Untitled Quiz

Liver Immunology

• Trinity College Dublin, a university in Dublin, Ireland offered an M.Sc in Immunology and M.Sc Immunotherapeutics focusing on liver immunology and liver cancer.
• The course included information on basic liver immunology, role in systemic inflammation and local hepatic immune repertoire, transplantation, liver disease, and liver malignancy.
• Immunopathological mechanisms and immunotherapeutic targets are also part of the course.

Liver Immunology Outline

• Basic liver immunology
• Role in systemic inflammation
• Local hepatic immune repertoire
• Transplantation immunology
• Liver disease
• Immunopathological mechanisms
• Liver malignancy
• Immunotherapeutic targets

What Liver Transplantation Tells Us About Liver Immunology

• The first Irish liver transplant occurred in 1993 at St Vincent's University Hospital.
• Liver transplantation typically does not require HLA matching.
• The immunosuppression for liver transplantation is significantly lower (1/10) compared to other organs.
• Calne et al (1969) researched immunological tolerance using porcine liver allografts.

What Makes Liver Transplantation Unique

• Solid organ transplantation, such as for a kidney, bone marrow or a liver has different levels of HLA matching.
• Liver transplantation often involves less HLA matching, potentially lowering the risk of rejection and requiring a lower immunosuppression level. Rejection in liver transplant is frequently reversible.

Liver Anatomy

• Blood is delivered to the liver through the hepatic artery (~20%) and the portal vein (~80%).
• The portal vein carries blood from the gut.
• Hepatocytes are the major functional cells within the liver, responsible for nutrition, synthesis, and detoxification.
• The liver receives nutrients from the ingested food from the gut and metabolic products from the venous circulation.
• The liver plays a key role in detoxification.
• Many components including proteins, carbohydrates, and lipids are transported to the blood through the hepatic vein.

Liver: Target for Microbiome MAMPs, Dietary Proteins, Pathogens & Metastases

• The liver is a target for microbiomes, dietary proteins, pathogens and cancer metastasis.
• Effective protection of the liver is needed against infection, autoimmunity, and malignancy.
• Local immune activity and systemic inflammation needs to be considered.

Liver Macrophages-Kupffer Cells

• Phenotype: Myeloid, TLR+ve, CD11b+HLA-DR+CD14+.
• Function: Recognizes and removes pathogens, undergoes phagocytosis, and produces cytokines for immune responses.
• TLRs: Toll-like receptors which play a vital role in recognizing pathogens and in production of cytokines
• The liver macrophages have a major function to present antigen

Innate Lymphoid Cells in Human Liver

• NK cells are highly enriched in human liver (30%-50%).
• The liver has a reversed ratio of CD4:CD8 T cells.
• Liver T cells are often memory phenotypes, specifically designed to respond to pathogens.

Hepatic Immune System–Lymphoid Repertoire

• Natural Killer (NK) cells: highly enriched in liver tissue.
• Activated phenotype: high cytotoxicity.
• Classical T cells: reversed CD4:CD8 ratio.
• Memory phenotype: enhanced response to pathogens.
• Invariant Natural Killer T (iNKT) cells.
• γδ T cells: potent cytotoxic and cytokine production and are highly enriched in liver tissue.

Liver NK Cells

• Liver natural killer cells are crucial in liver immunology.
• Subtypes and roles within liver immunity are important.
• Several articles discuss liver-resident NK cells and their roles in liver immunity and physiopathology.
• These cells are key in liver-resident immunity.

Liver Resident NK Cells

• Liver-resident NK cells: subsets and roles in immunity.
• Tissue-resident Eomeshi T-betlo CD56bright NK cells (from various research articles).
• The cells' roles in preventing and handling inflammation in the liver.

Acute Rejection

• Direct, indirect, semi-direct pathways.
• Donor APC (antigen-presenting cell), Recipient APC.
• Phagocytosis, cell-to-cell contact.
• Recipient T cells initiate an immune response against the donor MHC molecules.

Chronic Rejection

• Less well-defined than hyperacute or acute rejection.
• Develops over months to years.
• Progressive scarring and irreversible organ dysfunction.
• More prevalent in poorly HLA-matched transplants.
• Driven by antibody and cellular mediated processes.

Immunosuppression

• Early transplant failures due to graft rejection.
• Initial methods: whole-body irradiation, causing recipient death.
• Steroid use as sole treatment were insufficient.
• 1960s-70s: immunosuppressive drug development – DNA synthesis inhibitors, Antibody therapy, and calcineurin inhibitors, which block TCR signal pathways.
• mTOR inhibitors, Mycophenolate mofetil.
• Monoclonal Antibody therapies in 1990s.

