Regulation of alloantigen-mediated T-cell proliferation by endogenous interferon-gamma: implications for long-term allograft acceptance.
BACKGROUND
Recent data suggest that interferon (IFN)-gamma is not an essential mediator of acute rejection but, instead, is critical for the induction of long-term allograft acceptance. The in vivo mechanisms by which endogenous IFN-gamma regulates the alloimmune response and thus facilitates the induction of long-term allograft survival are not known.


METHODS
We examined long-term cardiac and skin allograft survival, alloantigen-induced T-cell proliferation, and alloantigen-induced T-cell apoptosis in wild-type (IFN-gamma+/+) and IFN-gamma gene-knockout (IFN-gamma-/-) mice treated with either B7-CD28 T-cell costimulation blockade alone or B7-CD28 T-cell costimulation blockade combined with donor splenocyte transfusion.


RESULTS
We found that IFN-gamma is essential for long-term allograft survival induced by treating mice with either B7-CD28 T-cell costimulation blockade alone or B7-CD28 T-cell costimulation blockade combined with donor splenocyte transfusion. Alloantigen-induced T-cell proliferation in vivo was significantly greater in IFN-gamma-/- mice than in IFN-gamma+/+ mice, and T-cell costimulation blockade abrogated alloantigen-induced T-cell proliferation in wild-type mice but failed to do so in mice that lack IFN-gamma. In contrast, alloantigen-induced T lymphocyte apoptosis in vivo did not differ between IFN-gamma+/+ and IFN-gamma-/- mice, and T-cell costimulation blockade enhanced alloantigen-induced T-cell apoptosis in both mouse strains.


CONCLUSIONS
These data suggest that endogenous IFN-gamma facilitates the induction of long-term allograft survival by limiting the proliferation of alloactivated T lymphocytes. The data also suggest that B7-CD28 T-cell costimulation blockade exerts immunosuppressive actions by inhibiting the proliferation of activated T lymphocytes and by promoting their apoptosis.
Hassan
A T
AT
The Carlos and Marguerite Mason Transplantation Research Center, Department of Medicine and Veterans Affairs Medical Center, Atlanta, Georgia 30033, USA.
Dai
Z
Z
Konieczny
B T
BT
Ring
G H
GH
Baddoura
F K
FK
Abou-Dahab
L H
LH
El-Sayed
A A
AA
Lakkis
F G
FG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001803:Blood Transfusion; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D020287:In Situ Nick-End Labeling / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology*; D007519:Isoantigens / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D007519:Isoantigens; D007371:Interferon-gamma