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Yimaitong edited and sorted, please do not reprint
without authorization.
Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infection and modulation of innate and acquired immune responses
.
Elevated blood levels of IL-18 have been reported in some patients with immune-related conditions such as
.
Animal model tests have also clearly shown that IL-18 is involved in the progression or development of
some inflammatory and autoimmune diseases.
This article reviews the biological characteristics of IL-18 and its pathological role in different autoimmune diseases, and also summarizes some monoclonal antibodies and other drugs
targeting IL-18.
Currently, most IL-18-targeted drugs have shown only partial efficacy or complete ineffectiveness
in vitro, in vivo and human studies.
IL-18 has been implicated in a variety of autoimmune diseases
Many types of cells, both hematopoietic and non-hematopoietic, produce IL-18
.
It was initially thought that IL-18 was secreted
only by Kupffer cells and intrahepatic resident macrophages.
In fact, most endothelial cells, keratinocytes, osteoblasts, most intestinal epithelial cells, and mesenchymal cells also release IL-18 precursors
.
IL-18 has a wide range of biological roles
on immune cells.
To trigger the innate immune system, IL-18 binds to IL-12 and stimulates natural killer cells to respond to
malignant tumors and infections.
In the adaptive immune system, IL-18 promotes the activation and differentiation
of T cells.
These findings reveal the potential role of IL-18 in inflammatory and autoimmune diseases such as RA, systemic lupus erythematosus, psoriasis, and type 1 diabetes (Figure 1).
Fig.
1 Cell source and signal transduction mechanism of interleukin 18
Monoclonal antibodies and drugs targeting IL-18
Given IL-18's role in inflammation, targeting IL-18 appears to be a potential treatment
.
Specifically, strategies targeting IL-18 include the use of monoclonal antibodies to block IL-18, inhibit the production of intracellular IL-18, and inhibit the secretion of intracellular IL-18
.
Table 1 shows some clinical trials
targeting IL-18 for the treatment of inflammatory diseases.
Table 1 Clinical trial progress of IL-18 targeting drugs
Combined with IL-18
IL-18-binding protein (IL-18BP), a natural antagonist of IL-18, belongs to the immunoglobulin-like receptor type, and was first identified
in 1999.
Histopathological analysis showed that under IL-18BP treatment, joint inflammation was inhibited, inflammatory infiltration and cartilage destruction were reduced
.
In addition, in vivo studies have shown that short-term supplementation with IL-18BPFc prevents the development
of autoimmune diabetes in
Low doses of IL-18BP inhibit the inflammatory response
in the RA model.
However, no therapeutic effect
has been seen in a recent clinical trial using human recombinant IL-18BP in patients with RA and psoriasis.
Inhibits the production of IL-18
Caspase 1 appears to be a suitable target to inhibit IL-18 and IL-1β production
.
The active form of caspase 1 is a tetramer that cleaves the forms of IL-1β and IL-18 into mature forms and then leaves the cytoplasm
.
Pralnacasan is an oral caspase 1 inhibitor that was clinically tested and observed
in patients in a Phase 2 RA clinical trial.
The results showed that it was well tolerated and inhibited inflammation, but was suspected of promoting hepatotoxicity
.
Monoclonal antibodies
Currently, a single-blind, randomized, placebo-controlled Phase 1 trial
of human monoclonal antibody GSK1070806 is underway for inflammatory bowel disease (
The study aimed to investigate the use of the drug in the treatment of IBD in healthy and obese male subjects, as well as its safety, tolerability, pharmacokinetics and kinetics
.
In this multicenter, randomized, single-blind, placebo-controlled, parallel-group Phase 2a trial,
.
The results showed that although it was well tolerated, inhibition of IL-18 did not improve
.
Recently, a novel anti-human IL-1R7 monoclonal antibody that blocks and inhibits IL-18 inflammatory signaling has been developed
.
It works
by reducing IL-18-induced activation of NFkB and IFN-g in human cell lines, as well as reducing IL-6 production.
It is worth noting that IL-1R7 is a potential treatment strategy that has not yet been tried, and its clinical potential for the treatment of IL-18-mediated disease remains to be explored
.
Another new development in IL-18 monoclonal antibodies is the recognition of new epitopes
produced after IL-18 is cleaved by caspase.
This new epitope can be used to distinguish between physiological and pathological IL-18
.
This finding suggests that pathogenic IL-18 may be controlled in a targeted manner to achieve therapeutic purposes
.
summary
Although there are numerous reports suggesting that IL-18 plays an integral role in autoimmune diseases, many of these mechanisms remain unknown
.
Many in vitro studies, animal models, and some clinical studies support the important role
of IL-18 in RA, psoriasis, and other diseases.
Further research
is needed to further understand the role of IL-BP and other drugs targeting IL-18 in the treatment and control of autoimmune diseases.
References: Ihim SA, Abubakar SD, Zian Z, et al.
Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment[J].
Front Immunol.
2022 Aug 11; 13:919973.
doi: 10.
3389/fimmu.
2022.
919973.
PMID: 36032110; PMCID: PMC9410767.
