immune response to hbv in...
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Immune response to HBV in Patients
Adam J. Gehring, Ph.D.Biology Lead
Toronto Centre for Liver DiseaseUniversity Health Network (UHN)
Assistant ProfessorDepartment of Immunology
University of Toronto
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Adaptive Immune Response to HBV
Acute/ResolvedRobust, coordinated adaptive immunity1. CD8 T cells mediate clearance of infected cells2. B cells - anti-HBs marker of resolution 3. CD4 T helper cells support CD8 & B cells
ChronicWeak Adaptive Immune response1. Low T cell frequency2. Lack of effective antibodies
X XX
T
T
TT
T
B B
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T cell responses do not correlate with clinical stages• Arbitrary definitions and many patients = indeterminate
Profile of the HBV-specific T cell Response in Chronic HBV
Park 2015 Dec;150(3):684–5.Kennedy Gastroenterology. 2012 Sep;143(3):637–45.
Age may be better correlation of T cell immunity• Higher T cell frequency detectable in younger patients• Lower PD-1 expression
T cell PD-1
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Pallett, J. Exp Med. 2017 Jun 5;214(6):1567–80. Tan J. Virol. 2008 Oct 24;82(22):10986–97.
Variation in T cell repertoire• Age of patients alters antigen-specific repertoire• Different Genotypes/HLA profiles elicit different T cell repertoires• Important for measuring immunity• Designing vaccines
Profile of the HBV-specific T cell Response in Chronic HBV
T cells in the liver do not equal T cells in the blood• Different phenotype• Different functional profile• Different transcription factor profile
Total T cells HBV-specific T cells
Blood
Liver
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Patients who lose HBsAg have higher T cell frequency• HBsAg loss on nuc treatment shows T cell recovery
• almost to level of acute response• T cell response in spontaneous clearance is higher than untreated• Cross-sectional study – chicken & egg?
Profile of the HBV-specific T cell Response in Chronic HBV
Boni, Gastroenterology. 2012 Oct;143(4):963–9.
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Hepatotropic virus Liver is generally a tolerizing organ
o Hepatocyte/LSEC Antigen presentation = bad for primingo Suppressive Dendritic cellso High IL-10, TGF-β, PD-L1, enzymes degrading essential amino
acids, hypoxia
Hepatitis B Virus Immune Evasion/Exhaustion
High Antigen burdenHigh viral load High viral antigen
HBsAg up to 1 mg/ml in serumHBc-related Ag = ?
Constant presentation?Hepatocytes, LSEC, Periphery?
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Inhibitory receptors often co-expresseda. Nebbia, PLoS ONE 2012; 7: e47648. b. Boni, J Virol 2007; 81: 4215–4225. c. Schurich Hepatology. 2011; 53: 1494–1503d. Bengsch, J. Hepatol. 2014 Dec;61(6):1212–9e. Fisicaro Gastroenterology. 2010 Feb;138(2):682–93
Significant mitochondrial dysfunction• Impairs T cell functionality• Antioxidants restore T cell functionality
a. Fisicaro Nat Med. 2017 Feb 6;23(3):327–36.
Active elimination of T cellsActivation induced apoptosis
a. Lopes J. Clin. Invest. 2008 May 1;118(5):1835–45
NK-TRAIL mediated killing of T cellsa. Peppa J. Exp Med. 210, 99–114 (2013).
Specific Mechanisms Suppressing HBV-specific T cells
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Non-specific Mechanisms Suppressing HBV-specific T cell Function in chronic HBV
Arginase elevated in HBV patients• Correlates with ALT level• Suppresses T cell proliferation & function
a. Sandalova. Gastro. 2012 Jul;143(1):78–87.e3.b. Das. J. Exp Med. 2008 Aug 11;205(9):2111–24
Myeloid Derived Suppressor Cells (MDSC)• Produce Arginase and IL-10• Suppress T cell expansion
a. Pallett, Nat Med. 2015 Jun;21(6):591–600.
