Many factors both in the donor and recipient including immune responses affect prognosis in HCV OLTr, (14
). This study evaluated the impact of donor graft steatosis on changes in post-OLT HCV immunity. In HCV OLTr, increasing grade of allograft steatosis positively correlated with fibrosis one-year post-OLT. These OLTr had increased HCV specific IL-17 and IL-10 with decreased IFN-γ secreting cells (). This was associated with an increase in serum IL-17, pro Th-17 (IL-6, IL-1β) and Th2 (IL-4, IL-10) cytokines (). Additionally, HCV OLTr also developed abs to self-antigens (Col I, II, III, V) whose titer was more in OLTr of moderate/severe steatotic grafts. These results support the contention of donor steatosis being an important factor in viral recurrence and fibrosis (18
) and further suggest a role for allograft steatosis in influencing post-OLT HCV immune responses development of immunity to self-antigens.
Earlier studies have associated graft steatosis with poor function (28
), but these grafts when appropriately selected can have functional recovery (5
). The degree of steatosis decreases soon after OLT (33
) and in this study also there was lack of any significant steatosis in the grafts one-year post-OLT(data not shown) with no difference in overall survival. Similar to previous findings (5
), this report demonstrates that OLTr of moderate/ severe steatotic grafts had higher transaminases (AST and ALT, p<0.05) in the first week following OLT () signifying increased reperfusion injury. OLTr of moderate to severe steatotic grafts have increased coagulopathy and a stormier post-operative period (5
). Several studies including by Verran and Chui et al (6
) report increased early poor function and survival in moderate/severe steatotic grafts. These could serve as a possible explanation for the poor early survival of steatotic allografts, however this was not statistically significant ().
HCV recurrence is universal (35
) and in peri-OLT period early preservation and reperfusion injuries have been associated with HCV recurrence and poor outcome (23
). Therefore, it is likely that post-operative stress sets up an inflammatory process that can alter the host immunological response to HCV. This in turn can promote HCV pathologic injury and recurrence resulting in development of allograft fibrosis. Although events immediately post-OLT couldn’t be analyzed due to non-availability of serial samples, the significant differences in cytokine levels 6 months post-OLT even with a smaller number of samples () support the hypothesis that early inflammatory events may determine the course and progression of HCV infection and fibrosis.
The immune response to HCV is a critical determinant of allograft fibrosis and a predominant Th2 (13
) and Th17 (15
) immunity is associated with increased fibrosis and poor outcome. Cytokines including IL-1β, IL-6 and IL-8 have been shown to promote fibrosis (38
). These cytokines also favor Th17 responses and suppress IFN-γ (15
). In this study we demonstrate that such HCV immune responses are more prominent in OLTr of grafts with higher grade of steatosis (, ). We propose that this prevents viral clearance and enhances liver damage, increased ECM turnover and the development of fibrosis.
The inflammatory process that follows ischemia reperfusion injury and HCV mediated liver damage may lead to exposure of cryptic self-antigens such as Col thus precipitating an immune response. A recent study from our laboratory found that Abs to Col I, II, V are associated with the development of fibrosis both in non-OLT and post-OLT HCV patients (16
). In this study as well, the degree of allograft steatosis demonstrated positive correlations with Abs titer and fibrosis (). The mechanistic role of these Abs in the development of fibrosis can be postulated from reports in lung and heart transplantation wherein humoral and cellular (especially Th17) responses to self-antigens are implicated in the immunopathogenesis of fibrosis and chronic allograft rejection (42
This is further explained by an increase in IL-17 that has been shown to play a role in the development of autoimmune B-cells and liver fibrosis (15
). An increase in IL-17 in steatotic allografts along with a pro-Th17 cytokine milieu (IL-6, IL-1β) may facilitate Th-17 immune responses to self-antigens (Col) leading to the production of Abs. These immune responses characterized by increased IL-6 and IL-17 can also lead to increase in other pro-fibrotic growth factors (transforming growth factor beta and connective tissue growth factor), which will result in ECM turnover and allograft fibrosis (45
In non-HCV OLTr however there is no significant immune response to self-antigens () and there is no significant fibrosis post OLT (data not shown). In these non-HCV OLTr, only ischemia reperfusion injury plays a role and the additional HCV mediated responses doesn’t occur. Thus both an early post operative stress and the continued HCV mediated liver damage may be critical for exposure of cryptic self-antigens or determinants for development of immune responses to self-antigens and subsequent allograft fibrosis.
A limitation of this study is that due to lack of serial samples post-OLT, early changes and effects of steatosis on HCV replication and immune responses as well as the temporal and mechanistic correlation of development of Abs to self-antigens and allograft fibrosis could not be determined.
In conclusion, this study demonstrates that extent of graft steatosis significantly influences post-OLT HCV specific immune responses and development of allograft fibrosis. Increasing grades of steatosis favors the development of predominant Th17 type HCV specific responses with a concomitant suppression of Th1 (IFN-γ). In addition, early inflammatory changes in the allograft due to steatosis and inflammatory cytokine milieu can perpetuate the development of Abs to self-antigens (Col). We propose that HCV specific as well as immune responses to self-antigens collectively promote allograft fibrosis and lead to a poor outcome especially in HCV OLTr of grafts with moderate to severe grades of steatosis.