High dose of antithrombin III induces indefinite survival of fully allogeneic cardiac grafts and generates regulatory cells

Background. The authors investigated whether antithrombin III (AT-III) could induce unresponsiveness to alloantigens. Methods. CBA mice were given intravenous injection of 50 or 500 U/kg AT-III or control plasma the same day as transplantation of a heart from a C57BL/6 mouse. An adoptive transfer study and mixed leukocyte culture analysis were. also performed. Results. Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 9 days). The 50-U/kg dose of AT-III induced a moderate increase in graft survival (MST, 25 days), whereas control mice rejected their graft acutely (MST, 7 days). With the 500-U/kg dose (if AT-III, all grafts survived indefinitely (> 100 days) and regulatory cells were generated. In vitro,,AT-III suppressed proliferation of mixed leukocyte responses and generation of inteileukin-2. Conclusion. AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.