Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans

Brian D. Livingston, Jeff Alexander, Claire Crimi, Carla Oseroff, Esteban Celis, Kieran Daly, Luca G. Guidotti, Francis V. Chisari, John Fikes, Robert W. Chesnut, Alessandro Sette

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

Theradigm-hepatitis B virus (HBV) is an experimental lipopeptide vaccine designed to stimulate induction of HBV-specific CTL responses in HLA-A2 individuals. Previous studies had demonstrated high immunogenicity in healthy volunteers, but comparatively weak CTL responses in chronically infected HBV patients. Herein, we examined helper T lymphocyte (HTL) responses in chronically infected patients. Despite normal proliferation and IL-2 secretion, IL-12 and IFN-γ secretion in vitro in response to the vaccine was reduced compared with healthy volunteers. A similar pattern of cytokine secretion was observed following mitogen stimulation, suggesting a general altered balance of Th1/Th2 responses. Further analysis indicated that HTL recall responses to whole tetanus toxoid protein were reduced in chronically infected subjects, and reduced responsiveness correlated with the outcome of Theradigm-HBV immunization. Finally, experiments in HBV transgenic mice indicated that the nonnatural Pan DR HTL epitope, PADRE, is capable of inducing high levels of IFN-γ secretion and that its inclusion in a lipopeptide incorporating an immunodominant L(d)-restricted CTL epitope resulted in breaking tolerance at the CTL level. Overall, our results demonstrate an alteration in the quality of HTL responses induced in chronically infected HBV patients and suggest that use of a potent HTL epitope may be important to overcome CTL tolerance against specific HBV Ags.

Original languageEnglish (US)
Pages (from-to)3088-3095
Number of pages8
JournalJournal of Immunology
Volume162
Issue number5
StatePublished - Mar 1 1999

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Chronic Hepatitis B
Virus Diseases
Helper-Inducer T-Lymphocytes
Hepatitis B virus
Vaccination
Lipopeptides
T-Lymphocyte Epitopes
Therapeutics
Healthy Volunteers
Vaccines
Th1-Th2 Balance
HLA-A2 Antigen
Tetanus Toxoid
Interleukin-12
Mitogens
Transgenic Mice
Interleukin-2
Epitopes
Immunization
Cytokines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans. / Livingston, Brian D.; Alexander, Jeff; Crimi, Claire; Oseroff, Carla; Celis, Esteban; Daly, Kieran; Guidotti, Luca G.; Chisari, Francis V.; Fikes, John; Chesnut, Robert W.; Sette, Alessandro.

In: Journal of Immunology, Vol. 162, No. 5, 01.03.1999, p. 3088-3095.

Research output: Contribution to journalArticle

Livingston, BD, Alexander, J, Crimi, C, Oseroff, C, Celis, E, Daly, K, Guidotti, LG, Chisari, FV, Fikes, J, Chesnut, RW & Sette, A 1999, 'Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans', Journal of Immunology, vol. 162, no. 5, pp. 3088-3095.
Livingston, Brian D. ; Alexander, Jeff ; Crimi, Claire ; Oseroff, Carla ; Celis, Esteban ; Daly, Kieran ; Guidotti, Luca G. ; Chisari, Francis V. ; Fikes, John ; Chesnut, Robert W. ; Sette, Alessandro. / Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans. In: Journal of Immunology. 1999 ; Vol. 162, No. 5. pp. 3088-3095.
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