Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology.
BACKGROUND
Acute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts.


METHODS
We transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG(-/-)) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection.


RESULTS
Acute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG(-/-) mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell-dependent chronic rejection.


CONCLUSIONS
The innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology.
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, United States. daniel.zecher@unibas.ch
Daniel
D
Zecher
Qi
Q
Li
Amanda L
AL
Williams
John T
JT
Walters
Fady K
FK
Baddoura
Geetha
G
Chalasani
David M
DM
Rothstein
Warren D
WD
Shlomchik
Anthony J
AJ
Demetris
Fadi G
FG
Lakkis
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous