Lecture 6 clinical immunology Cytokines Cut back on chemokine stuff Dave gives a lot of that in the prior lecture Focus on signaling pathways Add more on Th1/Th2 Dr. Dalia Galal

What Is A Cytokine? Cytokines: are soluble and small proteins produced in response to microbes and other antigens. They help in the communications between all leukocytes Low molecular weight proteins When released from mononuclear phagocytes, these are called monokines. When released from T-lymphocytes, they are called lymphokines. When released, cytokines bind to the receptors of the cells and alter gene expression

Cytokines play an important role in: Hematopoiesis Adaptive (specific) Immunity (T and B cells) Innate (non-specific) Immunity Inflammation Categories of cytokines TNF family Chemokine family Interferon family Hematopoietin family

Functional features Potent Local Highly interactive Some function acts in very small amount (at 10-15 Molar) Local Autocrine Paracrine (sometimes) Endocrine Highly interactive Pleiotropic Redundant Synergistic Antagonistic

Functional features Potent Some function at 10-15 Molar

Functional features Local Cytokines can bind on the membrane of the same cell that secreting it (Autocrine) Cytokines can bind another cell close by (Paracrine) Few cases, cytokines can bind another cell far away (Endocrine)

Functional features Highly interactive Pleiotropic One cytokine can act on different cells Redundant Multiple cytokines can have the same functional effects Synergistic - Two cytokines may produce additive or synergetic effects Antagonistic - Effect of one cytokine is opposite (or stop) to the other’s action

Effects (actions) of cytokines on the cells: Proliferation of cells (B cells) Differentiation of cells (Th2 cells) Inhibition of cells activation (Macrophages) Stimulate expression of certain molecules (Major Histocompatability Complex, MHC)

Key Cytokines Produced by Innate Immune Responses IL-1 – produced by macrophages, epithelial cells IL-6 – produced by macrophages, endothelial cells (also T cells) IL-12 – produced by macrophages, dendritic cells Tumor necrosis factor (TNF)-a – produced by macrophages, NK cells (also T cells) Interferone (IFN-a) – produced by marophages and dendritic cells and acts on virally infected cells Interferone (IFN-b) – produced by fibroblasts and acts on virally infected cells

Functions of cytokines in innate immunity Macrophages activation 2. Inflammation

Dual function of TNF: The release of TNF-a by macrophages induces local protective effects, but TNF-a can have damaging effects when released systemically (septic shock).

Antiviral effects of Type I Interferons (IFN-a/b) Induction of enzyme that block viral replication Increases expression of class I MHC molecules on virus-infected cells, thus help killing by cytotoxic T lymphocytes

Key Cytokines Produced by T Cells IL-2 - produced by CD8+ and CD4+Th1 cells IFNg - produced by CD8+ T cells and CD4+Th1 TNF-a - produced by CD8+ T cells, CD4+Th1 and some CD4+Th2 IL-4 – produced by CD4+Th2 IL-10 - produced by CD4+ Th2

Functions of cytokines in acquired immunity Antibody secretion by B cells 2. Cytotoxic T lymphocyte differentiation

Interferons (IFNs) * Interferons (IFNs): are proteins secreted in response to viral infections or other stimuli * They include: - INF-α produced by leucocytes induced by virus infected cells - INF-β produced by fibroblasts - INF-γ produced by NK cells,TH1 cells, CD8 T-cells

Interferons (IFNs) Action of INF-α and IFN-β : - Prevent viral replication - Increase MHC-I expression on viral infected cells helping their recognition by CD8 T-cells - Increase cytotoxic action of Nk cells - Inhibit cell proliferation and tumor growth

Interferons (IFNs) Action of IFN-γ : - Activate Macrophages - Increase expression of MHC-I and II on APCs - Enhance cytotoxic actions of Nk cells - Promote production of TH1 and inhibits proliferation of TH2

Therapeutic Uses of Cytokines 1) Interferon in treatment of viral diseases, cancer 2) Several cytokines are used to enhance T-cell activation in immunofideficincy diseases, e.g. IL-2, IFN-,TNF- 3) IL-2 and lymphokine activating killer cells (LAK) in treatment of cancer 4) Granulocyte-macrophage colony-stimulating factor) GM-CSF) induces increase in white cell count, it is used: a- To restore leukocytic count after cytotoxic chemotherapy induced neutropenia b- After bone marrow transplantation C- To correct AIDS-associated leukopenia

Therapeutic Uses of Cytokines 5) Anti-cytokines antibodies in management of autoimmune diseases and transplant rejection: a- Anti-TNF in treatment rheumatoid arthritis b- Anti-IL2R to reduce graft rejection 6) Anti-TNF antibodies in treating septic shock 7) Anti-IL-2R  in treating adult T-cell leukemia 8) Anti-IL-4 is under trial for treatment of allergies