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* Department of Medicine, Children’s Hospital,
Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, and
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
The mechanisms underlying physiological regulation of alloimmune
responses remain poorly defined. We investigated the roles of
cytokines, CTLA-4, CD25+ T cells, and apoptosis in
regulating alloimmune responses in vivo. Two murine cardiac transplant
models were used, B10.D2 (minor mismatch) and C57BL/6 (major mismatch),
into BALB/c recipients. Recipients were wild type,
STAT4-/- (Th1 deficient), or STAT6-/- (Th2
deficient) mice. Minor mismatched allografts were accepted
spontaneously in 
70% of wild type and STAT4-/- mice.
By contrast, there was significantly shorter graft survival in minor
mismatched STAT6-/- mice. Either the adoptive transfer of
STAT4-/- splenocytes or the administration of IL-4Fc
fusion protein into STAT6-/- mice resulted in long term
graft survival. Blocking CTLA-4 signaling accelerated the rejection in
all recipients, but was more pronounced in the minor combination. This
was accompanied by an increased frequency of alloreactive T cells.
Furthermore, CTLA-4 blockade regulated CD4+ or
CD8+ as well as Th1 or Th2 alloreactive T cells. Finally,
while anti-CD25 treatment prolonged graft survival in the major
mismatched combination, the same treatment accelerated graft rejection
in the minor mismatched group. The latter was associated with an
increased frequency of alloreactive T cells and inhibition of T cell
apoptosis. These data demonstrate that cytokine regulation, CTLA-4
negative signaling, and T cell apoptosis play critical roles in
regulating alloimmunity, especially under conditions where the
alloreactive T cell clone size is relatively
small.
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