Mechanisms of Immunosuppression

• Antigen-presenting cell
• MHC/peptides, antigen
• TCR complex, CD80/86, CD28
• Ciclosporin, Tacrolimus, Immunophilins (cyclophilin, FKBP)
• Calcineurin, NFAT
• Sirolimus, MPA, LFL, FKBP
• mTOR
• Cell cycle, Nuclear translocation of NFAT, IL-2 production.

Liver Transplantation Induces Tolerance

• Liver transplantation can induce tolerance in animals and is unique in transplantation compared to other organs.
• Specific absence of destructive immune response to transplanted tissue.
• Achieving transplant tolerance without immunosuppression is crucial in organ transplantation.

Natural Mechanisms of Tolerance

• Induction of transplant tolerance.
• Treg induction: important role that involves the increase in regulatory T cells (Treg).
• Microchimerism: important mechanism in organ transplantation.
• T-cell anergy: allogeneic T cell anergy (a specific type of cellular dysfunction).

Learning from Pathology

• Graft survival without immunosuppression which means the recipient immune system tolerate the graft.
• Trials on Treg (regulatory T cell) expansion and infusion to induce transplant tolerance are promising.
• In vivo and ex vivo Treg therapy.

A Role for Liver NK Cells

• Role of NK cells in liver transplantation and orchestrating rejection or tolerance responses.
• Hepatic CD56bright NK cells with unique transcriptional profiles.
• Key role in recognizing and eliminating allogenic CD8+ T cells.

Liver as a Site of Immunological Tolerance

• Liver is unique in tolerance mechanisms.
• Target of infection, autoimmunity, malignancy.

Liver Malignancy

• Chronic liver disease leads to hepatocellular carcinoma (HCC)
• Viral infections, alcoholic liver disease (ALD), and fatty liver disease cause inflammation and disrupt the liver's immune responses.
• Primary liver tumors are rare absent inflammation.
• Metastasis (tumors are common in the liver in patients with other cancers).
• Tumor adhesion promotes metastasis.
• Tolerogenic environment suppresses the systemic immune response.

Liver is Equipped with Significant Populations of Anti-Tumor Cells

• CD8 T cells, γδ T cells, and iNKT cells play important roles in liver.
• Innate lymphoid cells as targets for "altered self."

Tumor Immune Microenvironment Changes Immune Phenotype and Function

• Chronic inflammation, dysregulated cytokines, hypoxia, and alterations in cell metabolism.
• Changes in cell function in the tumour microenvironment lead to immune system dysfunction in liver cancer.

Liver NK cells in Metastatic Cancer

• The role of natural killer (NK) cells in colorectal liver metastasis (CRLM).
• Complicated by liver NK cells heterogeneity.
• Possible association between NK and T cells and favorable outcome.

γδ T Cells in Liver

• γδ T cells bridge innate and adaptive immunity.
• Three main subtypes in humans.
• Different classification system in mice.

γδ T Cells & Anti-Tumour Immunity

• γδ T cells are MHC unrestricted and non-peptide antigen-recognizing cells.
• They exhibit potent cytotoxic activity.
• Induce CD8+ T-cell cytotoxic activity.

γδ T Cells & Pro Tumour Activity

• Anergic phenotype: γδ T cells can take on an anergic phenotype or dysfunctional phenotype which can potentially facilitate tumor development.
• Upregulation of inhibitory checkpoints (ICs) that can be reversed with immunotherapies.
• γδ T cells are potentially tumor-promoting cells when they are dysfunctional.

Why Do Current Cancer Immunotherapies Work Poorly in Liver Cancers?

• Liver has a unique local immune system.
• Tumours in the liver grow and develop differently than in other organs.
• Liver's microenvironment affects immune cell phenotype and function.
• Liver metabolites affect cancer therapy.

How to Think About Making Liver Cancers Responsive to Immunotherapy

• Consider tumor/immune dynamics.
• Collect personalized data (clinical, immunological, tumor-immune interaction, histo-pathological/NK Immunoscore).
• Target therapies to immune cell sub-types in liver eg NK cells; focus on metabolic pathways in the liver.
• Consider combination therapies: Chemo and radiotherapy.

Liver Immunology Outline

• Basic Liver Immunobiology
• Systemic Inflammation
• Hepatic Immune Responses
• Transplantation Immunobiology
• Liver Disease
• Immunopathological Mechanisms
• Liver Malignancy
• Immunotherapeutic targets

Liver Microenvironment Determines NK Cell Phenotype

• Recreating liver cytokine milieu.
• Generating liver-conditioned media.
• Culturing liver NK cells + LCM.

Tumor Immune Micro-Environment: Changes in Immune Phenotype & Function

• Immune alterations in tumor microenvironment (inflammation, hypoxia, metabolites, etc.).
• Various immune cells affected by microenvironment (including myeloid cells, CD8 T cells, regulatory T cells NK cells) and their functions.