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. 2005;50(10):1793–1803. doi: 10.1007/s10620-005-2940-y

Multiplex Cytokine Profiling of Initial Therapeutic Response in Patients with Chronic Hepatitis C Virus Infection

Harlan Wright 1, Philip Alex 2,3, Thuan Nguyen 2, Teddy Bader 1, Ahmet Gurakar 1, Anthony Sebastian 1, Liberty Gonzales 2, Gemma Wallis 2, Mark Naylor 2,3, Igor Dozmorov 2, Michael Centola 2,3,4,✉, Bakr Nour 1
PMCID: PMC7087834  PMID: 16187176

Abstract

Currently available prognostic tools are inadequate to discern the molecular basis of the heterogenic response in hepatitis C virus (HCV)-infected patients treated with the current standard of therapy. The expression and biological function of immune mediators have been shown to be critical in all phases of the immune response to HCV infection and likely therefore influence host response. Herein, a biometric multiplex serum cytokine assay was utilized to characterize the immunomodulatory effects of host response in 10 HCV patients. Serum levels of 17 cytokines were compared before and after 1 month of treatment and against controls. Overall serum cytokine levels were significantly higher in patients (P < 0.05) than controls. Additionally, viral titers decreased in all patients after 1 month of therapy, as did overall serum cytokine levels in the cohort (P < 0.05). To assess relationships between changes in cytokine levels and changes in viral titer, the cohort was divided into three statistically distinct subgroups based on changes in viral titers. Specific sets of cytokines decreased in each group: decreases in CCL4, interleukin (IL)-2, CXCL8, and IL-1β correlated with the greatest drops in viral titer, decreases in IL-5, granulocyte colony stimulating factor (G-CSF), and CCL4 correlated with moderate drops in viral titer, and only CCL2 correlated with the lowest drops in viral titer. Interestingly, decreases in CCL4 levels correlated with decreases in viral titers in all patients. CCL4 controls leukocyte influx and thus propagates inflammation. In conclusion, these data raise the possibility that characteristic changes in host response modulate the therapeutic response, demonstrating the prognostic power of serum cytokine profiling in chronic HCV.

Key Words: cytotoxic and humoral cytokines, chemokines, pegylated interferon α ribavirin

Footnotes

This publication was made possible by grants from Joullian Foundation, Kerr McGee Corporation, Dr. Henry Freeds Foundation, Samuel Roberts Noble Foundation, and E. L. & Thelma Gaylord Foundation and Grants P20 RR 017703, R21-AR-48378, NIH 1 P20 RR15577, and NIH 1 P20 RR16478 from the National Institutes of Health.