Regulatory cells – Treg & Breg• frequency correlates with ALT• produce IL-10• Depletion in vitro can enhance CD8 expansion
a. Das, J. Immunol. 2012 Oct 4;189(8):3925–35b. Xu, J. Immunol. 2006 Jul 1;177(1):739–47
Tregs Bregs
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Acute/ResolvedRobust, coordinated adaptive immunity1. CD8 T cells mediate clearance of infected cells2. B cells - anti-HBs marker of resolution 3. CD4 T helper cells support CD8 & B cells
ChronicWeak Adaptive Immune response1. Low T cell frequency2. Lack of effective antibodies
X XX
T
T
TT
T
B B
Adaptive Immune Response to HBV- What About B Cells? -
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Bertoletti, J. Hepatol. 2016 Apr;64(1 Suppl):S71–83. Rehermann, Nature Medicine 19, 859–868 (2013)
Adaptive Immune Response to HBV- What About B Cells? -
Detection of the HBV antibody response• Antigen > Immune Complexes > anti-HBs• Immune complexes found in >90% of acute patients• memory anti-HBs-specific B cells detectable by elispot
• after resolution• after vaccination
Madaliński, Clin & Exp Immun, 1979 Jun;36(3):371–8. Pernice, Clin & Exp Immun, 1979 Aug;37(2):376–80. Böcher, Hepatology, 2000 Feb 1;31(2):480–7. Vanwolleghem, Hepatology. 2015 Jul;62(1):87–100.
Memory anti-HBs-specific B cells difficult to detect • Fewer immune complexes in chronic patients
• mainly patients with active disease• Correlates with activated B cell profile in patients with
active disease • IgG subclasses may be associated with better control
B
Activated
Dusheiko, J. Clin. Invest. 1983 May;71(5):1104–13. Barnaba, Clin & Exp Immun. 1985 May;60(2):259–66. Böcher, Clin & Exp Immun,1996 Jul 1;105(1):52–8.
Oliviero, J. Hepatol. 2011 Jul;55(1):53–60.Rath, Clin & Expl Immun. 1988 Apr;72(1):164–7Gregorek, J. Hepatol. 2005 Apr;42(4):486–90.
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Complexity of the Innate Immune Response to HBV
Arguably more complex than the T cell responseCD4 CD8NK
γδ T cell
MAIT
MN/MO
DC
Innate effectors• NK cells, MAIT cells, γδ T cells• Innate effectors can be negative regulators in chronic HBV patients• Little data on their role in recognizing/eliminating infected hepatocytes
Myeloid Cells• Dendritic Cells, Monocytes, Macrophages• Antigen presentation• Cytokine production
Parenchymal cell responses • Hepatocytes, Endothelial Cells, Stellate cells
Human innate immune response studied mainly in context of pathogenesis of chronic HBV• Limited data comparing innate immunity in acute - resolved – chronic HBV patients
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Innate Immune Response in Chronic HBV
Vertical transmission accounts for a majority of chronically infected patients
No acute response to HBV because virus is always present • Innate immune system is exposed to HBV before birth
Hong. Nat Comms 6, 1–12 (2015).
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NK cell IFN-γ production suppressed• Related to IL-10• Especially in hepatitis patients
Peppa, PLoS Pathog. 2010 Dec 16;6(12):e1001227.
Gehring J Clin Invest. 2013 Sep 3;123(9):3766-76 Boltjes PLoS ONE. 2014;9(5):e97006.
Myeloid cell function in chronic HBVDendritic cell • function highly variable• Inhibited, activated, restored with nucleoside analogues
Monocytes• Contain HBsAg in vivo• No evidence of altered stimulatory capacity • Intact cytokine production
TNF-α
Alterations in the Innate Immune Response to HBV
Caveats of myeloid cell analysis• Short-lived compared to T & B cells• Spend few days in circulation
• Susceptible to environmental changes• Bone marrow alteration?
Dapi HBsAg
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Innate cells dominate the immune composition of the liver
Innate Immune Response in Chronic HBV
(NK/γδ/MAIT)
Lymphocytes
Blood
(NK/γδ/MAIT)Liver Liver
Myeloid Cells
Blood
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Pattern Recognition receptors
Phase I/II Clinical Trials• TLR-7• TLR-8• Rig-I
Pre-clinical• STING• Inactivated viruses (PPOV)
Innate Targets for Immunomodulatory Drug Development
Induce innate/antiviral cytokine production• Cytokines: IL-1α, IL-1β, IL-10, IL-6, IL-12, IL-18, TNF-α, IFN-α, IFN-λ• Chemokines: CXCL-8, -9, -10, Mip1a, Mip1B, MCP-1
Gehring, Best Pract Res Clin Gastroenterol. 2017 Jun;31(3):337-345
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Summary
HBV-Specific T cell response• Not significantly different across different phases of HBV• Repertoire varies by genotype, HLA profile and localization• Multiple specific and non-specific mechanisms maintaining the exhausted state
B cell response• Top level data – more work is needed• Memory B cells are detectable in resolved/vaccinated• So far, difficult to detect in chronic patients – need better tools• activated profile during active disease: meaning?
Innate Immunity• Needed to enhance T cell immunity = antigen presentation• Significant antiviral potential if properly harnessed• Reduced NK cell function in chronic HBV• Negatively regulates T cell immunity = MDSC, NK-TRAIL