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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2523-2529
Stable Mixed Hematopoietic Chimerism in Dogs Given Donor Antigen,
CTLA4Ig, and 100 cGy Total Body Irradiation Before and Pharmacologic
Immunosuppression After Marrow Transplant
Rainer Storb,
Cong Yu,
J. Maciej Zaucha,
H. Joachim Deeg,
George Georges,
Hans-Peter Kiem,
Richard A. Nash,
Peter A. McSweeney, and
John L. Wagner
From the Clinical Research Division, Fred Hutchinson Cancer Research
Center; and the Department of Medicine, University of Washington,
Seattle, WA.
Stable mixed chimerism can be established in dogs given a sublethal
dose of 200 cGy total body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) for 28 and 35 days, respectively, after dog leukocyte
antigen-identical marrow transplantation. Most likely, the role of
pretransplant TBI was to provide host immunosuppression, since stable
mixed chimerism was also achieved in MMF/CSP-treated dogs when 450 cGy irradiation, targeted to cervical, thoracic, and upper abdominal lymph
nodes, was substituted for TBI. When TBI was reduced from 200 to 100 cGy, all grafts were rejected within 3 to 12 weeks. Here, we asked
whether stable engraftment after 100 cGy TBI could be accomplished by
first reducing the intensity of host immune responsiveness with help of
the fusion peptide CTLA4Ig, which blocks T-cell costimulation through
the B7-CD28 signal pathway. Accordingly, recipient T cells were
activated with intravenous (IV) injections of 106 donor
peripheral blood mononuclear cells (PBMC)/kg per day on days  7 to
1 before 100 cGy TBI, with concurrent administration of CTLA4Ig 4 mg/kg/d IV. All 7 dogs so treated showed initial mixed chimerism. Two
rejected their allografts after 8 and 20 weeks, respectively, and
survived with autologous marrow recovery; 1 mixed chimera was
unevaluable because of death at 3 weeks from intussusception; and 4 showed persisting mixed chimerism, including unirradiated marrow and
lymph node spaces, for now more than 46 to 70 weeks after transplant.
Data support the hypothesis that stable marrow allografts can be
established by combining nonmyeloablative pretransplant host
immunosuppression with posttransplant host and donor cell
immunosuppression using MMF/CSP.
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