References

  • 1.World Health Organization Hepatitis C. Wkly Epidemiol Rec. 1997;72:65–69. [Google Scholar]
  • 2.Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556–562. doi: 10.1056/NEJM199908193410802. [DOI] [PubMed] [Google Scholar]
  • 3.Alter MJ. Epidemiology of hepatitis C. Hepatology. 1997;26:62S–65S. doi: 10.1002/hep.510260711. [DOI] [PubMed] [Google Scholar]
  • 4.Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36(5; Suppl 1):S21–S29. doi: 10.1053/jhep.2002.36227. [DOI] [PubMed] [Google Scholar]
  • 5.Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–472. doi: 10.1053/gast.1997.v112.pm9024300. [DOI] [PubMed] [Google Scholar]
  • 6.Bruix J, Barrera JM, Calvet X, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet. 1989;2:1004–1006. doi: 10.1016/S0140-6736(89)91015-5. [DOI] [PubMed] [Google Scholar]
  • 7.Di Bisceglie AM, Simpson LH, Lotze MT, Hoofnagle JH. Development of hepatocellular carcinoma among patients with chronic liver disease due to hepatitis C viral infection. J Clin Gastroenterol. 1994;19:222–226. doi: 10.1097/00004836-199410000-00011. [DOI] [PubMed] [Google Scholar]
  • 8.Cummings KJ, Lee SM, West ES, et al. Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon: a meta- analysis of randomized trials. JAMA. 2001;285:193–199. doi: 10.1001/jama.285.2.193. [DOI] [PubMed] [Google Scholar]
  • 9.McHutchison JG, Gordon SC, Schiff ER. Interferon-α-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485–1492. doi: 10.1056/NEJM199811193392101. [DOI] [PubMed] [Google Scholar]
  • 10.August-Jorg BS, Borovicka J, Dufour JF, et al. Swiss Association for the Study of the Liver: Twenty-four vs. fourty-eight weeks of re-therapy with interferon alpha 2b and ribavirin in interferon alpha monotherapy relapsers with chronic hepatitis C. Swiss Med Wkly. 2003;23(33–34):455–460. doi: 10.4414/smw.2003.10300. [DOI] [PubMed] [Google Scholar]
  • 11.McHutchison JG, Manns MP, Garaud JJ, Albrecht J. Adherence to therapy enhances sustained response in chronic hepatitis C patients receiving peginterferon-α 2b plus ribavirin. Gastroenterology. 2002;123:1061–1069. doi: 10.1053/gast.2002.35950. [DOI] [PubMed] [Google Scholar]
  • 12.Fried MW, Shiffman ML, Reddy RK. Pegylated (40 kDa) interferon-α-2a (PEGASYS (R)) in combination with ribavirin: efficacy and safety results from a phase III, randomized, actively-controlled, multicenter study. N Engl J Med. 2002;347:975–982. doi: 10.1056/NEJMoa020047. [DOI] [PubMed] [Google Scholar]
  • 13.Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology. 1997;25(3):735–739. doi: 10.1002/hep.510250340. [DOI] [PubMed] [Google Scholar]
  • 14.Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19(12):1409–1417. doi: 10.1097/00000478-199512000-00007. [DOI] [PubMed] [Google Scholar]
  • 15.Bertoletti A, Ferrari C. Kinetics of the immune response during HBV and HCV infection. Hepatology. 2003;38(1):4–13. doi: 10.1053/jhep.2003.50310. [DOI] [PubMed] [Google Scholar]
  • 16.Tsai SL, Liaw YF, Chen MH, Huang CY, Kuo GC. Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity. Hepatology. 1997;25:449–458. doi: 10.1002/hep.510250233. [DOI] [PubMed] [Google Scholar]
  • 17.Woitas RP, Lechmann M, Jung G, Kaiser R, Sauerbruch T, Spengler U. CD30 induction and cytokine profiles in hepatitis C virus core-specific peripheral blood T lymphocytes. J Immunol. 1997;159:1012–1018. [PubMed] [Google Scholar]
  • 18.Napoli J, Bishop GA, McGuinness PH, Painter DM, McCaughan GW. Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. Hepatology. 1996;24:759–765. doi: 10.1002/hep.510240402. [DOI] [PubMed] [Google Scholar]
  • 19.Fan XG, Liu WE, Li CZ, et al. Circulating Th1 and Th2 cytokines in patients with hepatitis C virus infection. Mediators Inflamm. 1998;7(4):295–297. doi: 10.1080/09629359890992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Oxo Chemie Ag Initiates Macrokine Phase 2 Clinical Trials. Worldwide Biotech, August 2000
  • 21.Simmonds P, Alberti A, Alter HJ, et al. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology. 1994;19:1321–1324. doi: 10.1016/0270-9139(94)90887-7. [DOI] [PubMed] [Google Scholar]
