MSc Immunology & Immunotherapeutics 2023 Liver Immunology PDF

Liver Immunology & Liver Cancer M.Sc Immunology & MSc Immunotherapeutics 2023 Cliona O’Farrelly Professor of Comparative Immunology Liver Immunology For this session, need to know: a. NK ce...

Liver Immunology & Liver Cancer M.Sc Immunology & MSc Immunotherapeutics 2023 Cliona O’Farrelly Professor of Comparative Immunology Liver Immunology For this session, need to know: a. NK cell phenotype & function Outline b. gd T cells. c. Regulatory cells. c. Transplantation Immunology Basic liver immunology d. Immunosuppression Role in systemic inflammation Local hepatic immune repertoire Transplantation Immunopathological mechanisms Liver disease Immunotherapeutic targets Liver malignancy Trinity College Dublin, The University of Dublin  What Liver Transplantation tells us about Liver Immunology first Irish liver transplant : 1993 SVUH - no HLA matching - 1/10 immunosuppression as used for other organs WHY? Calne RY et al Induction of Immunological Tolerance by Porcine Liver Allografts. Nature (1969) 223:472-6 Trinity College Dublin, The University of Dublin  What makes liver transplantation unique? Transplant tolerance HLA matched Solid High IS Organ High risk of rejection Bone Closely HLA matched Marrow High IS GvHD or anti- leukemic effects No HLA matching Lower IS Liver Rejection common but reversible Trinity College Dublin, The University of Dublin  Liver Anatomy ~20% ~80% ~80%~20% Antigen-presenting cell function in the tolerogenic liver environment Angus W. Thomson & Percy A. Knolle Nature Reviews Immunology 10, 753-766 (November 2010) Trinity College Dublin, The University of Dublin Liver: Target for Microbiome MAMPs, Dietary Proteins, Pathogens & Metastases Nutrients Blood supply Immunological Tolerance And YET: LIVER NEEDS EFFECTIVE PROTECTION against infection, autoimmunity & malignancy Need to consider - Local immune activity - Role in systemic inflammation Trinity College Dublin, The University of Dublin Liver Immunology Outline Basic liver immunology Role in systemic inflammation Local hepatic immune repertoire Liver disease Immunopathological mechanisms Transplantation Immunotherapeutic targets Liver malignancy Trinity College Dublin, The University of Dublin Local Inflammation LIVER Systemic Inflammation Trinity College Dublin, The University of Dublin  Acute Phase Response Trinity College Dublin, The University of Dublin The hepatocyte has a major innate immune role - Detects inflammation - Produces acute phase proteins - Cytokines - Anti-microbial peptides - opsonins - C’ components - Anti-viral mechanisms Trinity College Dublin, The University of Dublin Liver Immunology Outline Basic liver immunology Role in systemic inflammation Local hepatic immune repertoire Liver disease Immunopathological mechanisms Transplantation Immunotherapeutic targets Liver malignancy Trinity College Dublin, The University of Dublin  Liver Macrophages - Kupffer Cells Phenotype: - myeloid - TLR+ve Bacterial lipoproteins Bacterial lipoarabinomannans - CD11b+HLA-DR+CD14+ LPS (leptospira, P.gingivalis) LPS (Gram-negative) Peptidoglycan (Gram-positive) Taxol (plant) Zymosan (yeast) Viral proteins GPI anchor (T.cruzi) Hsp60 (host) Fibronectin (host) Fibrinogen (host) Function TLR4/MD- 2 – Pathogen detection TLR 1, 2 & 6 TLR3, CD1 Host & 7&8 bacterial – Phagocytosis Viral dsRNA glycolipids Mannose, – Cytokine production glucan & TLR9 scavanger TLR5 Bacterial – Antigen presentation receptors CpG DNA Bacterial Bacterial flagellin carbohydrates Kupffer cell/Macrophage Trinity College Dublin, The University of Dublin Trinity College Dublin, The University of Dublin  Innate Lymphoid Cells Dominate in Human Liver B cells B cells NK cells 5% 6% 10% NKR+ T cells 3% NK cells T cells Blood T cells 31% 43% Liver 82% NKR+ T cells 20% CD3+ cells in health liver Trinity College Dublin, The University of Dublin  Liver NK Cells Trinity College Dublin, The University of Dublin  Liver Resident NK Cells CD56dim CD56dim NK cell subsets CD56brigh CD56brigh t t Liver Peripheral blood NK cells 30-50% NK cells 5-15% CD56bright 40% CD56bright 10% CD56bright phenotype Eomes Eomesl IFN-g hi o Tbetlo Tbethi IFN-g CXCR6+ CXCR6- IFN-glo IFN-ghi Trinity College Dublin, The University of Dublin  Liver Resident NK Cells Trinity College Dublin, The University of Dublin  Hepatic Immune System – Lymphoid Repertoire Natural Killer cells Highly enriched in liver (30-50%) Activated phenotype, increased cytotoxicity Classical T cells Reversed ratio of CD4:CD8 T cells Memory phenotype, enhanced response to pathogens Invariant Natural Killer T Cells MAIT (Mucosal Associated Invariant T) Cells gd T cells Potent cytotoxic and cytokine production Trinity College Dublin, The University of Dublin Cellular composition of the liver Hepatic microenvironment Hepatocytes ~60-80% Non- Hepatocytes ~20-40% Endothelial cells Myeloid cells Lymphocytes Biliary Stellate ~50% ~20% ~25% cells cells