Interleukin-17

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for the induction, progression and control of T-cell-mediated cytotoxic immune reactions and B-cell activation (antibody production). They are mainly produced and secreted by stimulated leukocytes, monocytes and macrophages. To date, >40 different interleukins have been clearly identified. Each cytokine of the interleukin group is nomenclatically assigned a number for its classification (IL-1 to IL-38).

A whole family of chemically related pro-inflammatory cytokines (IL17 family) is summarized under the term interleukin-17. All have the amino acid sequence of the IL-17 family members. This sequence contains four highly conserved cysteine building blocks (cysteine nodes), which are crucial for the 3-dimensional shape of the protein. There is no significant homology in the sequence to other cytokines. The members of the interleukin-17 family are produced and secreted by Th17 helper cells after stimulation with interleukin-23.

The IL-17 cytokines react with 3 specific surface receptors:

IL17RA (see IL17RA gene below)

IL17RB (seeIL17R gene below)

IL17RC (see IL17RA gene below).

The receptor binding leads to a cascade of further cytokines and chemokines in the target cells, which trigger inflammatory reactions. Thus, the IL-17 family is involved in the pathogenesis of inflammatory diseases: psoriasis, ulcerative colitis, rheumatoid arthritis, bronchial asthma, lupus erythematosus. Interleukin-17A plays a key role in the initiation and maintenance of the immune response in psoriasis.

Furthermore, members of the interleukin-17 family also play a role in allograft rejection and antitumor immunity.

In humans, the IL-17 family consists of:

• IL-17A (also known as IL-17)
• IL-17B
• IL-17C
• IL-17D
• IL-17E (also known as interleukin-25 )
• IL-17F (there is a homology with IL-17A)

Interleukin-17 is produced and secreted by neutrophil granulocytes, mast cells, gamma/delta T cells, natural killer cells (NK cells) and innate lymphoid cells. There appears to be an inflammatory network of cells in which these immunologically active cells communicate with each other. Interleukin-23 as an inducing cytokine as well as TH1 cells, macrophages and other cells of the innate immune system play a role here. IL-17 induces an inflammatory reaction by recruiting monocytes and neutrophil granulocytes after invasion by pathogens of different types. The cytokine acts synergistically with TNF and interleukin-1.

In fibroblasts, interleukin-17 increases the expression of ICAM-1. In endothelial, epithelial cells and fibroblasts, the cytokine causes the release of interleukin-6, interleukin-8 and prostaglandin E2 (PGE2). Interleukin-17 also plays a role in the activation of CD4-positive cells. In hematopoiesis, interleukin-17 promotes the maturation of neutrophil granulocytes.

It is certain that interleukin-17 (IL-17) plays a dominant role in the psoriatic inflammatory reaction as well as in other inflammatory (including autoimmunological) skin diseases. Due to this constellation, it was obvious to use monoclonal antibodies against IL-17 or its receptor therapeutically. It has been shown that therapeutic antibodies against TH 17/IL-17-mediated inflammation reduce the levels of inflammatory cytokines in the blood and skin (Malakouti M et al. 2015). This leads to a significant regression of the inflammatory reaction. Indications include psoriasis, rheumatoid arthritis, spondylarthritis, multiple sclerosis, non-infectious uvitis and others.

The IL-17 receptor A blocker brodalumab (Kyntheum®) is a therapeutic agent on the market that is suitable for the treatment of moderate to severe plaque psoriasis in adults.

Therapeutic approaches in psoriasis:

Secukinumab (Cosentyx®) is a fully humanized monoclonal antibody approved for psoriasis that targets the cytokine IL-17A. The compound is being tested for the treatment of various rheumatologic diseases - as well as psoriatic arthritis and psoriasis. The antibody secukinumab selectively binds to IL-17 and neutralizes this cytokine. Secukinumab has been shown to be successful in the treatment of psoriasis in several large studies. In the ERASURE1 study, 738 patients with moderate to severe psoriasis received either 300 or 150 mg of secukinumab or placebo subcutaneously at weeks 1, 2, 3, 4 and 8. At week 12, 81.6 percent (300 mg) and 71.6 percent (150 mg) of secukinumab patients, respectively, but only 4.5 percent of control patients met PASI-75 criteria. 65.3 vs. 51.2 vs. 2.4% of participants were largely free of clinical appearance. > 40% of study participants achieved PASI-100(complete clinical appearance-free). The effect of secukinumab reached a maximum after 16 weeks and remained constant until week 52.

Ixekizumab (^Taltz® ) is another monoclonal antibody approved for psoriasis that binds with high affinity and specificity to the pro-inflammatory cytokine interleukin-17A (IL-17A) and neutralizes it. The substance is applied as a subcutaneous injection. The initial dose is 80 mg twice. Thereafter, ixekizumab is administered every two weeks.

Brodalumab (Siliq® - approved by the FDA since 2017), a monoclonal antibody, binds to the receptor for the cytokine interleukin-17 (IL-17). In the AMAGINE 1 study, brodalumab was compared to placebo at the two doses (210 mg or 140 mg subcutaneously every two weeks). After 12 weeks, there was a 75% decrease in PASI scorein 83% (210 mg dose) and 60% (140 mg dose) (PASI 75). In the AMAGINE 2 and 3 studies, brodalumab was compared with ustekinumab (neutralizes interleukins IL-12 and IL-23) and placebo at the same doses. Brodalumab achieved a similar good result as ustekinumab at a low dosage, but under the higher dosage the results were better under brodalumab.

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