  • 22.Szodoray P, Alex P, Brun JG, Centola M, Jonsson R. Description of circulating cytokines in Sjögren's syndrome using a multiplex cytokine array system. Scand J Immunol. 2004;59(6):592–599. doi: 10.1111/j.0300-9475.2004.01432.x. [DOI] [PubMed] [Google Scholar]
  • 23.Chappell C, Wallis G, Alex P, et al.: Distinct immunopathological disease profiles of the spondyloarthropathies. FASEB J 18(3; Suppl), 2004 (abstr)
  • 24.Alex P, Wallis G, Szodoray P, et al. A powerful prognostic tool to predict treatment outcome in rheumatoid arthritis. Arth Rheum. 2003;29(9; Suppl):129. [Google Scholar]
  • 25.Chappell C, Scofield H, Wallis G, Kurien BT, Morris RI, Centola MB. Distinct molecular immunopathological disease profiles of ankylosing spondylitis. Arth Rheum. 2003;29(9; Suppl):1560. [Google Scholar]
  • 26.Dozmorov I, Centola M. An associative analysis of gene expression array data. Bioinformatics. 2003;22(2):204–211. doi: 10.1093/bioinformatics/19.2.204. [DOI] [PubMed] [Google Scholar]
  • 27.Dozmorov IM, Saban MR, Knowlton N, Centola M, Saban R. Connective molecular pathways of experimental bladder inflammation. Physiol Genom. 2003;15:209–222. doi: 10.1152/physiolgenomics.00130.2003. [DOI] [PubMed] [Google Scholar]
  • 28.EASL International Consensus Conference on Hepatitis C. Paris, 26-27 February Consensus statement [no authors listed] J Hepatol. 1999;31(Suppl 1):3–8. [PubMed] [Google Scholar]
  • 29.Heathcote EJ, Shiffman ML, Cooksley WG. Peginterferon-α-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med. 2000;343:1673–1680. doi: 10.1056/NEJM200012073432302. [DOI] [PubMed] [Google Scholar]
  • 30.Davis GL, Esteban-Mur R, Rustgi V. Interferon-α-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1493–1499. doi: 10.1056/NEJM199811193392102. [DOI] [PubMed] [Google Scholar]
  • 31.Olivieri I, Palazzi C, Padula A. Hepatitis C virus and arthritis. Rheum Dis Clin North Am. 2003;29(1):111–122. doi: 10.1016/S0889-857X(02)00097-2. [DOI] [PubMed] [Google Scholar]
  • 32.Aceti A, Taliani G, Sorice M, Amendolea MA. HCV and Sjogren's syndrome. Lancet. 1992;6(8806):1425–1426. doi: 10.1016/0140-6736(92)91252-4. [DOI] [PubMed] [Google Scholar]
  • 33.Hirohata S, Inoue T, Ito K. Development of rheumatoid arthritis after chronic hepatitis caused by hepatitis C virus infection. Intern Med. 1992;31(4):493–495. doi: 10.2169/internalmedicine.31.493. [DOI] [PubMed] [Google Scholar]
  • 34.Siegel LB, Cohn L, Nashel D. Rheumatic manifestations of hepatitis C infection. Semin Arth Rheum. 1993;23(3):149–154. doi: 10.1016/s0049-0172(05)80035-6. [DOI] [PubMed] [Google Scholar]
  • 35.Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol. 1999;163:6236–6243. [PubMed] [Google Scholar]
  • 36.Murai M, Yoneyama H, Harada A, et al. Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J Clin Invest. 1999;104:49–57. doi: 10.1172/JCI6642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Westermann J, Bode U. Distribution of activated T cells migrating through the body: a matter of life and death. Immunol Today. 1999;20:302–306. doi: 10.1016/S0167-5699(99)01474-7. [DOI] [PubMed] [Google Scholar]
  • 38.Bigger CB, Guerra B, Brasky KM, Hubbard G, Beard MR, Luxon BA, Lemon SM, Lanford RE. Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees. J Virol. 2004;78(24):13779–13792. doi: 10.1128/JVI.78.24.13779-13792.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Lichterfeld M, Leifeld L, Nischalke HD, Rockstroh JK, Hess L, Sauerbruch T, Spengler U. Reduced CC chemokine receptor (CCR) 1 and CCR5 surface expression on peripheral blood T lymphocytes from patients with chronic hepatitis C infection. J Infect Dis. 2002;15(12):1803–1807. doi: 10.1086/340829. [DOI] [PubMed] [Google Scholar]
  • 40.Lau C, Yam LY, Cheung TM, Poon E, Yung RW, Yuen KY. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003;10(9369):1615–1617. doi: 10.1016/S0140-6736(03)13265-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

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