Recent developments in genome sequence techniques have enabled GWASs, which have resulted in tailored therapies for various diseases. For patients affected with HCV-related liver diseases, two important genetic polymorphisms, IL28B and ITPA, have been reported recently, which hopefully will lead to appropriate antiviral therapy for each individual.
Although splenectomy is useful for improving liver function in type C cirrhotic patients for the induction of PEG-IFN/RBV therapy, even less invasive laparoscopic surgery carries some risks and has a high cost. The precise prediction for the outcome of PEG-IFN/RBV therapy following LS is urgently needed.
The current study revealed that IL28B genetic variant also correlated with response to PEG-IFN/RBV following LS. Interestingly, compared to cirrhotic patients who had not undergone splenectomy (non-Spx group) and were carrying the TG/GG allele at the IL28B gene, those who underwent splenectomy (Spx group) and carried the TG/GG allele had a significantly higher SVR rate, whereas TT carriers showed no difference between the SPx and non-Spx groups.
One of the mechanisms by which splenectomy improves antiviral response could be the restoration of cytopenia, leading to enhanced treatment tolerance. Although patients carrying the CC allele at the ITPA gene had greater susceptibility to anemia in the non-Spx group, there was no difference between the ITPA genotypes in the Spx group. Hitomi et al
. recently clarified that ITPA genetic variant protected anemia by accumulated inosine triphosphates been used for decreased ATP via adnylosuccsinate synthase. In that study, however, the authors reported that erythrocytes with RBV in vitro did not show hemolysis by themselves, suggesting that hemolysis occurred in other tissues in vivo. In the current study, splenectomy did not improved anemia, which was significantly worse than that in the non-Spx group. Nevertheless, Hb levels during the course of PEG-IFN/RBV therapy were similar in the Spx and non-Spx groups among patients carrying the CC allele. These data suggest that splenectomy does not improve anemia, but protects against RBV-induced hemolysis, especially among patients carrying the ITPA CC allele.
In contrast to anemia, splenectomy itself significantly improved thrombocytopenia, which enabled us to perform PEG-IFN/RBV therapy safely.
The restoration of peripheral blood cells does not explain why SVR was improved by splenectomy in patients carrying the IL28B minor genotype. The current study also revealed that splenic ISG expression was higher in patients carrying the IL28B major genotype, which was opposite to the liver. We consider that this resulted from the difference in constituent cells in each organ. In fact, the liver mainly comprises hepatocytes, whereas the spleen mainly comprises monocytes. In a previous report, IL28 mRNA expression was higher in peripheral blood monocytes of patients carrying the TT allele than those carrying the TG/GG allele
. ISG expression was also reported to be higher in liver-infiltrating lymphocytes of responders to PEG-IFN/RBV than those of non-responders
. Although it is unclear whether monocytes have similar phenotypes in peripheral blood, liver and spleen, pretreatment ISG expression was higher in monocytes of patients carrying the IL28B major genotypes. Similarly, Chen et al. have shown by immunohistochemistry that ISG15 protein upregulation was pronounced in Kuppfer cells among responders to IFN therapy
. Contrary to monocytes, ISGs from liver parenchyma or hepatocytes are known to be greater in number in non-responders to PEG-IFN/RBV
[16, 18]. These data suggest that pretreatment ISG upregulation in hepatocytes in which HCV replicates induces refractoriness to IFN, whereas monocytes that express little endogenous ISG have some dysfunction for eradication of HCV. Spleens in patients carrying the IL28B minor genotype have some of these dysfunctional monocytes. Therefore, it is possible that splenectomy removes such monocytes and improves the outcome of PEG-IFN/RBV therapy, especially in patients carrying the IL28B minor genotype.
In addition, we have previously demonstrated that the inhibitory signal, programmed-death 1(PD-1), is upregulated in splenic CD4+ T cells and they promote peripheral tolerance to IFN
. In fact, splenectomy is followed by an increase in cytokine production and a reduction of PD-1 in peripheral blood lymphocytes. Not only PD-1, but also Tim-3, a well-known inhibitory signal, are upregulated in HCV-specific T cells, which are predominantly central memory T cells that are located in lymphatic tissues such as the spleen
. These data suggest that splenectomy does improve the immune response to HCV, but confirmation of the correlation of IL28B minor genotype with inhibitory signals in T cells needs further investigation.