Adoptive immunotherapy in canine mixed chimeras after nonmyeloablative hematopoietic cell transplantation

Development of nontoxic and nonmyeloablative regimens for allogeneic hemato poietic stem-cell transplantation will decrease transplantation-related mor tality caused by regimen-related toxic effects. In pursuit of this goal, a dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen-identical litter mates are given sublethal total-body irr adiation (2 Gy) before stem-cell transplantation and immunosuppression with mycophenolate mofetil and cyclosporine afterward. In the current study, we examined whether donor lymphocyte infusion (DLI) could be used as adoptive immunotherapy to convert mixed to complete donor chimerism. First, 8 mixed chimeras were given unmodified DLI between day 36 and day 414 after stem-c ell transplantation. After a 10-to 47-week follow-up period, there were no significant changes in the percentage of donor engraftment, Next, we immuni zed the donor to the minor histocompatibility antigens (mHA) of the recipie nt by means of repeated skin grafting. Lymphocytes from the mHA-sensitized donor were infused between day 201 and day 651 after transplantation. All 8 recipients of mHa-sensitized DLI had conversion to greater than 98% donor chimerism within 2 to 12 weeks of the infusion. Complications from mHA-sens itized DLI included graft-versus-host disease in 2 dogs and marrow aplasia in 1, These results showed that the low-dose transplant regimen establishes immune tolerance, and mHA-sensitized DLI is required to break tolerance, t hereby converting mixed to complete donor chimerism, We propose that mixed chimerism established after nonmyeloablative allogeneic stem-cell transplan tation provides a platform for adoptive immunotherapy that has clinical pot ential in the treatment of patients with malignant diseases. (C) 2000 by Th e American Society of Hematology.