Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance.
BACKGROUND
Fully allogeneic liver grafts from piebald virol glaxo to dark agouti rats are spontaneously tolerated, whereas kidney transplants between these strains are rejected. Liver tolerance is broken by donor irradiation or peritransplant corticosteroid treatment of recipient rats, both of which interfere with the activation of recipient cells.


METHODS
In this study we used a combination of immunohistochemical staining, reverse transcription-polymerase chain reaction, and terminal deoxynucleotide transferase-mediated dUTP nick end labeling and Annexin-V apoptosis assays to compare donor cell migration, cytokine profiles, and leukocyte apoptosis in grafts and lymphoid organs from tolerant liver and rejecting kidney recipients. We then examined the effect on apoptosis of treatments which abrogate liver tolerance.


RESULTS
Liver transplantation in this tolerant strain combination is accompanied by rapid migration of many passenger leukocytes to the recipient spleen and lymph node, concurrent with a marked but transient increase in the amount of mRNA for the cytokines interleukin-2 and interferon-gamma. Apoptotic cells appear promptly in the spleen, their numbers reaching a peak 2 days earlier than has been previously shown for the graft infiltrate. Both CD4+ and CD8+ T cells undergo apoptosis and apoptotic cells are most concentrated among CD25+ T cells. In contrast, renal transplant rejection is associated with limited donor cell migration to lymphoid tissues and significantly less up-regulation of interleukin-2 and interferon-gamma in the spleen. Few apoptotic cells are detected in spleen or graft infiltrate during rejection, whereas apoptotic renal tubular and glomerular cells are found from day 5. Either recipient steroid treatment or donor irradiation significantly reduced the number of apoptotic cells in liver graft infiltrates and recipient spleen.


CONCLUSIONS
Taken together, these findings suggest that a mechanism akin to activation-induced cell death, with apoptosis of alloreactive recipient cells may be responsible for the induction of spontaneous liver transplant tolerance.
Sharland
A
A
AW Morrow Liver Immunobiology Laboratory, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, NSW, Australia.
Yan
Y
Y
Wang
C
C
Bowen
D G
DG
Sun
J
J
Sheil
A G
AG
McCaughan
G W
GW
Bishop
G A
GA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement; D016207:Cytokines / Q000235:genetics; D007108:Immune Tolerance; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D007962:Leukocytes / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016031:Liver Transplantation / Q000276:immunology*; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D008775:Methylprednisolone / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000502:physiology*; D014184:Transplantation, Homologous
D016207:Cytokines; D012333:RNA, Messenger; D008775:Methylprednisolone