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*
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215;
LeukoSite, Inc., Cambridge, MA 02142; and
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101
T cell growth factors (TCGFs) play a critical role in allograft
rejection by promoting the activation and proliferation of alloreactive
T cells. To determine whether IL-2 and IL-4 are of quintessential
importance in allograft rejection and to identify possible alternative
TCGFs, we have bred IL-2-/- and
IL-4-/- double knockout (DKO) mice and studied islet
allograft rejection using the DKO mice as allograft recipients.
Although mononuclear leukocytes from DKO mice did not mount a
proliferative response in vitro in response to anti-CD3
stimulation, crude islet allografts were vigorously rejected by DKO
mice (mean survival time 17 ± 7, n = 8) as
compared with wild-type controls (mean survival time 13 ± 4,
n = 7). Treatment of DKO mice with anti-CD3 or
rapamycin markedly prolonged the islet allograft survival. An analysis
of intragraft cytokine gene transcripts showed robust expression of
IL-7 and IL-15. In contrast, intragraft IL-9 gene transcripts were not
detected in either wild-type or DKO mice. Provision of exogenous IL-2,
IL-4, IL-7, or IL-15, but not IL-9, supports the proliferation of
anti-CD3 activated DKO splenic leukocytes in vitro. Blocking the
common 
c of IL-2 receptor, a shared essential signaling component by
receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, prolonged the survival
of islet allografts in DKO mice. Hence, a T cell dependent allograft
rejection enabled by rapamycin-sensitive signals or signals mediated by
binding of the c chain occurs in the absence of both IL-2 and IL-4.
Non-T cell-derived TCGFs, especially IL-7 and IL-15, may play an active
role in supporting allograft rejection.
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