**3.4.1 Immunosuppressive medication**

Highly complicated interaction and vulnerable balance in the immune answer to HCV is compromised by the inevitable use of immunosuppressive medication. The inappropriate T-cell mediated response to HCV-re-infection is accused to be responsible for disease progression. Stronger immunosuppressive regimen may accelerate fibrosis progression [38, 39]. Calcineurin-inhibitors (cyclosporine and tacrolimus) represent the backbone of current immunosuppressive medication and have been suspected to influence the extent of HCVrecurrence. In spite of similar pharmacological mechanisms, cyclosporine has been proposed to have a positive effect on interferon-based antiviral treatment. However, clinical significance currently remains unclear [40]. Levels of HCV-viremia seem to be the CNI-type [41].

Mycophenolate mofetil (MMF) inhibits the lymphocyte proliferation and may decrease the overall inflammatory activity in the graft. MMF was strongly suspected to have a positive impact on fibrogenesis [42]. However, the theoretically promising antiviral effect of MMF in-vitro could not be demonstrated as substantial, regarding fibrosis development. Nevertheless, dual immunosuppression based on CNIs and MMF is frequently used in patients with HCV-recurrence and is believed to exhibit a positive effect on the severity of HCV-recurrence [42].

Sirolimus as a representative of mTOR-inhibitors seems to decelerate fibrosis progression in graft re-infection by blocking post-receptor signal transduction and interleukin-2-dependant proliferation. Although, no definite statement can currently be made, sirolimus may represent a reasonable therapeutic option [43, 44].

#### **3.4.2 Acute cellular rejection**

The occurrence of acute cellular rejection (ACR), its severity and frequency have been reported to aggravate the course of HCV-related graft disease [16]. Administration of corticosteroid pulses and antibodies (OKT-3) in case of steroid-resistant rejection as ACRtherapy are associated with a significant elevation of viral load and accelerated fibrosis development [21, 22]. The extent of immunosuppression, CNI-type and previous episodes of rejection are widely considered to affect the incidence of ACR. Furthermore, individually different genetic background of ACR-mediating cytokines might be involved in the pathogenesis [45]. Furthermore, individually different genetic background of ACRmediating cytokines might be involved in the pathogenesis [45]. Mannose-binding-lectin-2 (MBL-2) plays an important role in the innate immune system acting as opsonine by activation antibody-independent pathway of the complement system [46, 47]. Polymorphisms of MBL-2-gene (rs7096206; G/C) have been shown to affect the occurrence of ACR in a homogenous cohort of HCV-re-infected patients (Eurich et al).

#### **3.5 Antiviral therapy**

Antiviral therapy is the cornerstone of graft cirrhosis prevention in HCV-infected recipients. The clinical and histological course of hepatitis-C is inseparably associated with antiviral treatment strategies. Recent introduction of new formulations of interferons (IFN) such as pegylated interferons (PEG-IFN) in the treatment of HCV-infection before and after LT revealed promising results. Application of pegylated interferon 〈-2a and ribavirin (RBV) provide a sustained virologic response (SVR) in 40-50% of all treated cases with HCVgenotype 1 and in 80% with genotypes 2 or 3. In post-transplant setting, the success of antiviral therapy is significantly lower, and only a maximum of 30-40% of all patients achieve SVR [21, 39]. Some evidence exists that IFN/RBV-treatment may prevent graft cirrhosis even in unsuccessfully treated patients. Interestingly, fibrosis progression may occur in spite of successful IFN-based antiviral treatment [48]. Hence, this issue remains controversial. Moreover, immunologically active IFN may trigger rejection (5-6%) and induce chronic rejection processes during the antiviral treatment [12, 49].

#### **3.6 Genetic diversity**

HCV-re-infection can trigger the excess synthesis and deposition of ECM usually by activation of cytokine release. Activated macrophages, lymphocytes, bile duct epithelia but also endothelia and myofibroblasts are sources of fibrogenic cytokines and growth factors that can stimulate hepatic stellate cells HSCs to produce ECM-molecules leading to fibrosis during chronic liver injury [50, 51]. Genetic polymorphisms of enzymatic systems, cytokines and growth factors which are involved in the process of immunomodulation, inflammation, ECM-turnover and anti-oxidative stress defense, may explain the widely different individual extent of HCV-induced graft damage [52-54]. Highly variable rates of functional impairment defined by inflammation, tissue remodeling but also antiviral capabilities and antiviral therapy response suggest the existence of endogenous risk compounds both in natural and post-transplant settings of the disease [33]. The maximal capacity to produce different levels of cytokines in response to noxious stimulation has been shown to be under genetic control and differs among liver graft recipients [32, 55]. Genetically different backgrounds in transplant population, consisting of donor and recipient, may differently contribute to disease development. Although the exact mechanism is not yet understood in detail both, donor and recipient genetics may interact. The expression of disease-related effectors may be individual, time and tissue dependant [56]. Therefore, the interaction between two different individual backgrounds may theoretically influence post-transplant processes in the graft and be therefore pathogenetically relevant [57].
