Targeting Cytokines

Tumor Necrosis Factor (TNF)

one of the first cytokines discovered; produced by innate immune systems; binds specific receptors called TNF receptors (TNFRs); early response cytokine, one of the first inflammatory mediators at site of injury or infection; induces controlled death of old cells, targeting of cells infected by viruses or tumoral cells by lymphocytes; promotes fever

Anti-TNF Therapies

a treatment currently used for various chronic inflammatory diseases; antibodies and fusion proteins specifically target TNF, preventing binding to TNFRs

antibodies target products secreted by pathogens to:

1. block pathogenic functions of microorganisms

2. make them a target to other immune cells

3. block secreted pathogenic products, such as toxins

fusion proteins

engineered by joining portions of a gene of interest resulting in a protein combining attributes of the two original proteins; cab be used to create a protein that incorporates immunoglobulin fragments fused to targeting regions of receptors

Etanercept

fusion protein using TNFR2 binding site fused to IgG

Certolizumab

includes TNF-recognition fraction without IgG

Therapeutic applications in IBD

TNF abundant in intestine; TNF-TNFR1 mediates intestinal epithelial cell apoptosis; anti-TNF mediated therapy can prevent IEC apoptois and reduce activity of adaptive immune cells

infliximab, adalimumab and certolizumab are successful treatments of IBD (NO ETANERCEPT)

Therapeutic applications in RA

infliximab, adalimumab, etanercept, and certolizumab all approved for RA; exact mechanism not clear; believed to be due to a decrease in the release of mediators that participate in cartilage destruction

Downsides of anti-TNF therapies

in IBD, 30% of patients don’t respond (primary response)

patients may lose response over time (secondary response)

side effects - may impair host response to infections

etanercept has a high risk of reactivating tuberculosis

Interleukin-1

binds IL-1R-1 triggering activation of downstream inflammatory pathways; important player in RA; can be targeted with drugs blocking IL-1R-1 or drugs that bind IL-1

Anakinra

recombinant human IL-1 receptor antagonist; binds IL-1R-1 with high affinity and does NOT trigger activation of signaling events downstream; reduces magnitude of IL-1 mediated response

canakinumab

moleculer anti-IL-1B antibody; binds circulating IL-1B; antigen-antibody complex phagocytosed and cleared, preventing IL-1B binding the receptor; decreases magnitude of IL-1 mediated response

Cytokines in Allergy

IL-4 and IL-13 play important roles in chronic allergy diseases; severe atopic dermatitis is a chronic inflammatory diesease with uncontrolled itch and lesions to skin associated with increase activity of IL-13; Duplimab binds and blocks receptors of IL-4 and IL-13, preventing them from acting on cells