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Member Information
Kyong-Mi Chang, MD
Assistant Professor, Department of Medicine, Gastroenterology Division
Office Phone: 215-823-5893
Office Fax: 215-823-4394
Email: kmchang@mail.med.upenn.edu
Website(s): http://www.med.upenn.edu/camb/faculty/mv/chang.html
Education: MD 1987, Medical College of Pennsylvania
Keywords: HCV Immune Pathogenesis, HCV Persistence, Viral Escape, Viral Persistence, Epitope Mapping, Liver Disease, T Cell Suppression, HIV/HCV Coinfection, Alcohol.
Research and/or Clinical Interests:
The main interest of our translational research laboratory is the immune mechanisms of viral persistence and liver disease progression in patients infected with hepatitis C virus (HCV), an RNA virus with high rate of persistence (50-80%) associated with chronic necroinflammatory liver disease that can progress to liver cirrhosis and hepatocellular carcinoma.
Summary:
Our research focuses on the immune pathogenesis of human HCV infection, testing the hypothesis that antiviral T cells play an important role in the outcome of HCV infection and identifying the relevant immunological features of successful HCV clearance or liver disease progression. In the absence of convenient animal model of HCV, we have identified valuable cohorts of persons with distinct clinical and virological outcome (e.g. acute, resolved, chronic infection with varying degrees of liver disease and treatment stage). Using patient samples in various in-vitro and ex-vivo T cell assays, we are addressing a number of hypotheses, including the following:
1. The outcome of HCV infection is determined by quantitatively and qualitatively distinct anviral T cell response. We are studying the relative frequency, repertoire, cytokine profile and activation level of HCV-specific CD4 and CD8 T cell response using both in vitro and ex vivo methods that allow determination of immunological hierarchy. In particular, we are examining the mechanisms whereby antiviral T cells are suppressed during chronic HCV infection. These studies will define the features of antiviral T response relevant in natural and therapeutic control of HCV.
2. Selection of T cell escape variants contribute to HCV persistence, disease progression and antiviral treatment resistance. HCV is a highly mutable virus that readily escapes recognition from neutralizing antibody. Based on the initial immunological analysis, we are looking for potential T cell escape variants to determine its prevalence and their effect in antiviral T cell response.
3. Alcohol and HIV accelerate the progression of HCV-associated liver disease by modulating the antiviral T cell response. The effect of these potential immunosuppressive factors in HCV-specific T cell response and the virus is currently being investigated.
We are also investigating the impact of various host and viral factors as well the interplay between the T cell subsets and regulatory T cells in HCV infection. It is hoped that the results of our study will be relevant in clinical care and vaccine development.
Lab Rotation Projects and Methods:
1. Identification of T cell epitopes using overlapping peptide library
2. HCV dynamics and T cell response in patients with acute and chronic hepatitis C
3. Analysis of intrahepatic T cell response and T cell compartmentalization
4. HCV-specific T cell response in antiviral therapy
Representative Publications (Peer Reviewed ):
Rehermann*, B, Chang, K.M.*, J.G. McHutchison, R. Kokka, M. Houghton, F.V. Chisari. Quantitative Analysis of the Peripheral Blood Cytotoxic T Lymphocyte Response in Patients with Chronic Hepatitis C Virus Infection. Journal of Clinical Investigation . 1996; 98:1432-1440. * equal contribution to the work
Rehermann, B., K.M. Chang, J.G. McHutchison, M. Houghton, C.M. Rice, F.V. Chisari. Differential Cytotoxic T Lymphocyte Responsiveness to the Hepatitis B and C Viruses in Chronically Infected Patients. Journal of Virology . 1996; 70: 7092-7102.
Pasquinelli, C., J. Shoenberger, J. Chung, K.M. Chang, L.G. Guidotti, M. Selby, K. Berger, R. Lesniewski, M. Houghton, F.V. Chisari. Hepatitis C Virus Core and E2 Protein Expression in Transgenic Mice. Hepatology . 1997; 25: 719-727.
Chang, K.M., B. Rehermann, J.G. McHutchison, C. Pasquinelli, M. Houghton, F.V. Chisari. Immunological Significance of Hepatitis C Virus Cytotoxic T Lymphocyte Epitope Variants in Chronically Infected Patients. Journal of Clinical Investigation . 1997; 100: 2376-2385.
Alexander, J., M-F. Del Guercio, J.D. Fikes, R.W. Chesnut, F.V. Chisari, K.M. Chang, E. Appella, A. Sette. Recognition of a Novel Naturally Processed, A2 Restricted, HCV-NS4 Epitope Triggers IFN-gamma Release in Absence of Detectable Cytopathicity. Human Immunology 1998; 59: 776-782.
Chang, K.M., N.H. Gruener, S. Southwood, J. Sidney, G.R. Pape, F.V. Chisari, A. Sette. Identification of HLA-A3 and -B7 restricted Cytotoxic T Lymphocyte Response to Hepatitis C Virus in Patients with Acute and Chronic Hepatitis C. Journal of Immunology 1999; 162: 1156-1164.
Chang, K.M., R. Thimme, J. J. Melpolder, D. Oldach, J. Pemberton, J. Moorhead-Loudis, J. G. McHutchison, H. J. Alter and F. V. Chisari. Differential CD4 + and CD8 + T cell responsiveness in hepatitis C virus infection. Hepatology . 2001; 33: 267-276.
Thimme, R., K.M. Chang, J. Pemberton, A. Sette, F.V. Chisari. Degenerate immunogenicity of an HLA-A2-restricted hepatitis B virus nucleocapsid cytotoxic T-lymphocyte epitope that is also presented by HLA-B51. Journal of Virology . 2001; 75: 3984-7.
Thimme, R., D. Oldach, K.M. Chang, C. Steiger, S. Ray, and F.V. Chisari. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 2001; 194 (10): 1395-1406.
K. Sugimoto, J. Stadanlick, F. Ikeda, C. Brensinger, E. E. Furth, H.J. Alter and K.M. Chang. Influence of ethnicity in the outcome of hepatitis C virus infection and cellular immune response. Hepatology 2003 ; 37:590-599.
Representative Publications (Chapters, Reviews and Editorials) :
Chang, K.M., B. Rehermann, F.V. Chisari. Immunopathology of hepatitis C. Springer Serminars in Immunopathology . 1997; 19: 57-68.
Chang, K.M. The Mechanisms of Chronicity in Hepatitis C Virus Infection. Gastroenterology . 1998;115: 1015-8.
Chang, K.M., F.V. Chisari. Immune response in hepatitis B virus infection. Liver Clinics of North America . 1999; 3 (2): 221-240.
Piasecki, B, K. R. Reddy, K.M. Chang. Hepatology Elsewhere: Acute hepatitis C: To treat or not to treat. Hepatology . 2002; 35(6): 1538-1540
Chang, K.M. Immunopathogenesis of Hepatitis C Virus Infection. In: Clinics in Liver Disease . 2003; 7(1): 89-105.
Piasecki, B, L. Forman, K.M. Chang. Chapters in Viral Hepatitis . In: Requisites for Gastroenterology 2003 (In press).
