Tolerance promoting cells were derived from infused donor bone marrow cell (DBMC) in dogs treated with fractionated lymphoid irradiation (FLI) and FK506 (FK)

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We have developed safe regimen that can produce chimerism and tolerance to kidney allografts between histoincompatible beagles. The basic regimen included preoperative FLI, DBMC-infusion at kidney grafting (KGT) and postoperative IM of FK. Methods; Dogs were selected on the basis of MLR (S.I.=10), sex-mismatched, unrelated pairs and matching grade was confirmed by PCR-SSCP. They were treated with FLI (150rad/day) for 3 days, PHA-nonresponding DBMC-infusion(2x10ィイD17ィエD1/kg) and FK (0.08mg/kg/d for 90 days). As for monitoring, MLR-blocking test was performed; Responder cells(preoperatively frozen stored cells) against (D) or fixed third-party(T) cells as stimulator cells were prepared, and cocultured cells were as follows; R peripheral lymphocytes, R lymphnode cells, and R BMCs; chimerism analysis by karyotyping; lymphocytotoxicity test; and skingrafting(SGT) from kidney (D) and (T). Results; They were divided into 5 groups, as follows; group A) non-treated(n=9); B)FK,(n=6); C)FLI,DBMC, … More (n=3); D)FLI, FK(n=8); E)FLI, DBMC, and FK(n=l3). In group A), B), C), MSD;11, 5, 7.3 days. In group D), all KGs in 7/8 were rejected within 90 days(MSD; 53.2 days). One KG rejected on 118th days without prolongation of SGs from both (D) and (T). In group E) (MSD; 178.8 days), Rs with persistent chimerism(5/8), survived >70 days, one of which had complete acceptance or SGs only from kidney (D)'s. And also, two of three with same sex-comination survived >200 days with acceptance of SGs only from kidney (D)s. Rs with temporary chimerism in 3/8 were rejected by 137 days without prolongation of SGs from both (D) and (T). In 2 long survivors with chimerism in group E), specific suppression by repopulated R's peripheral lymphocyte, lymphnode cells and BMCs was observed in MLR-blocking study. On the contrary, in (R )s which were rejected with disappearance of chimerism, nonsuppression by any lymphoid cells observed with elevation of (D) specific lymphocytotoxic antibody. Conclusion; Combined treatment with FLI, DBMC-infusion, and Fk was effective in prolongation of KGs. Graft promoting factors derived from chimerric bone marrow specifically blocked R anti-(D) activity. Less