Dynamic interplay between CXCL levels in chronic Hepatitis C patients treated by Interferon

Virology Journal

Ashraf Omar Abdel-Aziz²  Dina H Eldahshan⁴  Naglaa Zayed²  Hend I Shousha²  Hanaa M Alam EL-Din³  Waleed S Mohamed³  Abeer A Bahnassy¹  Abdel-Rahman N Zekri³ 

[1] Pathology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st, Cairo, Egypt;Tropical Medicine Department, Faculty of Medicine, Cairo University, Kasr El-Aini st, Cairo, Egypt;Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st, Cairo, Egypt;Clinical Pathology Department, Faculty of Medicine, Benisuef University, Cairo, Egypt

关键词: E-Cadherin;    Chemokine’s;    IFN;    HCV;   

Others  :  1149156
DOI  :  10.1186/1743-422X-10-218

 received in 2011-08-05, accepted in 2013-05-17,  发布年份 2013

【 摘 要 】

Background

Combined pegylated interferon-α and ribavirin therapy has sustained virological response (SVR) rates of 54% to 61%. Pretreatment predictors of SVR to interferon therapy have not been fully investigated yet. The current study assesses a group of chemokines that may predict treatment response in Egyptian patients with chronic HCV infection.

Patients and methods

CXCL5, CXCL9, CXCL11, CXCL12, CXCL 13, CXCL 16 chemokines and E-Cadherin were assayed in 57 chronic HCV patients’ sera using quantitative ELISA plate method. All studied patients were scheduled for combined pegylated interferon alpha and ribavirin therapy (32 patients received pegylated interferon α 2b, and 25 patients received pegylated interferon α 2a). Quantitative hepatitis C virus RNA was done by real time RT-PCR and HCV genotyping by INNOLIPAII.

Results

There was no significant difference (p > 0.05) in baseline HCV RNA levels between responders and non-responders to interferon. A statistically significant difference in CXCL13 (p = 0.017) and E-Cadherin levels (P = 0.041) was reported between responders and nonresponders at week 12. Significant correlations were found between changes in the CXCL13 levels and CXCL9, CXCL16, E-cadherin levels as well as between changes in E-cadherin levels and both CXCL16 and ALT levels that were maintained during follow up. Also, significant changes have been found in the serum levels of CXCL5, CXCL13, and CXCL16 with time (before pegylated interferon α 2 a and α 2 b therapy, and at weeks 12 and 24) with no significant difference in relation to interferon type and response to treatment.

Conclusion

Serum levels of CXCL13 and E-Cadherin could be used as surrogate markers to predict response of combined PEG IFN-α/RBV therapy, especially at week 12. However, an extended study including larger number of patients is needed for validation of these findings.

