For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

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Radiofrequency ablation (RFA) is one of the treatments for hepatocellular carcinoma (HCC) and is known to enhance host immune response. However, the epitopes to which enhanced immune responses occur, the impact on patient prognosis, and the functions and phenotype of T cells induced are still unclear. To address these issues, we analyzed immune responses before and after RFA in 69 HCC patients using 11 tumor-associated antigen (TAA)-derived peptides that we identified to be appropriate to analyze HCC-specific immune responses. The immune responses were analyzed using enzyme-linked immunospot (ELISPOT) assay and tetramer assays using peripheral blood mononuclear cells. An increase in the number of TAA-specific T cells detected by interferon-c ELISPOT assays occurred in 62.3% of patients after RFA. The antigens and their epitope to which enhanced T cell responses occur were diverse, and some of them were newly induced. The number of TAA-specific T cells after RFA was associated with the prevention of HCC recurrence, and it was clarified to be predictive of HCC recurrence after RFA by univariate and multivariate analyses. The number of TAA-specific T cells after RFA was inversely correlated with the frequency of CD14 1 HLA-DR 2/low myeloid-derived suppressor cells (MDSCs). The modification of T cell phenotype was observed after RFA. The number of TAA-specific T cells at 24 weeks after RFA was decreased. Conclusion: Although RFA can enhance various TAA-specific T cell responses and the T cells induced contribute to the HCC recurrence-free survival of patients, besides immunosuppression by MDSCs, the memory phenotype and lifetime of TAA-specific T cells are not sufficient to prevent HCC recurrence completely. Additional treatments by vaccine or immunomodulatory drugs might be useful to improve the immunological effect of RFA. (HEPATOLOGY 2013; 57:1448-1457 H epatocellular carcinoma (HCC) is the sixth most frequent type of cancer worldwide, and it is becoming an important public health concern due to its increased incidence in Western and Asian countries. 1,2 Although there are many types of treatments for HCC, the posttreatment recurrence rate is very high. 3 To inhibit HCC recurrence and improve prognosis, an immunotherapeutic approach is considered an attractive strategy.Radiofrequency ablation (RFA) is one of the treatments for HCC and is now widely used for curative strategies. 4 In recent studies, it has been reported that

Many tumor-associated antigens (TAAs) recognized by cytotoxic T cells (CTLs) have been identified during the last two decades and some of them have been used in clinical trials. However, there are very few in the field of immunotherapy for hepatocellular carcinoma (HCC) because there have not been comparative data regarding CTL responses to various TAAs. In the present study, using 27 peptides derived from 14 different TAAs, we performed comparative analysis of various TAA-specific T-cell responses in 31 HCC patients to select useful antigens for immunotherapy and examined the factors that affect the immune responses to determine a strategy for more effective therapy. Twenty-four of 31 (77.4%) HCC patients showed positive responses to at least one TAA-derived peptide in enzymelinked immunospot assay. The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. HCC treatments enhanced TAA-specific immune responses with an increased number of memory T cells and induced de novo T-cell responses to lymphocyte-specific protein tyrosine kinase, human epidermal growth factor receptor type 2, p53, and hTERT. Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides. Conclusion: Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy. TAA-specific immunotherapy combined with HCC treatments and anti-CTLA-4 antibody has the possibility to produce stronger tumor-specific immune responses. (HEPATOLOGY 2011;53:1206-1216 H epatocellular carcinoma (HCC) is the most common primary malignancy of the liver and becoming an important public health concern. 1,2 Although many kinds of treatments have been performed for HCC, their effects are limited because the recurrence rate of HCC is very high; therefore, the development of new therapeutic options to prevent recurrence is necessary. 3,4 To protect against recurrence, tumor antigen-specific immunotherapy is an attractive strategy. Many tumorassociated antigens (TAAs) and their epitopes recognized by cytotoxic T cells (CTLs) have been identified during the last two decades and some of them have been used in clinical trials for several cancers. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] The epitopes have been under investigation for the treatment of cancer, with major clinical responses in some trials. 22,23 With regard to immunotherapy for HCC, few kinds of TAAs and their epitopes have been used and only clinical data of a-fetoprotein (AFP) have been reported. 24,25 In human trials targeting AFP, it is...

The fatty acid composition in liver tissue and expression of genes related to fatty acid metabolism were different between the SS and NASH groups, suggesting that the acceleration of fatty acid metabolism is deeply involved in pathogenesis of NASH.