Apoptosis and allograft rejection in the absence of CD8+ T cells.
BACKGROUND
The requirement for cytotoxic T lymphocytes during allograft rejection is controversial. We previously demonstrated that CD8+ T cells are not necessary for allograft rejection or for the induction of apoptosis in rat small intestinal transplantation. In this study, we examined the mechanisms of apoptosis and rejection after liver transplantation in the absence of CD8+ T cells.


METHODS
Either Lewis or dark agouti rat liver grafts were transplanted into Lewis recipients to create syngeneic and allogeneic combinations. CD8+ T cells were depleted in an additional allogeneic group by treatment with OX-8 mAb on day -1 and day 1 after liver transplant.


RESULTS
Apoptosis and rejection were observed in both the CD8+ T cell-depleted allogeneic and allogeneic grafts by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and radiolabeled-annexin V in vivo imaging. Granzyme B and FasL were expressed in all allogeneic transplants, including those depleted of CD8+ T cells, indicating that a mononuclear cell other than a CD8+ T cell can be the source of these molecules during allograft rejection. Activation of the caspase cascade was detected in all rejecting allografts. Caspases 3, 8, and 9 were activated at similar significantly elevated levels in both allogeneic and CD8+ T cell-depleted liver grafts.


CONCLUSIONS
These data indicate that in the absence of CD8+ T cells an alternative pathway, associated with granzyme B and FasL expression and activation of the caspase cascade, can mediate apoptosis and graft rejection.
Ogura
Y
Y
Transplant Immunobiology Laboratory, Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305-5492, USA.
Martinez
O M
OM
Villanueva
J C
JC
Tait
J F
JF
Strauss
H W
HW
Higgins
J P
JP
Tanaka
K
K
Esquivel
C O
CO
Blankenberg
F G
FG
Krams
S M
SM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000503:physiopathology*; D053804:Granzymes; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D012697:Serine Endopeptidases / Q000235:genetics; D014184:Transplantation, Homologous
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053804:Granzymes; C509215:Gzmb protein, rat; D012697:Serine Endopeptidases; D020169:Caspases