Clinical trial No

NCT01758939

【 授权许可】

   
2013 Zekri et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Mukherjee S: Hepatitis C. Medscape. 2011. http://emedicine.medscape.com/article/177792-overview webcite
• [2]Frank C, Mohamed MK, Strickland GT, Lavanchy D, Arthur RR, Magder LS, El Khoby T, Abdel-Wahab Y, Aly Ohn ES, Anwar W, Sallam I: The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000, 355(9207):887-891.
• [3]El-Zanaty F, Way A: Egypt demographic and health survey 2008. Cairo, Egypt: Ministry of Health, El-Zanaty and Associates, and Macro International; 2009. Available at http://www.measuredhs.com/pubs/pdf/FR220/FR220.pdf webcite
• [4]Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL: Genetic epidemiology of hepatitis C virus throughtout Egypt. J Infect Dis 2000, 182:698-707.
• [5]Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H Jr, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM, PEGASYS International Study Group: Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004, 140:346-355.
• [6]Reddy KR, Messinger D, Popescu M, Hadziyannis SJ: Peginterferon alfa-2a (40kDa) and ribavirin: comparable rates of sustained virological response in Sub-sets of older and younger HCV genotype 1 patients. J Viral Hepat 2009, 16(10):724-731.
• [7]Gao B, Hong F, Radaeva S: Host factors and failure of interferon-a treatment in hepatitis C virus. Hepatology 2004, 39:880-890.
• [8]Lee SS, Abdo AA: Predicting antiviral treatment response in chronic hepatitis C: how accurate and how soon? J Antimicrob Chemother 2003, 51:487-491.
• [9]Kamal S: Improving outcome in patients with hepatitis C virus genotype 4. Am J Gastroenterology 2007, 102:2582-2588.
• [10]Roulot D, Bourcier V, Grando V, Deny P, Baazia Y, Fontaine H, Bailly F, Castera L, De Ledinghen V, Marcellin P, Poupon R, Bourlière M, Zarski JP, Roudot-Thoraval F, Observational VHC4 Study Group: Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection. J Viral Hepatitis 2007, 14:460-467.
• [11]Zekri AR, Haleem HA, Esmat GE-D, Bahnassy AA, El-Din HMA, Hafez MM MM, Sharaby AF, Sharaf H, Zakaria MSE-D: Immunomodulators, sFas and Fas-L as potential noninvasive predictors of IFN treatment in patients with HCV genotype-4. J Viral Hepatitis 2007, 14:468-477.
• [12]El Makhzangy H, Esmat G, Said M, Elraziky M, Shouman S, Refai R, Rekacewicz C, Gad RR, Vignier N, Abdel-Hamid M, Zalata K, Bedossa P, Pol S, Fontanet A, Mohamed MK: Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4. J Med Virol 2009, 81:1576-1583.
• [13]Zekri AR, Ashour MS, Hassan A, Alam El-Din HM, El-Shehaby AM, Abu-Shady MA: Cytokine profile in Egyptian HCV genotype-4 in relation to liver disease progression. World J Gastroenterol 2005, 11(42):6624-6630.
• [14]Wald O, Weiss ID, Galun E, Peled A: Chemokines in hepatitis C virus infection: pathogenesis, prognosis and therapeutics. Cytokine 2007, 39:50-62.
• [15]Diago M, Castellano G, García-Samaniego J, Pérez C, Fernández I, Romero M, Iacono OL, García-Monzón C: Association of pretreatment serum interferon c inducible protein 10 levels with sustained virological response to peginterferon plus ribavirin therapy ingenotype 1 infected patients with chronic hepatitis C. Gut 2006, 55:374-379.
• [16]Casrouge A, Decalf J, Ahloulay M, Lababidi C, Mansour H, Vallet-Pichard A, Mallet V, Mottez E, Mapes J, Fontanet A, Pol S, Albert ML: Evidence for an antagonistform of the chemokine CXCL10 in patients chronically infected with HCV. J Clin Invest 2011, 121(1):308-317.
• [17]Moura AS, Carmo RA, Teixeira AL, Teixeira MM, Rocha MO: Soluble inflammatory markers as predictors of virological response in patients with chronic hepatitis C virus infection treated with interferon-α plus ribavirin. Memorias do Instituto Oswaldo Cruz 2011, 106(1):38-43.
• [18]Zeremski M, Petrovic LM, Talal AH: The role of chemokines as inflammatory Mediators in Chronic Hepatitis C Virus Infection. J Viral Hepat 2007, 14(10):675-687.
• [19]Rot A, Von Andrian UH: Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 2004, 22:891-928.
• [20]Wan L, Kung YJ, Lin YJ, Liao CC, Sheu JJ, Tsai Y, Lai HC, Peng CY, Tsai FJ: Th1 and Th2 cytokines are elevated in HCV-infected SVR(+) patients treated with interferon-a. Biochemical and Biophysical Research Communications 2009, 379:855-860.
• [21]Dou J, Wang J, Liu PB, Zhang XJ: Gene expression profiles on three kinds of genotype hepatitis C virus core protein in Huh-7 cell line with microarray analysis. Zhonghua Yu Fang Yi Xue Za Zhi 2006, 40(1):38-41.
• [22]Butera D, Marukian S, Iwamaye AE, Hembrador E, Chambers TJ, Di Bisceglie AM, Charles ED, Talal AH, Jacobson IM, Rice CM, Dustin LB: Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C. Blood 2005, 106:1175-1182.
• [23]Perney P, Turriere C, Portalès P, Rigole H, Psomas C, Blanc F, Clot J, Corbeau P: CXCR3 expression on peripheral CD4+ T cells as a predictive marker of response to treatment in chronic hepatitis C. Clin. Immunol 2009, 132(1):55-62.
• [24]Cicinnati VR, Kang J, Sotiropoulos GC, Hilgard P, Frilling A, Broelsch CE, Gerken G, Beckebaum S: Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon. Journal of General Virology 2008, 89:1243-1253.
• [25]Sansonno D, Tucci FA, Troiani L, Lauletta G, Montrone M, Conteduca V, Sansonno L, Dammacco F: Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vacuities. Blood 2008, 112(5):1620-1627.
• [26]Balian A, Naveau S, Zou W, Durand-Gasselin I, Bouchet L, Foussat A, Galanaud P, Chaput JC, Emilie D: Pretreatment expression of the perforin gene by circulating CD8(+) T lymphocytes predicts biochemical response to interferon-alpha in patients with chronic hepatitis C. Eur. Cytokine Netw 2000, 11:177-184.
• [27]Biron CA: Interferons alpha and beta as immune regulators—a new look. Immunity 2001, 14:661-664.
• [28]Hirohashi S, Kanai Y: Cell adhesion system and human cancer morphogenesis. Cancer Sci 2005, 94:575-581.
• [29]Arora P, Kim E, Jung J, Jank KL: Hepatitis C virus core protein downregulates E- cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Letters 2008, 261:244-252.
• [30]National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C. Hepatology 2002, 36(supp1):S3-S20. http://consensus.nih.gov/2002/2002HepatitisC2002116html.htm webcite
• [31]Zekri AR, Bahnassy AA, Alam El-Din HM, Salama HM: Consensus siRNA for inhibition of HCV genotype-4 replication. Virology J 2009, 6:13. BioMed Central Full Text
• [32]Zekri AR, El-Din HM, Bahnassy AA, El-Shehabi AM, El-Leethy H, Omar A, Khaled HM: TRUGENE sequencing versus INNO-LiPA for sub-genotyping of HCV genotype-4. J Med Virol 2005, 75(3):412-420.
• [33]Knodell RG, Ishak KG, Black WC: Formulation and application of numerical scaring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981, 1:431-435.
• [34]Desmet VJ, Gerber M, Hoofnagle JH: Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994, 19:1513-1520.