**3.6.1 Genetic variants in donor**

212 Liver Transplantation – Basic Issues

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

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

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

of ACR in a homogenous cohort of HCV-re-infected patients (Eurich et al).

induce chronic rejection processes during the antiviral treatment [12, 49].

processes in the graft and be therefore pathogenetically relevant [57].

**3.5 Antiviral therapy** 

**3.6 Genetic diversity** 

The ability to produce different levels of cytokines in response to stimulation is suspected to be gene-associated [58]. Liver graft is usually colonized by recipient cell populations such as endothelia and lymphatic tissue thus theoretically forming a functional chimerism of donor and recipient regarding biochemical processes [56, 59]. Furthermore, the impact of genetic differences in donor and recipient may vary according to the duration of post-transplant follow-up [57]. Results of intensive investigations demonstrated that donor polymorphisms of IL-28B-gene may partially predict the outcome of antiviral treatment [60].
