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-TCR+, and 
-TCR+ Cells in the Recipient Hematopoietic Environment Mediate Resistance to Engraftment of Allogeneic Donor Bone Marrow1
*
Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202;
Department of General and Thoracic Surgery, University of Kiel, Kiel, Germany; and
Department of Microbiology and Immunology, Medical College of Pennsylvania, Hahnemann University, Philadelphia, PA 19129
Historically, conditioning for engraftment of hematopoietic
stem cells has been nonspecific. In the present study, we characterized
which cells in the recipient hematopoietic microenvironment prevent
allogeneic marrow engraftment. Mice defective in production of
-TCR+, 
-TCR+, - plus
-TCR+, CD8+, or CD4+ cells
were transplanted with MHC-disparate allogeneic bone marrow.
Conditioning with 500 cGy total body irradiation (TBI) plus a
single dose of cyclophosphamide (CyP) on day +2 establishes chimerism
in normal recipients. When mice were conditioned with 300 cGy TBI plus
a single dose of CyP on day +2, all engrafted, except wild-type
controls and those defective in production of CD4+ T cells.
Mice lacking both - and -TCR+ cells engrafted
without conditioning, suggesting that both - and -TCR T
cells in the host play critical and nonredundant roles in preventing
engraftment of allogeneic bone marrow. CD8 knockout (KO) mice engrafted
without TBI, but only if they received CyP on day +2 relative to the
marrow infusion, showing that a CD8- cell was targeted by
the CyP conditioning. The CD8+ cell effector function is
mechanistically different from that for conventional T cells, and
independent of CD4+ T helper cells because CD4 KO mice
require substantially higher levels of conditioning than the other KO
phenotypes. These results suggest that a number of cell populations
with different mechanisms of action mediate resistance to engraftment
of allogeneic marrow. Targeting of specific recipient cellular
populations may permit conditioning approaches to allow mixed chimerism
with minimal morbidity and could potentially avoid the requirement for
myelotoxic agents altogether.
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