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Departments of
*
Surgery and
Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109
Anti-CD2 mAb plus anti-CD3 mAb induce alloantigen specific
tolerance. We sought to determine whether Th2 cytokines are involved in
the induction of tolerance in this model. Addition of anti-IL-4 mAb
or anti-IL-10 mAb to anti-CD2 plus anti-CD3 treatment
abrogated tolerance and resulted in graft survivals of 26 ± 4 and
25 ± 5 days, respectively. Splenocytes from the anti-IL-4 mAb
and anti-IL-10 groups had greater proliferation in response to
alloantigen than either tolerant or naive groups. Cytokine analysis of
MLR supernatants showed increased IL-10 in the tolerant group and
increased IFN-
in the anti-IL-4 mAb treated group.
Donor-specific alloantibody responses in untreated immune animals had a
predominantly Th1 (IgG2a) alloantibody response, while the tolerogenic
regimen reduced the ratio of IgG2a:IgG1 titers. The addition of
anti-IL-4 mAb to the tolerogenic regimen partly restored the
Th1-related IgG2a response. Tolerance did not develop in IL-4 knockout
animals treated with anti-CD2 plus anti-CD3 (mean graft
survival, 27 ± 5 days). Restoration of IL-4 to IL-4 knockout
animals by gene transfer with plasmid DNA resulted in prolongation of
survival to 46 ± 7 days, while adoptive transfer of wild-type
splenocytes into IL-4 knockout recipients resulted in indefinite graft
survival (>60 days) and indefinite survival of second donor-type
grafts. IL-10 gene transfer to IL-4 knockout recipients did not prolong
graft survival (28 ± 4). These results demonstrate that tolerance
in this model is mediated at least in part by Th2-type cells that
secrete IL-4, promote IL-10 and IgG1 production, and inhibit
alloantigen reactivity.
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