Cyclosporine enhances liver regeneration: the role of hepatocyte MHC expression and PGE2--a study relevant to graft immunogenicity.
OBJECTIVE
We have investigated CsA induced liver hyperplasia to explore the potential effects on the immunogenicity of the regenerating liver within the clinical context of rejection after transplantation.


METHODS
Flow cytometry analysis of hepatocytes, isolated 48 hours after 2/3 partial hepatectomy (PH2/3) or sham operation in rats, was performed to determine the effect of CsA on DNA synthesis and MHC molecule expression. The possible role of PGE2 was evaluated by the administration of SC-19220, an EP1-PGE2 receptor antagonist.


RESULTS
CsA augmented liver regeneration and this was partially attenuated by SC-19220. The moderate expression of class I MHC expression, as well as the very low class II MHC expression detected in normal hepatocytes by flow cytometry was augmented after PH2/3 and reduced by CsA. The CsA-mediated decrease of hepatocyte immunogenicity was not SC-19220 dependent.


CONCLUSIONS
It is proposed that the enhancing effect of CsA on hepatocyte proliferation is by means of an indirect mechanism that can be attributed to a) reduced immunogenicity of the regenerating liver as a result of inhibition of class I and II MHC hepatocyte expression and b) increased PGE2 synthesis in the liver mediated by its action on EP1 receptor.
Fouzas
Ioannis
I
Organ Transplant Unit, Hippokration Hospital, Aristotle University Medical School, 49, Konstantinoupoleos Ave, Thessaloniki 54642, Greece. ifouzas@auth.gr
Daoudaki
M
M
Sotiropoulos
G C
GC
Vrochides
D
D
Papanikolaou
V
V
Imvrios
G
G
Sgourakis
G
G
Molmenti
E P
EP
Vavatsi
N
N
Thalhammer
T
T
Takoudas
D
D
Broelsch
C E
CE
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005434:Flow Cytometry; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008115:Liver Regeneration / Q000187:drug effects* / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype
D007166:Immunosuppressive Agents; D011448:Prostaglandin Antagonists; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; D016572:Cyclosporine; D004247:DNA; D015232:Dinoprostone