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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-12-3867.
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Blood, 15 June 2003, Vol. 101, No. 12, pp. 5068-5075
TRANSPLANTATION
Selective T-cell ablation with bismuth-213–labeled anti-TCR  as nonmyeloablative conditioning for allogeneic canine marrow transplantation
Wolfgang A. Bethge,
D. Scott Wilbur,
Rainer Storb,
Donald K. Hamlin,
Erlinda B. Santos,
Martin W. Brechbiel,
Darrell R. Fisher, and
Brenda M. Sandmaier
From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Washington, Seattle; Department of Radiation Oncology, University of Washington, Seattle; National Cancer Institute, National Institutes of Health, Bethesda, MD; and Pacific Northwest National Laboratory, Richland, WA.
Two major immunologic barriers, the host-versus-graft (HVG) and graft-versus-host (GVH) reactions, have to be overcome for successful allogeneic hematopoietic cell transplantation. T cells were shown to be primarily involved in these barriers in the major histocompatibility complex identical setting. We hypothesized that selective ablation of T cells using radioimmunotherapy together with postgrafting immunosuppression would suffice to ensure stable allogeneic engraftment. We had described a canine model of nonmyeloablative marrow transplantation in which host immune reactions were impaired by a single dose of 200 cGy total body irradiation (TBI), and both GVH and residual HVG reactions were controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Here, we substituted the  -emitter bismuth-213 (213Bi) linked to a monoclonal antibody (mAb) against T-cell receptor (TCR)  , using the metal-binding chelate diethylenetriaminepentaacetic acid (DTPA) derivative cyclohexyl–(CHX)-A'', for 200 cGy TBI. Biodistribution studies using a  -emitting indium-111–labeled anti-TCR mAb showed uptake primarily in blood, marrow, lymph nodes, spleen, and liver. Four dogs were treated with 0.13 to 0.46 mg/kg TCR mAb labeled with 3.7 to 5.6 mCi/kg (137-207 MBq/kg) 213Bi. The treatment was administered in 6 injections on days –3 and –2 followed by transplantation of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF/CSP. The therapy was well tolerated except for elevations of transaminases that were transient in all but one of the dogs. No other organ toxicities or signs of graft-versus-host disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5% to 55% after more than 30 weeks of follow up.
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