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,¶
*
Department of Immunology, National Children’s Medical Research Center, Tokyo, Japan; Divisions of
Rheumatology and
Pathobiology, Department of Internal Medicine, and
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; Departments of
¶ Molecular Immunology and
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Oral Surgery, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and
#
Department of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
We investigated the effect of CD137 costimulatory blockade in the
development of murine acute and chronic graft-vs-host diseases (GVHD).
The administration of anti-CD137 ligand (anti-CD137L) mAb at
the time of GVHD induction ameliorated the lethality of acute GVHD, but
enhanced IgE and anti-dsDNA IgG autoantibody production in chronic
GVHD. The anti-CD137L mAb treatment efficiently inhibited donor
CD8+ T cell expansion and IFN-
expression by
CD8+ T cells in both GVHD models and CD8+ T
cell-mediated cytotoxicity against host-alloantigen in acute GVHD.
However, a clear inhibition of donor CD4+ T cell expansion
and activation has not been observed. On the contrary, in chronic GVHD,
the number of CD4+ T cells producing IL-4 was enhanced by
anti-CD137L mAb treatment. This suggests that the reduction of
CD8+ T cells producing IFN- promotes Th2 cell
differentiation and may result in exacerbation of chronic GVHD. Our
results highlight the effective inactivation of CD8+ T
cells and the lesser effect on CD4+ T cell inactivation by
CD137 blockade. Intervention of the CD137 costimulatory pathway may be
beneficial for some selected diseases in which CD8+ T cells
are major effector or pathogenic cells. Otherwise, a combinatorial
approach will be required for intervention of CD4+ T cell
function.
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