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Immunomodulators as Therapeutic Agents

Sumeet Gullaiya

Immunomodulation refers to any biological or receptor-mediated process that alters the desired level of an immune response. Numerous microorganisms can modulate the level of the immune response to establish or consolidate an infection. Thus, immunomodulation can be either beneficial or detrimental to the host.

The immunomodulatory potential of bacterial microbiota is directed by small molecules in the immune system called cytokines. These molecules function as the messengers of the immune system, acting to stimulate various immune responses such as inflammation or the production of antibodies. Some microorganisms can produce proteins that mimic the structure and function of these cytokines, often doing so as a means to down-regulate the host’s immune response. Additionally, other microorganisms can suppress the immune response by blocking cytokine expression at the level of transcription.

Therapeutically, the manipulation of cytokine expression and action can be used to produce a variety of beneficial therapies for autoimmune disease, leukaemia, lymphoma, and lymphocyte-resident viral diseases such as HIV/AIDs. Immunomodulation is especially useful in preventing transplant rejection – Sirolimus [1] (R124000), isolated from Streptomyces hygroscopicus, is an immunosuppressant drug used to prevent rejection in organ transplantation, particularly in kidney transplants. It has also shown its efficacy against neurodegenerative diseases, including Alzheimer's and Parkinson's, and is a potent autophagy activator.

An immune-mediated disorder such as Multiple sclerosis (MS) can also be treated with immunomodulating drugs. A typical example is Fingolimod [2] (F342045), a fungal metabolite known for inhibiting lymphocyte emigration from lymphoid organs. Preventing them from contributing to an autoimmune reaction reduces the chance of acute inflammatory relapses. 5‐Aminoimidazole‐4‐carboxamide ribonucleoside (AICAR) [3] (A611700), an activator of AMP‐activated protein kinase (AMPK), has also been reported to show anti-inflammatory and immunomodulatory effects in various models of MS inflammation.

Moreover, molecules such as Lovastatin [4] (L472225), a fungal metabolite which acts as a potent inhibitor of HMG-CoA reductase and which also has immunomodulatory effects in treating MS, have emerged as promising tools in combating atherosclerosis. Originally designed to target elevated lipids, the “traditional” cause of atherosclerosis, statins might also confer cardiovascular benefits by directly or indirectly modulating the inflammatory component of this prevalent disease. More recent studies suggest that Lovastatin could be repurposed for as anticancer therapeutics for the treatment of nasopharyngeal carcinoma. [5]

Bardoxolone methyl [6] (C228100) also known as CDDO-methyl ester, is an experimental and orally-bioavailable semi-synthetic triterpenoid, based on the scaffold of the natural product oleanolic acid. Pre-clinical studies indicate that the compound acts as an inhibitor of the NF-κB pathway, which controls DNA transcription as well as cytokine production.

Currently, there is extensive research being done in the field of immunomodulation and other immunologic therapies. Much of this research is focused on treating cancer-related diseases, as well as autoimmunity and immunodeficiency. But perhaps the most successful use of immunomodulation is in fighting infection via vaccination. In vaccination, protective adaptive immune responses are generated by exposing the host to a harmless form of a pathogen. This is very appropriate as currently researchers around the world are looking at several different immunomodulation therapies to deal with the COVID-19 pandemic, ranging from modifying anti-rheumatic drugs, such as hydroxychloroquine and tocilizumab, to using more unconventional immunomodulatory agents such as IFN-alpha and Phytocannabinoids to help alleviate many of the symptoms associated with COVID-19.

 

About the author

Sumeet Gullayia holds a PhD in pharmacology & toxicology from the University of Delhi. He has been TRC’s product manager for pharmacology & toxicology since 2016.

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