Natural Immunomodulators: Promising Therapy for Disease Management

The immune system is a complex, intricate organ system with features like flexibility, recognition, discriminating potential between self from non-self, and memory to defeat notorious external and internal threats to human health functioning. Innate immunity is inborn, and acquired immunity develops through secondary education; they are interconnected, interdependent, and execute tasks with bidirectional communications. A deeper understanding of immune biology revealed a remarkable contribution of the immune system in several chronic illnesses, and has taken a central stage in pathophysiology. In essence, the weakened or overactivated immune system leads to these chronic illnesses. Modulation of the immune system is an efficient and valid approach to prevent the underlying pathophysiology of such diseases. A gamut of natural immunomodulators targeted at specific or non-specif immune cells has delineated their potential to achieve the equilibrated and balanced immune system. Preclinical and clinical studies demonstrated the implication of microbiota, nutrients, natural herbs, and micronutrients for immunostasis. The immune system's complexity, its close association with the endocrine and nervous system, target identification, and convenient, reliable tools to assess immune function and modulation are a few limitations that hampered the attainment of immunostasis. Despite these limitations, novel therapies targeted at immunomodulation in chronic diseases are promising and paving the future path to novel therapeutics.

The human immune system is one of the complex systems of the body, which works against both external and internal invasion. It has two parts: the innate and the acquired immune systems. We have been born with the innate system which gives a quick response for the invading pathogen non-specifically. To deal with the typical environmental antigens, immune system adapts to changes. The acquired (or adaptive) component develops over time and produces antibodies that “remember” invaders to fight them if they return. Failure of it could be due to genetic defect (weak natural immunity), inability to adapt to the change, hyper-responsiveness, or inability to distinguish self from foreign, leading to various diseases and disorders. Various genetic defects of the immune system are at the core of Primary Immune disorders (PIDs), while overactivity is responsible for allergic diseases. Autoimmune diseases are mostly due to malfunction of the adaptive immune system, while in Systemic Autoinflammatory Disorders (SAIDs), the innate immune system is affected. Advancements in technology and genetics have improved our understanding of the pathogenesis, diagnosis, and management of these diseases.

Nature is replete with an arsenal of compounds that can be investigated for their therapeutic potential. The immune system involvement in severe chronic illnesses or emerging infectious diseases has provided clinical evidence. The prevention and treatment of these diseases targeted at the immune system with natural immunomodulators are gaining momentum, owing to their diverse array of activities. Treating acute illnesses with modern medicines has been successful; however, treating chronic illness treatment remains elusive and disappointing. Notably, this chapter reviews the natural resources of immunomodulators. Natural immunomodulators from plants, marine, and animals are of prime importance, and they possess many pharmacological activities. Similarly, microbiota modifiers - prebiotics, probiotics, and micronutrients- are imperative in restoring immune homeostasis. This chapter summarizes these natural immunomodulators and their power to boost immunity and human well-being. 

Natural medications are gaining popularity as people become more aware of their benefits and accept their use in modern medicine. Natural drugs have demonstrated extensive suitability as curative agents for various disorders due to their fewer side effects and toxicity. Scientists face a tremendous problem in developing accurate analytical techniques that can efficiently profile the contents of phytochemicals. This is in addition to quantitative studies of marker or bioactive chemicals and some other important ingredients. Natural medicines, on the other hand, lack standardized parameters. Standardization is a vital step towards the formation of a constant chemical profile, consistent biological activity, or just a quality assurance programme for the production and manufacturing of natural products. As a requirement for global harmonization, the WHO criteria for assessing the safety, efficacy, and quality of natural drugs are extremely important. Scientific research of some of the natural origin plants regarded in Ayurvedic Rasayana for their beneficial potential has generated good results. The number of plants with a potential immunomodulatory activity that has been cultivated using conventional or cell culture methods is standardized. This can help to portray and validate their usage in folk medicine in the early days, as well as give an establishment for future investigation. The goal of this chapter is to showcase the findings of research evidence on standardized natural plantorigin immunomodulators. The chapter also goes through biological screening strategies for diverse plant medications with the goal of revealing the immunomodulation mechanism. Researchers will hopefully be encouraged to pursue more research on medicinal plants with immunomodulatory potential as a result of this study.

