449
MAY
PLAY A "PROTECTIVE" ROLE IN A RAT-TO-MOUSE HEART TRANSPLANT MODEL
We previously reported that transplanting a Lewis rat heart into a
BALB/c mouse produced vigorous rejection (MST: 6.0±0.6 days), while
transplanting a Lewis heart into a C57BL/6 mouse produced "weak"
rejection (MST: 20.6±4.9 days). The present study was undertaken to
explore cellular and molecular mechanisms attributing the different
pattern of rejection between these two recipient strains. Sequential
routine and immunopathology, and cytokine expression measured by northern
blotting were studied in both BALB/c and C57BL/6 mice with a Lewis heart
xenograft. Vascular rejection characterized by vasculitis, infarction,
thrombosis and hemorrhage was dominated in Lewis xenografts transplanted
in BALB/c mice, while cellular rejection was dominant in those of C57BL/6
mice. Immunopathology studies further revealed that these infiltrating
cells in C57BL/6 mice were CD4+ and CD8+ T cells,
NK cells and macrophages. Notably, strong intragraft IFN-expression
measured by northern blotting and immunopathology was found in heart
xenografts in C57BL/6 mice compared to relatively weak expression in
BALB/c mice. To further define the role of IFN-
in xenograft rejection, Lewis heart grafts were transplanted into IFN-
knock-out (IFN-
-/-) mice. Interestingly, the heart xenograft survival was
significantly shortened in IFN-
-/- C57BL/6 mice (MST: 9.0±1.0 days) as compared with that of
wild-type C57BL/6 mice (MST: 20.6±4.9 days, P <0.001). In
contrast, there was no difference between wild-type BALB/c mice and IFN-
-/- BALB/c mice (MST: 6.0±0.6 days vs. 6.1±1.5
days). Furthermore, the rejection pattern was shifted from cellular
rejection to vascular rejection when IFN-
was knocked out from C57BL/6 mice. We conclude that 1) predominant
cellular rejection in C57BL/6 mice produces "weak" xenograft
rejection; 2) high expression of IFN-
is present in these grafts and 3) depleting IFN-gene
shifts cellular rejection to vascular rejection, thereby accelerating
xenograft rejection. These data indicate that IFN-
may play a "protective" role in xenograft rejection. Studies are
currently underway to see whether manipulating cytokine network could
attenuate xenograft rejection.