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Interleukin 23 and autoimmune diseases: current and possible future therapies

Abdo AIK, Tye GJ

Inflamm Res, 2020 May;69(5):463-480.
PMID: 32215665 DOI: 10.1007/s00011-020-01339-9

PURPOSE: IL-23 is a central proinflammatory cytokine with a wide range of influence over immune response. It is implicated in several autoimmune diseases due to the infinite inflammatory loops it can create through the positive feedbacks of both IL-17 and IL-22 arms. This made IL-23 a key target of autoimmune disorders therapy, which indeed was proven to inhibit inflammation and ameliorate diseases. Current autoimmune treatments targeting IL-23 are either by preventing IL-23 ligation to its receptor (IL-23R) via antibodies or inhibiting IL-23 signaling by signaling downstream mediators' inhibitors, with each approach having its own pros and cons.
METHODS: Literature review was done to further understand the biology of IL-23 and current therapies.
RESULTS: In this review, we discuss the biological features of IL-23 and its role in the pathogenesis of autoimmune diseases including psoriasis, rheumatoid arthritis and inflammatory bowel diseases. Advantages, limitations and side effects of each concept will be reviewed, suggesting several advanced IL-23-based bio-techniques to generate new and possible future therapies to overcome current treatments problems.

Matched MeSH terms: Interleukin-23/immunology*
Selection and evaluation of single domain antibody against p19 subunit of IL-23 by phage display for potential use as an autoinflammatory therapeutic

Abdo AIK, Nordin F, Tye GJ

Int Immunopharmacol, 2024 Aug 20;137:112371.
PMID: 38852516 DOI: 10.1016/j.intimp.2024.112371

IL-23 is a double-subunit cytokine that plays an important role in shaping the immune response. IL-23 was found to be associated with several autoinflammatory diseases by generating sustained inflammatory loops that lead to tissue damage. Antibody neutralization of IL-23 was proven to be effective in ameliorating associated diseases. However, antibodies as large proteins have limited tissue penetration and tend to elicit anti-drug antibodies. Additionally, anti-IL-23 antibodies target only one subunit of IL-23 leaving the other one unneutralized. Here, we attempted to isolate a recycling single domain antibody by phage display. One of IL-23 subunits, p19, was expressed in E. coli fused to Gamillus protein to stabilize the α-helix-only p19. To remove Gamillus binders, two biopanning methods were investigated, first, preselection with Gamillus and second, challenge with IL-23 then on the subsequent round challenge with p19-Gam. The isolation of calcium-dependent and pH-dependent recycling binders was performed with EDTA and citrate buffers respectively. Both methods of panning failed to isolate high-affinity and specific p19 recycling binders, while from the second panning method, a high affinity and specific p19 standard binder, namely H11, was successfully isolated. H11 significantly inhibited the gene expression of IL-17 and IL-22 in IL-23-challenged PBMCs indicating H11 specificity and neutralizing ability for IL-23. The new binder due to its small size can overcome antibodies limitations, also, it can be further engineered in the future for antigen clearance such as fusing it to cell penetrating peptides, granting H11 the ability to clear excess IL-23 and enhancing its potential therapeutic effect.

Matched MeSH terms: Interleukin-23/immunology
Immunohistochemical evaluation of interleukin-23 and cyclooxygenase-2 in the muscles of mice infected with Trichinella spiralis

El-Aswad BEW, Ammar AI, Mahmoud SF, Soliman SS, Abd El-Atty AF

Trop Biomed, 2020 Mar 01;37(1):75-88.
PMID: 33612720

The course of Trichinella (T.) spiralis infection includes intestinal and muscle phases. The aims of this work were to evaluate IL-23 and cyclooxygenase-2 (COX-2) by immunohistochemistry in the muscles of T. spiralis infected mice in a time-course study and to correlate their level with the serum levels of IL-23, IFN-γ, IL-4 and IL-10 cytokines. The mice were divided into an un-infected control group (UC) (10 mice) and 5 infected mouse groups (each 10 mice/group. Each mouse was infected with 200 T. spiralis larvae) and sacrificed on days 7, 14, 21, 28 and 35 post-infection (dpi). IL-23 showed weak expression (+1) on the 21st dpi, then it became moderately expressed (+2) on the 28th dpi and on day 35 pi, the immunoreactivity was strong (+3). COX-2 expressed weakly on 14 dpi, while the other mouse groups (21, 28 and 35) showed strong (+3) expression. IL-23 serum concentrations increased gradually in a significant pattern, in comparison to that of UC mice, from the 21st dpi to the end of the experiment. IFN-γ increased gradually and was significantly higher than those of UC mice from the 7th dpi, reached its maximum level on the 21st dpi, after which it decreased non-significantly. IL-4 up-regulated significantly in all infected groups in comparison to UC mice achieving its highest level on the 21st dpi and decreased after that. IL-10 increased significantly on the 7th dpi, but dropped at the 14th dpi, then reached its peak on the 21st dpi, and decreased again on the 28th and 35th dpi. In conclusion, T. spiralis infection caused increased expression of IL-23 and COX-2 in the muscle of infected mice, the effect being strongest on the 35th day. Also, the infection induced a mixed Th1/Th2 profile with a predominance of Th2 at the early muscle phase, after which the immune repose became mainly Th2.

