5. Cytokine therapeutics

Cytokines

Small proteins act as signalling molecules in the immune system, secreted by cells of the innate and adaptive immune system. Cytokines play a central role in regulating the immune response. They mediate communication with immune cells

Autocrine manner

Cytokines that act on cells that produce them

Pro-inflammatory cytokines

Initiate immune responses against infection or injury, e.g., IL-1, TNFα, IL-6, IL-12.

Pleiotropy

Cytokines having multiple effects on different cell types, e.g., activation, differentiation, proliferation.

IL-6

Pro-inflammatory cytokine with pleiotropic activities, involved in haematopoiesis, B cell maturation, T cell activation. It is expressed by mononuclear phagocytes, T cells, B cells, fibroblasts, endothelial cells and many more. It can give systemic and local inflammatory effects

Anti-inflammatory cytokines

Control and inhibit pro-inflammatory mediators to balance the immune response, e.g., IL-10, IL-4, IL-13.

Paracrine manner

Cytokines that act on cells nearby those that produce them

Endocrine manner

Cytokines that are secreted by one tissue into the blood, and acting on a different tissue

No “one cytokine – one cell” rule

• 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.

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

Role of cytokines in inflammation

A state of inflammation is induced in the tissue by cytokines. Inflammatory response initiated within hours of infection/wounding

What does too many pro-inflammatory cytokines lead to?

Sepsis

What does too many anti-inflammatory cytokines lead to?

Immunosuppression

What does lead to cytokine release syndrome?

Massive T cell stimulation lead so overproduction of cytokine (cytokine storm)

What triggers cytokine release syndrome?

It is triggered by infections, drugs (antibody, proptein and non-protein based) and other factors. Observed in the setting of transplantation and GVHD

What limit cytokines efficacy?

Cytokines have short half-lifes

What does systemic administration of cytokines?

Limited efficacy and more toxicities

Anti-IL-6 antibodies treatment is used for

Dieases like SLE, rheumatoid arthritis

TNFα

Pro-inflammatory cytokine with pleiotropic activities, involved in stimulation of cell proliferation, cytolytic and cytostatic affects against tumour cells, exhibits antiviral effects and regulates the immune system and associated with diverse physiological processes such as blood coagulation, insulin resistance, and endothelial function. It is mainly secreted from activated macrophages, monocytes, NK cells, T cells, neurons and others.

IL-2

Pleiotropic cytokine is primarily produced and antigen-stimulated CD4+ T cells but is also produced by CD8+ T cells, NK cells, and activated DCs

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

IL-2 therapy

IL-2 stimulates the proliferation and maturation of T cells. This stimulates T cells to target and attack cancer cells. Used a treatment for metastatic melanoma and renal cell carcinoma

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

What does IL-1 dysregulation implicate?

Autoimmune diseases (e.g. psoriasis and lupus), autoinflammatory diseases (e.g. Chron’s disease and UC) and asthma.