Immunomodulators are substances that either enhance or suppress the immunity of the host. Immunomodulators have been used for ages in Ayurvedic Medicine and Traditional Chinese Medicine. In the surge of modern medicine, many chemically derived substances are used as immunomodulators. Historically, plants present a rich source of these therapeutic agents. Researchers have used these lead structures for exploring the underlying mechanisms of immunomodulation so that newer, safer agents can be designed and used clinically. Microbial sources have also been tried in search of immunomodulators. Chemically, these are a diverse group of substances that act on varied signaling pathways to cause immunomodulation. The involvement of the immune system in many diseases and disorders makes these agents essential in the treatment of these diseases, e.g., cancer. This chapter discusses the chemistry of a selected few commonly known plant-derived immunomodulators along with their biological evaluation methods and provides a broad overview of their therapeutic potential with particular emphasis on the mechanism of immunomodulation.

The availability of appropriate animal models is essential for effective translation of immunomodulatory research into clinical settings. Bioassays and other methods for immunomodulators in the preclinical and clinical setting are being used to assess the quality and quantification of the immune response, find the best suitable route of administration and formulation method, protect the transmission of infection, and assess the safety and toxicity of immunomodulators. Identifying the appropriate animal model has become very important, since each model has its own pro's and cons. The scope of this chapter is to outline the assaying of immunomodulatory activity, the approaches and the experimental strategies. This chapter discusses various in-vitro models such as cell lines, assays and murine models, which are being used for quantification of the immune response, assessment of overall immune functions, immunosuppressive activity, screening of anti-allergic drugs and agents used in the treatment of various autoimmune disorders and transplant-related and autoimmune diseases. The most important questions that we should keep in mind while choosing a suitable animal model are, selection of suitable species, physiological relevance of model, immunological functions to be evaluated, and its practical implications.

Cancer is a complex disease, ranking among the top causes of mortality worldwide. There are numerous therapies available however, they are showing limited success in a complete cure. The advanced treatment regime includes immunotherapy that improves the body's natural defences. The approved immunotherapies are imiquimod (Zyclara®), lenalidomide (Revlimid®) pomalidomide (Pomalyst®), and thalidomide (Thalomid®). However, these therapies have severe side effects like nausea, high blood pressure, blood clot, severe allergies, etc. Hence, natural products with immunomodulatory properties are being widely used as adjuvant therapy in cancer treatment. Plant secondary metabolites, such as curcumin, resveratrol, zerumbone, quercetin, genistein and betulinic acid, which are used as a member of the cancer medications and possess immunomodulatory potential, have been described in this chapter. We have discussed the mode of action, in vitro, in vivo, formulation studies and plant source of these natural immunomodulators. This chapter also discusses the current state of these pure compounds in context to their development as anticancer treatments in the future.

Infection is one of the most common occurring issues in an individual. Diseases caused by infections hamper the immune system of an individual. To modulate the immune system, immunomodulatory drugs work by either stimulating or suppressing the immune system. Several drugs like levamisole and azathioprine are available in the market today to overcome various infections. But an alternative is required to overcome the drug resistance and other side effects associated with these available drugs. To tackle these problems, many plant-based immunomodulators are being explored and have proven to be beneficial against these infections. This chapter focuses on the mechanism of action and application of natural immunomodulators like Curcumin, Resveratrol, and Genistein on various infections. The primary goal of this chapter is to understand the role of natural immunomodulators in the body for various infections and related disease conditions. With the help of findings, one can conclude that all-natural immunomodulators have areas that need attention, including their therapeutic risk-benefit ratio and their target binding affinity for various infections. However, further investigations into these drugs are necessary for a clear understanding to maximize their clinical applications 

