A novel application of cyclosporine A in nonmyeloablative pretransplant host conditioning for allogeneic BMT

The treatment of mice with anti-CD4 and anti-CD8 monoclonal antibodies (mAb s) on day -5, plus 3 Gy whole body irradiation (WBI) and 7 Gy thymic irradi ation (TI) on day 0, allows fully major-histocompatibility-complex-mismatch ed allogeneic bone marrow engraftment and the induction of immunologic tole rance. TI is required in this model to overcome alloreactivity and possibly to make "space" in the recipient thymus so that lasting central tolerance can be achieved. In addition to suppressing mature T cells in the periphery , Cyclosporine A (CYA) and glucocorticoids have a powerful influence on the thymus, In this study, we evaluated whether the administration of CYA to r ecipient mice for 12 days prior to bone marrow transplant (BMT), of glucoco rticosteroids on the day of BMT, or a combination of both, could create spa ce and overcome alloresistance in the thymus by specifically depleting imma ture and mature thymocytes prior to BMT. High levels of multilineage donor hematopoietic repopulation and specific transplantation tolerance were achi eved in mice treated from days -15 to -3 with CYA (20 mg/kg/d subcutaneousl y), anti-CD4/CD8 mAbs on day -5, followed by 3 Gy WBI and 15 x 10(6) alloge neic bone marrow cells on day 0, VP analysis suggested a central deletional tolerance mechanism. The same treatment without CYA pretreatment allowed o nly transient chimerism, without tolerance. Corticosteroid treatment abolis hed the engraftment-promoting and tolerance-inducing effects of CYA, These results demonstrate a novel pretransplantation-only application of CYA, whi ch facilitates allogeneic marrow engraftment with minimal conditioning, by creating thymic space and/or overcoming intrathymic alloresistance. (C) 200 0 by The American Society of Hematology.