Donor graft steatosis influences immunity to hepatitis C virus and allograft outcome after liver transplantation.
BACKGROUND
Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal, often with accelerated allograft fibrosis. Donor liver steatosis is frequently encountered and often associated with poor early postoperative outcome. The aim of this study was to test the hypothesis that allograft steatosis alters immune responses to HCV and self-antigens promoting allograft fibrosis.


METHODS
Forty-eight HCV OLT recipients (OLTr) were enrolled and classified based on amount of allograft macrovesicular steatosis at time of OLT. Group 1: no steatosis (0%-5% steatosis, n=21), group 2: mild (5%-35%, n=16), and group 3: moderate (>35%, n=11). Cells secreting interleukin (IL)-17, IL-10, and interferon gamma (IFN-γ) in response to HCV antigens were enumerated by Enzyme Linked Immunospot Assay. Serum cytokines were measured by Luminex, antibodies to Collagen I, II, III, IV, and V by ELISA.


RESULTS
OLTr of moderate steatotic grafts had the highest incidence of advanced fibrosis in protocol 1 year post-OLT biopsy (10.8% vs. 15.8% vs. 36.6%, r=0.157, P<0.05). OLTr from groups 2 and 3 had increased HCV-specific IL-17 (P<0.05) and IL-10 (P<0.05) with reduced IFN-γ (P<0.05) secreting cells when compared with group 1. This was associated with increase in serum IL-17, IL-10, IL-1β, IL-6, IL-5, and decreased IFN-γ. In addition, there was development of antibodies to Collagen I, II, III and V in OLTr with increased steatosis (P<0.05).


CONCLUSIONS
The results demonstrate that allograft steatosis influences post-OLT HCV-specific immune responses leading to an IL-17 T-helper response and activation of humoral immune responses to liver-associated self-antigens that may contribute to allograft fibrosis and poor outcome.
Department of Surgery, Washington University, St. Louis, MO 63110, USA. subramanianv@wustl.edu
Vijay
V
Subramanian
Anil B
AB
Seetharam
Neeta
N
Vachharajani
Venkataswarup
V
Tiriveedhi
Nataraju
N
Angaswamy
Sabarinathan
S
Ramachandran
Jeffrey S
JS
Crippin
Surendra
S
Shenoy
William C
WC
Chapman
Thalachallour
T
Mohanakumar
Christopher D
CD
Anderson
D001706:Biopsy; D018925:Chemokines / Q000097:blood; D003430:Cross-Sectional Studies; D005234:Fatty Liver / Q000503:physiopathology*; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000453:epidemiology / Q000276:immunology* / Q000601:surgery*; D006801:Humans; D007109:Immunity / Q000502:physiology*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D008099:Liver / Q000276:immunology / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012720:Severity of Illness Index; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D018925:Chemokines; D020381:Interleukin-17; D016753:Interleukin-10; D007371:Interferon-gamma