over 7 or 18 days) of FK506 at suboptimal do ses (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 sk in graft survival was not induced by either of a single DSP or FK trea tment (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 B1 0.QBR skin grafts. Under conditions in which lymphoid cells from mice receiving both treatments failed to generate CTL responses, the additi on of recombinant IL-2 to cultures restored the CTL generation, sugges ting 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 combin ed treatment was performed in a particular protocol. These results ind icate that (1) DSP alone fails to prolong graft survival in class I an d class I and II MHC-disparate combinations; (2) such failure is ascri bed to the induction of CTL responses by CTL precursors and CTL helper s, both of which are DSP-resistant; (3) the administration of suboptim al doses of FK506 is not sufficient for the suppression of CTL respons es, but is effective selectively for suppressing DSP-resistant CTL hel pers; and (4) the combination of DSP with FK506 treatment in an approp riate protocol can thus prolong graft survival through the suppression of CTL-involved as well as CTL-independent graft rejection pathways.