 Immunomodulators can be either synthetic in origin or naturally obtained. Natural plant-based compounds can influence the immune system by either affecting antibody secretion to control the infection or affecting the functions of immune cells, thus contributing to maintaining immune homeostasis. Phytochemicals in plants, such as polysaccharides, lactones, flavonoids, alkaloids, diterpenoids and glycosides, have been reported to possess immunomodulating properties. However, there are many challenges limiting the clinical use of natural immunomodulators. In this chapter, we have discussed in detail standardization, formulation development, route of administration and regulatory concerns of natural immunomodulators. In order to overcome these challenges and ensure that natural immunomodulators reach the target site at therapeutic concentrations, different polymer and lipid-based nanocarrier delivery systems have been developed. These nanocarriers by virtue of their size, can easily penetrate and reach the target site and deliver the drugs. Many nanocarriers like liposomes, niosomes, nanoparticles, microemulsions, phytosomes and other vesicular systems designed for natural immunomodulators are discussed in this chapter.

Many natural products, such as Azardicaindica, Curcuma longa, and Ocimumsanctum, are often used as immunomodulators. The increased prevalence of chronic diseases, along with the negative effects of synthetic immunomodulators, has resulted in the establishment of a global natural immunomodulator market. For researchers, complementary and alternative medicine provides a new target for drug discovery approaches and medication development. Ayurveda, Homeopathy, Naturopathy, and the Chinese medicine system are examples of complementary and alternative medicine approaches. Phytoconstituents with therapeutic action are included in the Complementary and Alternative Medicine (CAM) categories of natural goods. In Europe, natural immunomodulators are considered food supplements, while in the United States, they are utilized as dietary supplements. In India, it is controlled by the Ministry of AYUSH (Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homeopathy). With the help of the literature findings, we understand that even natural phytoconstituents also require and must undergo well-defined regulatory approval processes to launch in the market. But the regulation slightly differs as per the country and region. With the help of all the findings, one can conclude that the regulation of natural immunomodulators is equally important to set its marketing strategies as well as for its post-marketing surveillance as compared to the synthetic molecules. With this objective, the primary goal of this chapter is to draw more attention to the regulatory aspects of natural immunomodulators by comprehending the information on natural immunomodulator marketing strategy as well as the legislation that governs it.

Immunomodulators are key components in deciding immunity status and development in an individual. The topic has been under more emphasis, especially during and after the COVID-19 pandemic phase. Several plants with medicinal potentials are appreciated in traditional medicines for their healing perspective and have been technically examined for their immunomodulation potential. A number of plant-based bioactive compounds have been extracted and purified with such bioactivities that can rationalise their usage in conventional medication in the past and can stimulate further research in the future as well. Synthetic immunomodulators are significant for generating remedial or prophylactic formulations with defined chemical ingredients from regulatory perspectives. The review highlights the key immunomodulators, both synthetic and natural, until 2020. It also emphasises on market potential and commercial aspects of these. We have explained and listed several plants and their active scaffolds having immunomodulation activities along with synthetic compounds with similar bioactivity. We envisage the review to be an organised compilation and comparison of natural and synthetic immunomodulators and also focus on new chemical immunomodulator scaffolds.

Immunity is the inherent ability of the body to fight against various infections, and foreign invaders. When the host body comes in contact with a foreign body, a series of chemical mediators are released, which collectively elicit an immune response. The biomolecules capable of stimulating, suppressing and modulating innate or acquired immunity, biological or synthetic in origin, are termed as immunomodulators or immunoaugmentors. Limited clinical use of synthetic immunomodulators has attracted the attention of researchers toward immunomodulatory characteristics of natural therapeutics. Though natural immunomodulators render their efficacy in several chronic illnesses, there are challenges that need to be addressed and resolved to make them viable alternate therapeutics. This chapter highlights the challenges and future perspectives of natural immunomodulators.