UCLA researchers from the Department of Microbiology, Immunology and Molecular Genetics have identified key inhibitors and inhibitory pathways targeting a pro- inflammatory molecule implicated in a vast array of autoinflammatory diseases.
BACKGROUND: Inflammatory autoimmune diseases are a broad group of disorders of the immune system where the body attacks its own tissues. These disorders affect all age ranges and can be debilitating diseases with inadequate treatment options. Interleukin (IL)-12 and IL-23 are inflammatory molecules critical for generating T helper cell immune responses. IL-12p40 is a shared component of IL-12 and IL-23 that is critical for their function and aberrantly expressed in several autoinflammatory diseases. IL-12 and IL-23 are known to contribute to the pathogenesis of diseases such as psoriasis, chronic eczema, vitiligo, Behcet’s disease, ulcerative colitis, and Crohn’s disease. Thus, it is crucial to identify new inhibitors of these interleukins in order to develop therapies that can dampen autoimmunity in a multitude of autoinflammatory diseases.
INNOVATION: UCLA researchers have identified several potent, highly selective inhibitors and inhibitory pathways that target expression of the gene encoding the inflammatory molecule IL-12p40, which is implicated in various autoimmune diseases. Researchers conducted a double fluorescence reporter screen of over 60,000 small molecule compounds in macrophages to identify selective inhibitors, as well as non-selective inhibitors of the gene encoding for IL-12p40. They further confirmed that one particular inhibitor was an exquisitely selective inhibitor in human macrophages. Additionally, they found that ablation of an identified pathway worsened skin disease in a model of the autoimmune disease psoriasis, confirming the role of this pathway in inflammation. Thus, these novel inhibitors and pathways are extremely valuable targets for developing treatments to dampen the autoimmune response in these various diseases, as well as potentially promote the host immune response in diseases such as cancer and infection.
POTENTIAL APPLICATIONS:
- Developing treatments for autoinflammatory diseases
- Developing therapies that boost host immune cell activation for cancer or infection
ADVANTAGES:
- Have identified specific targets of current clinical treatments (and clarified what targets are potently inhibited, contrary to current hypothesis of drug mechanism)
- Can be used as both pro-host immunity and anti-autoinflammation therapies
- Highly selective inhibitor in human macrophages
DEVELOPMENT-TO-DATE: UCLA researchers have identified selective inhibitors and pathways targeting an inflammatory molecule that leads to a host of autoinflammatory diseases and have confirmed that these pathways play a role in inflammation.
Keywords: Auto-inflammatory disease, fluorescent reporter screen, immune activation, oncology, psoriasis, interleukins, autoimmunity, selective inhibitors, drug development, small molecule