HEMOPOIETIC GRAFTS BETWEEN DLA-IDENTICAL CANINE LITTERMATES FOLLOWING DIMETHYL MYLERAN

Abstract

Dogs were given a single (supralethal) dose of 10 mg of dimethyl myleran (DMM) per kg i.v. followed by infusions of marrow, 0.4 ± 0.2 × 109 (SD) cells/kg, and blood leukocytes, 1.4 ± 0.5 × 109 (SD)/kg, from DLA-identical littermates of opposite sex. DLA identity was determined by serological histocompability typing and mutual nonreactivity in mixed leukocyte culture. Sixteen dogs were given only DMM before the hemopoietic graft: two never showed evidence of marrow engraftment, six had initial engraftment but subsequently rejected the graft, and eight had sustained engraftment. Four of the eight were alive between days 557 and 739. Ninety-seven, 70, and 65%, respectively, of metaphases analyzed in their marrows, peripheral blood, and lymph nodes showed the donor karyotype. Ten dogs were given antithymocyte serum (ATS) for 6 days before DMM and the hemopoietic graft: one had initial engraftment but subsequently rejected the graft and nine had sustained engraftment. Eight of the nine were alive between 174 and 382 days. Between 82 and 97% of their hemopoietic cells showed the donor karyotype. Three dogs were given a combination of procarbazine and ATS for 6 days before DMM and the hemopoietic graft: all three had sustained engraftment, and 99 to 100% of their hemopoietic cells showed the donor karyotype. In conclusion, a dose of 10 mg of DMM per kg was sufficiently immunosuppressive to permit sustained engraftment of DLA-identical marrow in 50% of the dogs studied. Fifty percent of the dogs rejected the graft, presumably as a result of resistance to “minor” histocompability systems not associated with DLA. The addition of ATS or procarbazine and ATS to DMM successfully abrogated resistance. Its profound antitumor activity with marrow toxicity reversible by marrow transplantation combined with its moderate immunosuppressive properties suggest that DMM is useful in combination with other agents to condition human patients with hematologic malignancy for marrow transplantation.