autologous blood and marrow transplantation - Blog Science ...

Canine Hematopoietic Stem Allografts
Using Nonmyeloablative Therapy
Brenda M. Sandmaier, Cong Yu, Alexander Barsoukov, Rain
Clinical Research Division (B.M.S., C.Y., A.B., R.S.), Fred Hutchinson
Cancer Research Center, and Department of Medicine (B.M.S., R.S.),
University of Washington, Seattle, WA
ABSTRACT
A major limitation in the application of stem cell transplantation has been
complications related to the conditioning regimens that have been intensified to the
point where organ toxicities have been common, resulting in morbidity and
mortality. Because of potentially severe complications, the use of transplantation
has been restricted to relatively young patients at most transplant centers.
Preliminary studies have shown that stable, allogeneic mixed donor-host
chimerism can be accomplished in random-bred dogs by administering a sublethal
dose of 200 cGy total-body irradiation (TBI) before, and a brief course of immunosuppression
with mycophenolate mofetil (MMF) and cyclosporine (CSP) after,
major histocompatibility complex (MHC)-identical marrow transplantation. MMF
and CSP are capable of controlling both host-vs.-graft (HVG) and graft-vs.-host
reactions and establishing a stable state of graft-host tolerance in this model as
manifested by stable mixed donor-host hematopoietic chimerism. Based on
additional preliminary data using lymphoid radiation instead of TBI, we
hypothesize that the major role of TBI is to provide host immunosuppression.
Current efforts are directed at replacing pretransplant radiation by anti-T cell
reagents such as a monoclonal antibody (mAb) to the T cell receptor aB (TCRaB).
Initial data suggest that in vivo administration of an mAb against TCRaB enhanced
allogeneic engraftment following an otherwise suboptimal dose of 450 cGy TBI
similar to the degree of immunosuppression accomplished by an additional dose of
470 cGy TBI. In the MHC-haploidentical setting, cytokine-mobilized peripheral
blood stem cells (PBSC) given after conditioning with 450 cGy TBI with
postgrafting immunosuppression consisting of MMF and CSP resulted in sustained
donor engraftment in three of six dogs. Current studies are underway evaluating a
mAb directed at CD44, a cellular adhesion molecule expressed on hematopoietic
as well as nonhematopoietic cells. The majority of dogs treated with the mAb in
addition to MMF/CSP have engrafted. These approaches developed in the canine
model have minimal toxicity, are non-marrow ablative and, thus, are safe enough
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