Matched MeSH terms: Interleukin-23/immunology*
IL-23/IL-17 axis in the pathogenesis and treatment of systemic lupus erythematosus and rheumatoid arthritis

Farah Izati A, Wong KK, Che Maraina CH

Malays J Pathol, 2020 Dec;42(3):333-347.
PMID: 33361714

Interleukin-23 (IL-23) and IL-17 are the gatekeepers of CD4+ T helper 17 (Th17) cells where IL-23 is required for the development and expansion of Th17 cells that subsequently produce IL-17 to promote inflammation. Owing to such pro-inflammatory properties, the IL-23/IL-17 axis has emerged as an important mechanism in the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In recent years, therapeutic antibodies targeting IL-23 (e.g. ustekinumab, tildrakizumab, guselkumab) or IL-17 (e.g. brodalumab, secukinumab, ixekizumab) have been approved for the treatment of various autoimmune diseases. In this review, we describe the pathogenic mechanisms of IL-23/IL-17 axis in SLE and RA, as well as summarising the findings from phase II and III clinical trials of anti-IL-23/IL-17 therapeutic antibodies in SLE and RA patients. In particular, phase II study has demonstrated that the anti-IL-23 antibody (ustekinumab) confers enhanced treatment outcomes in SLE patients, while anti-IL-17 antibodies (secukinumab and ixekizumab) have shown improved clinical benefits for RA patients in phase II/III studies. Our review highlights the emerging importance of targeting the IL-23/IL-17 axis in SLE and RA patients.

Matched MeSH terms: Interleukin-23/immunology*
Fulltext Increased IL-23R+ Th Cells Population Exhibits Higher SLEDAI-2K Scores in Systemic Lupus Erythematosus Patients

Izati AF, Mohd Shukri ND, Wan Ghazali WS, Che Hussin CM, Wong KK

Front Immunol, 2021;12:690908.
PMID: 34484186 DOI: 10.3389/fimmu.2021.690908

The IL-23/IL-17 axis plays causative roles in the development and progression of systemic lupus erythematosus (SLE). However, it remains unclear if the IL-17RA+ and IL-23R+ T helper (Th) cells populations are associated with the serum IL-17 and IL-23 levels, or with the immunological parameters and disease activities in SLE patients. Herein, we examined the proportion of IL-17RA+ and IL-23R+ Th cells and serum levels of IL-17 and IL-23 in established SLE patients (n = 50) compared with healthy controls (n = 50). The associations of these interleukins and their receptors with immunological parameters [anti-nuclear antibody (ANA), anti-dsDNA antibody, and C-reactive protein (CRP)] and SLE disease activity (SLEDAI-2K scores) in SLE patients were assessed. CD3+CD4+ Th cells of SLE patients demonstrated significantly elevated IL-17RA+ (p = 1.12 x 10-4) or IL-23R+ (p = 1.98 x 10-29) populations compared with the healthy controls. Serum IL-17 levels were significantly lower in SLE patients compared with the healthy controls (p = 8.32 x 10-5), while no significant difference was observed for the IL-23 serum levels between both groups. IL-23R+ Th cells population was significantly associated with higher SLEDAI-2K scores (p = 0.017). In multivariate analysis, the proportion of IL-23R+ Th cells remained significantly associated with higher SLEDAI-2K scores independent of prednisolone intake (p = 0.027). No associations were observed between the interleukin parameters (i.e., IL-17, IL-23, IL-17RA+ Th cells, and IL-23R+ Th cells) with ANA, anti-dsDNA, and CRP status, suggesting that the IL-17/IL-23 axis acts independently of these immunological parameters. In conclusion, our results support that therapeutic inhibition of the IL-23/IL-17 axis receptors on Th cells, particularly IL-23R, is potentially relevant in SLE patients.

Matched MeSH terms: Interleukin-23/immunology*