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Supplementary material, approximately 4.44 MB.

Most studies on the effects of naturally occurring autoantibodies (NAbs) on immune cells have been performed in the context of research on the immunomodulatory effects of intravenous immunoglobulin (IVIG). Among others, IVIG inhibits the differentiation, maturation and functions of dendritic cells (DC), thereby suppressing T-cell activation. In addition, IVIG stimulates expansion and suppressive function of regulatory T cells (Treg) carrying the antigens CD4, CD25 and Foxp3. Current data on the immunomodulatory effects of IVIG on DC and Treg are summarized, and possible molecular interactions between NAbs and DC or Treg that mediate these effects are discussed.

The goal of this study was to determine the risk factors for de novo cancer after liver transplantation (LTx). Retrospective analyses were performed in 385 LTx patients who underwent transplantation between 1986 and 2007. In total, 50 (13.0%) recipients developed de novo malignancy. The cumulative incidence of de novo cancer at 1, 5, 10, and 15 years after LTx was 2.9% +/- 0.9%, 10.5%+- 1.8%, 19.4% +/- 3.0%, and 33.6% +/- 6.8%, respectively. The standardized incidence ratio of malignancy in LTx patients compared to the general population was 2.2 (95% confidence interval: 1.6-2.8). After excluding posttransplant lymphoproliferative disorder and skin cancer, patients with de novo cancer had a significantly lower survival rate compared to recipients who remained cancer-free. The identified univariate risk factors for de novo cancer were cyclosporine A (CsA) treatment, time period of LTx, and recipient age. In multivariate analysis, only CsA treatment emerged as an independent risk factor for de novo cancer, which was attributed to more aggressive cancer types. A surprising finding was that CsA treatment specifically enhanced cancer risk in patients who underwent transplantation after 2004, when C-2 monitoring (blood concentration at 2 hours postdose) was introduced. In addition, these patients showed a significantly lower acute rejection rate, which might reflect a more robust immunosuppressive status caused by the CsA-C-2 regimen. When age was considered, only patients

Immunosuppression considerably affects hepatitis C virus (HCV) recurrence and the outcome of antiviral treatment after liver transplantation. Recent findings have suggested that the calcineurin inhibitor tacrolimus (Tac), unlike cyclosporine A (CsA), interferes with the antiviral activity of interferon-alpha (IFN-alpha) in vitro. The aim of this study was to more extensively investigate the effects of calcineurin inhibitors on IFN-alpha signaling and antiviral activity in subgenomic and infectious HCV models. Treatment with Tac and CsA did not affect Huh7 cell proliferation at doses of 10 to 500 ng/mL; however, it completely inhibited T cell proliferation. In contrast to previous reports, Tac had no effect on IFN-alpha-stimulated reporter gene expression, even at the dose of 5 mu g/mL. Furthermore, in Huh7 subgenomic HCV replicon cells, treatment with Tac had no significant effect on the suppression of viral replication by IFN-alpha. In the infectious HCV model, treatment with IFN-alpha effectively inhibited both viral RNA replication and de novo production of virus particles, and neither was attenuated at any concentration of Tac. CsA had no significant effect on IFN-alpha-stimulated reporter gene expression; however, as shown previously, a combination of CsA (at 500 ng/mL and higher) and IFN-a resulted in enhanced inhibition of viral replication in both the subgenomic and infectious HCV models. In conclusion, our study shows no evidence that Tac or CsA interferes with IFN-alpha-mediated inhibition of HCV replication and virion production in vitro. Therefore, no further mechanistic arguments have been found to break the clinical controversy about the choice of calcineurin inhibitors during posttransplantation antiviral therapy. Liver Transpl 16:520-526, 2010. (C) 2010 AASLD.

The aim of this thesis was to improve the treatment of cancer by manipulation of the immune system. In chapters 2 and 3 the effects of several immune checkpoint inhibitors and stimulators were evaluated on T cells isolated from several types of cancer. Blockade of the inhibiting immune checkpoint receptor LAG3 and PD-L1 promoted the ex vivo capacities of intra-tumoral T cells isolated from liver metastases of mismatch repair proficient colorectal carcinomas. In the proof-of-concept study, described in Chapter 3, the biclonic CD137xPD-L1 antibody stimulated proliferation of intratumoral T cells isolated from hepatocellular carcinoma samples. In chapters 4 and 5 a vaccination strategy was explored; in chapter 4 a panel of 12 tumor antigens was found to be expressed in the majority of hepatocellular carcinoma patients and in chapter 5 the immunogenicity of several of these antigens was explored. Interestingly, the expression of tumor antigens in adjacent macroscopically tumor-free tissues was a predictive factor for tumor recurrence. Finally, the effect of low-dose cyclophosphamide on circulating regulatory T cells was evaluated in patients synergistically treated with dendritic cell therapy, as a manner to reduce the immunosuppressive environment and tip the balance.