5. Cytokine therapeutics

Cytokine and its role

  • Cytokines are small proteins that act as signalling molecules in the immune system.
  • They are secreted by cells of the innate and adaptive immune system.
  • Their effect is mediated by binding to specific receptors on the surface of target cells.
  • Cytokines play a central role in regulating the immune response. They mediate communication with immune cells, influencing the movement of immune cells to sites of infection or injury.
  • There is no “one cytokine – one cell” rule:
    • Made by many cell types
    • Same cytokine made by different cell types
    • Cytokine receptors are found on many cell types

Examples of cytokines: interleukins, interferons, tumor necrosis factors (TNFs), and chemokines.

Cytokines’ mechanism of actions- Three different ways that cytokines can act in response to an activating stimulus and upon binding to their receptor:

1) Autocrine manner: acting on cells that produce it (helps them to get activated)

2) Paracrine manner: acting on cells nearby those that produce it (they can act on other cells nearby)

3) Endocrine manner: Secreted by one tissue into the blood, and acting on a different tissue. This depends on their ability to enter the blood circulation and their half-life

Cytokine traits- They have different traits

• Pleiotropy: Many different effects e.g. activation, differentiation, proliferation on tissue on different cell types by the same cytokine

• Redundancy: Different cytokines can have the same effect on one particular cell type

• Synergy: The effect of two cytokines together on one cell type is greater than the effect

of one cytokine alone

• Antagonism: The effects of one cytokine inhibit those of another

Cytokines and the immune system

• Cytokines produced as a result of activation of the innate immune system

•Typical cytokines: Type I interferon, interleukin (IL-) 1, IL-6, tumor necrosis factor (TNF)

• Cytokines produced as a result of activation of the adaptive immune system

• Interferon-γ, IL-2, IL-4, IL-5

• Cytokines that stimulate immature leukocyte growth and differentiation

• IL-3, colony-stimulating factors

All interleukins are cytokines, but not all cytokines are called interleukins

Role of cytokines inflammation-

Inflammation: Detected some damaged or abnormal activity

Inflammatory response initiated within hours of infection/wounding!

A state of inflammation is induced in the tissue by cytokines

1) Destruct invading microorganisms

2) Induce local blood clotting

3) Repair injured tissue

Pro-inflammatory vs anti-inflammatory cytokines-

Pro-inflammatory cytokines:

  • Set-up/initiate an immune response against infection/injury.
  • Eg. IL-1, TNFα, IL-6, IL-12

Anti-inflammatory cytokines:

  • Control and inhibit the release of pro-inflammatory mediators (to keep a balance)
  • Limit the inflammatory response
  • eg. IL-10, IL-4, IL-13, TGFβ

There needs to be a balance between pro-inflammatory and anti-inflammatory cytokines in a healthy immune response.

Too many pro-inflammatory cytokines → sepsis

Too many anti-inflammatory cytokines → Immunosuppression

IL-1 family

  • 11 members (incl. IL-1α, IL-1β, IL-18, IL-33), both pro- and anti-inflammatory
  • Two main members: IL-1α and IL-1β (pro-inflammatory).
  • Promotes the activity of cells of the innate immune system (e.g. neutrophils, eosinophils, basophils etc.)
  • Activates and reinforces T cell function
    • T helper 17 (TH17) cells require IL-1 to differentiate from naive T cells
    • TH1 cells are mainly affected by IL-18
    • TH2 cells are mainly affected by IL-33

IL-1 dysregulation is implicated in autoimmune diseases (e.g. psoriasis and lupus), autoinflammatory diseases (e.g. Chron’s disease and UC) and asthma.

IL-1 family

• Comprised of 11 members (incl. IL-1α, IL-1β, IL-18, IL-33), both pro- and anti-inflammatory members

• Promote the activity of cells of the innate immune system (e.g. neutrophils, eosinophils, basophils etc)

• Activate and reinforce T cell function

• T helper 17 (TH17) cells require IL-1 to differentiate from naïve T cells

• TH17 cells mediate autoimmune and chronic inflammatory diseases

• TH1 cells are mainly affected by IL-18

• TH2 cells are mainly affected by IL-33

• Closely related receptors – signalling!

IL-6

  • Pro-inflammatory cytokine
  • Expressed by mononuclear phagocytes, T cells, B cells, fibroblasts, endothelial cells and many more
  • It has pleiotropic activity involved in:
    • Haematopoiesis (blood cell formation)
    • Maturation of B cells into antibody-producing plasma cells
    • Activation of T cells
      • plays a role in the differentiation and regulation of helper T cells type 2 and Treg phenotype.
  • Signals through a specific receptor complex. It binds to the IL-6 receptor α chain and the signal transducing component gp130, which triggers intracellular signaling events that mediate the biological effects of IL-6 on target cells
  • Systemic and local inflammatory effects
  • Anti-IL-6 antibodies as treatment for many diseases (e.g. SLE, rheumatoid arthritis)

TNFα-

  • Pro-inflammatory cytokine
  • Mainly secreted from activated macrophages, monocytes, NK cells, T cells, neurons and others.
  • Pleiotropic cytokine
    • Stimulates cell proliferation
    • Exerts cytolytic and cytostatic activity against tumour cells
      • plays a role in the body’s defense against cancer
    • Has antiviral effects and plays a role in regulating the immune system
    • Linked to various physiological processes, including blood coagulation, insulin resistance and endothelial function

IL-2

  • Pleiotropic cytokine
  • Mainly produced b Secreted predominantly by antigen-stimulated CD4+ T cells
  • Produced also by CD8 T cells, NK cells, activated DCs
  • Stimulate differentiation of naïve CD8 T cells, into memory T cells

Cytokine release syndrome

• Massive T cell stimulation → overproduction of cytokine (it was called cytokine storm)

• One of the most frequent adverse events of such therapies

• Systemic inflammatory response, triggered by infections, drugs (antibody, proptein and non-protein based) and other factors

• Observed in the setting of transplantation and GVHD

• The severity of CRS can vary from mild to severe/life-threatening

A long way to go..

  • Cytokines’ half life is small – limits their efficacy (excert their function)
  • Systemic administration
    • Limited efficacy
    • More toxicities!
  • Why are many immunotherapies given at a late disease stage? Risk of systemic, not a high response. Their immune system is tired → they can’t respond as you wish
  • Why are they given to specific subcategories of diseased patients?

Know at least two examples of cytokine therapeutics used for the treatment of diseases.

anti-TNFα therapy-

  • Monoclonal antibodies that target TNFα (anti-TNF therapy) to treat autoimmune diseases such as rheumatoid arthritis.
  • By inhibiting TNFα, the overactive immune response is regulated.
  • An example of Anti-TNF Therapy is Humira

IL-2 therapy

  • IL-2 stimulates the proliferation and maturation of T cells.
  • Aldesleukin (a recombinant form of IL-2) can be used as a treatment for metastatic melanoma and renal cell carcinoma.
  • This stimulates T cells to target and attack cancer cells.
  • Often provided as a systemic injection (short half-life), which can lead to toxicities (e.g. cytokine release syndrome).