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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2963-2970
Role of CD28 in Acute Graft-Versus-Host Disease
Xue-Zhong Yu,
Paul J. Martin, and
Claudio Anasetti
From the Division of Clinical Research, Fred Hutchinson Cancer
Research Center, Seattle, WA; and the Department of Medicine, Division
On Oncology, University of Washington, Seattle, WA.
Because CD28-mediated T-cell costimulation has a pivotal role in the
initiation and maintenance of T-cell responses, we tested the
hypothesis that CD28 is critical for the development of
graft-versus-host disease (GVHD). We compared the in vivo effects of
CD28 / T cells transplanted from B6 donor with the
CD28 gene deleted by homologous recombination with those of
CD28+/+ T cells transplanted from wild-type C57BL/6
(B6) donor. Fifty million CD28/ or
CD28+/+ splenocytes from B6 mice were transplanted into
unirradiated (B6 × DBA/2)F1 (BDF1) recipients. Unlike
CD28+/+, CD28/ T cells from
B6 mice had lower levels of proliferation and interleukin-2 production,
had a limited ability to generate cytotoxic T lymphocytes against the
recipient, and did not induce immune deficiency, despite survival in
the recipient for at least 28 days. The ability to prevent rejection
was reduced by the absence of CD28, because as many as 1.0 × 107 CD28/ CD8+ cells were
needed to prevent rejection of major histocompatibility complex (MHC)
class-I incompatible marrow in sublethally irradiated (550 cGy) bm1
recipients, whereas 8.0 × 105 CD28+/+
CD8+ T cells were sufficient to produce a similar effect,
indicating that CD28 on donor CD8+ cells helps to
eliminate host immunity. Two million CD4+
CD28/ or CD28+/+ T cells were
transplanted into sublethally irradiated (750 cGy), MHC class-II
incompatible (B6 × bm12)F1 recipients. With CD28/
cells, 44% of the recipients died at a median of 20 days compared with
94% at a median of 15 days with CD28+/+ cells
(P < .001). Two million CD8+
CD28/ or CD28+/+ T cells were
transplanted into sublethally irradiated (750 cGy), MHC class-I
incompatible (B6 × bm1) F1 recipients. With CD28/
cells, 25% of the recipients died at a median of 41 days compared with
100% at a median of 15 days with CD28+/+ cells
(P < .001). (B6 × bm12)F1 and (B6 × bm1)F1 mice surviving after transplantation of CD28/ cells recovered
thymocytes, T cells, and B cells in numbers and function comparable
with that of irradiation-control F1 mice. We conclude that CD28
contributes to the pathogenesis and the severity of GVHD. Our results
suggest that the severity of GVHD could be decreased by the
administration of agents that block CD28 function in T lymphocytes.
© 1998 by The American Society of Hematology.
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