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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3262-3269
Adoptive immunotherapy in canine mixed chimeras after
nonmyeloablative hematopoietic cell transplantation
George E. Georges,
Rainer Storb,
Jennifer D. Thompson,
Cong Yu,
Ted Gooley,
Benedetto Bruno, and
Richard A. Nash
From the Clinical Research Division, Fred Hutchinson Cancer Research
Center, Department of Medicine, University of Washington, Seattle, WA.
Development of nontoxic and nonmyeloablative regimens for
allogeneic hematopoietic stem-cell transplantation will decrease transplantation-related mortality 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 irradiation (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-cell
transplantation. After a 10- to 47-week follow-up period, there were no
significant changes in the percentage of donor engraftment. Next, we
immunized the donor to the minor histocompatibility antigens (mHA) of
the recipient 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-sensitized 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,
thereby converting mixed to complete donor chimerism. We propose that mixed chimerism established after nonmyeloablative allogeneic stem-cell
transplantation provides a platform for adoptive immunotherapy that has
clinical potential in the treatment of patients with malignant diseases.
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