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Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given
sublethal total body irradiation before and pharmacological
immunosuppression after marrow transplantation
R Storb, C Yu, JL Wagner, HJ Deeg, RA Nash, HP Kiem, W Leisenring and H Shulman
Clinical Research Division, Fred Hutchinson Cancer Research Center,
Seattle, WA 98104-2092, USA.
Postgrafting cyclosporine (CSP) given for 35 days resulted in establishment
of stable marrow grafts from DLA-identical canine littermates after
otherwise suboptimal, but nevertheless, lethal conditioning with 450 cGy of
total body irradiation (TBI). We now asked whether sustained allografts
could be achieved after sublethal TBI or without TBI. Five groups of
recipients were studied. Dogs in group 1 were given 200 cGy TBI and
postgrafting CSP, 15 mg/kg twice daily by mouth on days -1 to 35
posttransplant. Dogs in group 2 were given 200 cGy TBI and methotrexate
(MTX), 0.4 mg/kg intravenously (I.V.) on days 1, 3, 6, and 11 along with
CSP. Dogs in group 3 were given 200 cGy TBI and CSP along with
mycophenolate mofetil (MMF), 10 mg/kg twice daily subcutaneously (S.C.) on
days 0 to 27 after transplant, a novel immunosuppressive combination. Dogs
in group 4 were given 100 cGy TBI and MMF/CSP. Dogs in group 5 were not
given TBI and they received MMF/CSP posttransplant. Allografts were
assessed by (Ca)n dinucleotide repeat polymorphism studies in cells from
peripheral blood, lymph nodes, and marrow. Dogs in group 1 had transient
mixed donor-host hematopoietic chimerism for no more than 4 weeks. Three of
six dogs in group 2 had transient mixed chimerism for 3 to 11 weeks, and
three have remained stable mixed chimeras for up to 60 weeks now. Four of
five dogs in group 3 have remained stable mixed chimeras for 54 to 57 weeks
now, while one lost the allograft after 12 weeks. All dogs in groups 4 and
5 rejected their allografts after 2 to 12 weeks. In summary, the
establishment of stable mixed hematopoietic chimerism following
nonmyelosuppressive and nontoxic conditioning programs has remained a
difficult goal. Here we present evidence in a large random-bred animal
species that this goal may be achievable with pharmacological
immunosuppression postgrafting, capable of inhibiting both host-versus-
graft (HVG) and graft-versus-host (GVH) reactions in the setting of DLA-
identical grafts.
Volume 89,
Issue 8,
pp. 3048-3054,
04/15/1997
Copyright © 1997 by The American Society of Hematology
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