Cytokines and Immune Response Quiz

Cytokine Therapeutics

• Cytokines are low molecular weight proteins (<30 kDa) secreted by cells of the innate and adaptive immune systems
• Cytokines are typically not stored, but are synthesized by new gene transcription upon cellular stimulation
• Cytokines mediate their effects by binding to specific receptors on the surface of target cells, affecting cell behavior
• Cytokines act as a means of communication between cells and tissues, mediating responses to external stimuli or tissue damage
• Cytokines can act in three different ways: autocrine (on cells producing them), paracrine (on nearby cells), and endocrine (on distant cells)

Lecture Objectives

• Understand what a cytokine is, its role, mechanisms of action, and traits
• Recognize cytokines of the innate and adaptive immune system
• Understand the role of cytokines in inflammation (pro- vs. anti-inflammatory)
• Describe effects of different cytokines in disease
• Know at least two examples of cytokine therapeutics used for disease treatment

Cytokine Biology

• Cytokines are chemical messengers
• Cytokines are crucial for immune system function
• Cytokine effects are pleiotropic (cytokine has many effects on different cell types)
• Cytokines act in a redundant manner (several cytokines may have the same effect)

Cytokines and Their Actions

• Cytokines can act via autocrine, paracrine, or endocrine mechanisms.

Cytokine Traits

• Many cytokines have different effects (activation, differentiation, proliferation) on multiple cell types (pleiotropy)
• Cytokines can be produced by various cell types and act on many different cell types
• Different cytokines can have similar effects on a cell type (redundancy)
• Combinations of cytokines can have a stronger effect than either cytokine alone (synergy)
• The effects of one cytokine can inhibit another (antagonism)

Cytokines and the Immune System

• Cytokines are produced in response to innate and adaptive immune system activation.
• Cytokine production is associated with type I interferon, interleukins (IL-) 1, 6, and tumor necrosis factor (TNF).
• Cytokines produced by the adaptive immune response include interferon-y, IL-2, 4, and 5.
• Other cytokines stimulate immature leukocyte growth and differentiation (IL-3, colony stimulating factors)
• Interleukins are a subset of cytokines.

Cytokines Affecting Many Organ Systems and Cell Types

• Cytokines affect various organ systems and different cell types throughout the body
• Cytokines influence cells in different parts of the body
• Cytokines can be produced by numerous cells and tissues, affecting cells in many tissues and organs. 

Cytokines and Inflammation

• Inflammation involves responses initiated within hours of infection or injury
• Inflammation's effects include destruction of invading microorganisms, induction of blood clotting, and repair of injured tissue.

Cytokines Drive the Inflammatory Response

• Cytokines play a key role in amplifying inflammatory responses
• Cells release cytokines and chemokines following infection to trigger vasodilation, increased vascular permeability, and recruitment of inflammatory cells
• Cytokines stimulate the production of antimicrobial and antiviral proteins, and cause the killing of infected cells

Pro-inflammatory vs Anti-inflammatory Cytokines

• Pro-inflammatory cytokines stimulate an immune response to infection or injury.
• Anti-inflammatory cytokines control and limit the pro-inflammatory response to prevent its over-escalation and tissue damage.

Disturbing the Balance of Cytokine Production

• An excess of either pro-inflammatory or anti-inflammatory cytokines can lead to serious complications, such as sepsis or immunosuppression
• Sepsis is caused by an excessive pro-inflammatory response
• Immunosuppression is caused by an excessive anti-inflammatory response

Cascade Effects of Cytokines (Produced by Macrophages)

• Activated macrophages secrete a range of cytokines
• Cytokines produced by macrophages induce local and systemic effects, including inflammation, fever, and the production of acute-phase proteins.

Cascade Effects of Cytokines (Produced by T Cells)

• Activated T cells produce a range of cytokines
• Cytokines produced by T cells affect various cell types and contribute to immune regulation and inflammatory responses

Cytokine Signaling

• Cytokines signal via their receptors.
• Cytokine receptors are a part of families of receptor proteins
• This signaling involves binding of ligands (e.g., cytokines) to extracellular domains of receptors.

Cytokine Effects in Disease

• Diseases can result from dysregulation of cytokine production
• Cytokines are involved in various pathological conditions

Cytokines - IL-1 Family

• Comprised of 11 members
• Promote innate immune system cells' activity (e.g., neutrophils, eosinophils, basophils)
• Activate and reinforce T cell functions
• Help differentiate T helper 17 (TH17) cells from naïve T cells

Cytokines - IL-1a and IL-1β

• IL-1β is secreted and circulates systemically; IL-1α acts locally.
• Monocytes and macrophages produce IL-1β.
• Keratinocytes and endothelial cells express high levels of IL-1α.

Cytokines - IL-18 and IL-33

• IL-18 and IL-33 are involved in various immune responses
• These cytokines have crucial immunomodulatory functions

Cytokines - IL-6

• Member of the same family as IL-11
• Expressed by mononuclear phagocytes, T cells, B cells, fibroblasts, and endothelial cells
• Involved in hematopoiesis, B cell maturation, and T cell activation

IL-6 and Immune-Mediated Diseases

• Cytokine dysregulation plays a significant role in various diseases
• Elevated levels of IL-6 can be a predictor of disease activity in several contexts

IL-2

• Pleiotropic cytokine, initially identified as a T cell growth factor
• Produced by antigen-stimulated CD4+ T cells, CD8 T cells, NK cells, and activated DCs
• Plays a role in T cell differentiation and memory cell formation

IL-2 Therapy

• IL-2 is a key factor for Treg cell survival and maintenance
• Low-dose IL-2 is effective in various conditions
• The short half-life of IL-2 necessitates repeated injections

IL-2 Therapy in Cancer

• Approved treatment for metastatic melanoma and renal cell carcinoma (ALDESLEUKIN)
• Administered systemically

The Other Side of the Coin…

• Low-dose IL-2 therapy is an important approach to regulating immune responses in various disease states
• High-dose IL-2 therapy has safety concerns

Cytokine Release Syndrome

• Cytokine release syndrome is a systemic inflammatory response triggered by various factors
• The resulting cytokine storm often involves massive T cell stimulation, leading to serious adverse events.

A Long Way to Go…

• Limitations of cytokine therapies include short half-lives, efficacy, systemic administration requirements requiring repeated injections, and potential toxicities prompting further investigations into disease-specific treatments and strategies for improving outcomes

TNF-α

• Pro-inflammatory mediator with cytolytic and cytostatic effects on tumor cells.
• Linked with coagulation, insulin resistance, and endothelial function (pleiotropic effects)

TNF-α and Immune-Mediated Diseases

• Pro-inflammatory cytokine implicated in rheumatoid arthritis, psoriasis, and certain cardiovascular diseases.
• Anti-TNF therapies (e.g., Humira, Remicade, Enbrel, Simponi Aria, and Cimzia) are widely used for managing TNF-related conditions.

Anti-TNF Therapies

• Treatment strategies mainly for autoimmune diseases
• Various categories of therapies exist, including fully human monoclonal antibodies and fusion proteins

Key Points and Clinical Uses

• Many cytokines have specific roles in disease, but they are not always beneficial
• Cytokine therapeutics are an emerging approach to treat a variety of diseases, but further research is still needed to improve efficacy in clinical applications and find safer delivery methods.