Immunomodulators and a focus on immunosuppressants

Immunomodulators are drugs that can either suppress or enhance the activity of the immune system.

These are two types:

  1. Immunosuppressants
  2. Immunostimulants


Immunosuppressants are substances that suppress or inhibit the immune system’s activity. They are often used in medical treatments to prevent the rejection of transplanted organs or to treat autoimmune disorders where the immune system mistakenly attacks healthy tissues.

1. Glucocorticoids: The Commonly Used Immunosuppressant Drugs

Glucocorticoids are the most commonly used immunosuppressant drugs. They work by inhibiting the production of prostaglandins, leukotrienes, histamine, bradykinin, and PAF. Additionally, they diminish the chemotactic activity of neutrophils and monocytes. Glucocorticoids cause the sequestration of lymphocytes in lymphoid tissue, resulting in lymphopenia. By inhibiting IL-1 production, these drugs cause a decrease in IL-2 and IFN γ production. Continuous administration of glucocorticoids can increase the catabolism of IgG. These drugs are used as first-line immunosuppressive drugs for solid organ as well as haematological stem cell transplant recipients. They are also used for the treatment of graft rejection and graft versus host disease (GVHD), treatment of ITP, rheumatoid arthritis, and bronchial asthma.

2. Calcineurin Inhibitors: Targeting T-Cell Activation

Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506), are potent immunosuppressive agents that target T-cell activation. They work by inhibiting calcineurin, an enzyme required for the activation of the nuclear factor of activated T cells (NFAT), which in turn increases the transcription of IL-2 in activated T cells. Some key points about calcineurin inhibitors include:

  • Cyclosporine and tacrolimus bind to immunophilins (cyclophilin and FK Binding Protein (FKBP), respectively) to inhibit NFAT activation (see below picture for detailed mechanism of action).
  • Used for organ transplantation, GVHD, and certain autoimmune diseases like rheumatoid arthritis and psoriasis.
  • Common side effects of cyclosporine include nephrotoxicity, hepatotoxicity, hypertension, hyperkalemia, hyperlipidemia, hyperuricemia, hyperglycemia, hirsutism, gum hyperplasia, and neurotoxicity.
  • Tacrolimus is more potent than cyclosporine and is associated with a higher incidence of hyperglycemia and neurotoxicity but does not cause hirsutism, gum hyperplasia, hyperuricemia, or hyperlipidemia.
Mechanism of Action of Cyclosporine and Tacrolimus

FKBP: FK Binding Protein

Proliferation Signal Inhibitors: Targeting the mTOR Pathway

Proliferation signal inhibitors, such as sirolimus (rapamycin) and everolimus, are immunosuppressive agents that target the mammalian target of the rapamycin (mTOR) pathway. They work by inhibiting the action of IL-2 without affecting its transcription. Key aspects of proliferation signal inhibitors include:

  • Utilized in organ transplantation and Graft versus Host Disease (GVHD) management
  • Sirolimus is incorporated in cardiac stents to reduce the chances of reocclusion
  • Major adverse effects include thrombocytopenia, bone marrow suppression, and hyperlipidemia
  • Everolimus has a shorter half-life than sirolimus and is approved for subependymal giant cell astrocytoma (SEGA) treatment associated with tuberous sclerosis.

Purine Synthesis Inhibitor: Mycophenolate Mofetil

Mycophenolate mofetil is an immunosuppressive drug that inhibits inosine monophosphate dehydrogenase, an enzyme necessary for the denovo synthesis of purines. It is converted to its active metabolite, mycophenolic acid, in the body. Mycophenolate mofetil is used in patients who are refractory to steroids. Common side effects include gastrointestinal disturbances and myelosuppression.

Antimetabolites: Azathioprine

Azathioprine is an antimetabolite used as an immunosuppressant but not as an anticancer drug. It is a prodrug that is activated in the body to 6-mercaptopurine, an anticancer drug. Azathioprine selectively targets lymphoid cells, sparing their anticancer properties. The major toxic effect is bone marrow suppression. When used with allopurinol, the dose of azathioprine should be reduced due to the shared metabolism by xanthine oxidase.

Other Cytotoxic Agents: Cyclophosphamide, Chlorambucil, and Methotrexate

These are anticancer drugs that can also be used as immunosuppressants. They are employed in treating childhood nephrotic syndrome, systemic lupus erythematosus (SLE), and Wegener’s granulomatosis.

Leflunomide: Inhibiting Pyrimidine Synthesis

Leflunomide is a prodrug that, upon conversion to its active metabolite, inhibits dihydro-orotate dehydrogenase, resulting in the inhibition of pyrimidine synthesis. It is an orally active drug with a long half-life of several weeks. Major toxicities include liver and kidney damage. Cholestyramine increases its excretion. Leflunomide is increasingly used for polyomavirus nephropathy.

Antibodies: Polyclonal and Monoclonal

Polyclonal antibodies, such as anti-lymphocyte and anti-thymocyte antibodies, hyperimmune immunoglobulins, and Rho(D) immunoglobulin, are used as immunosuppressive drugs. Several monoclonal antibodies have been synthesized to produce a similar effect. Monoclonal antibodies are classified based on their prefix, target subsystem, origin subsystem, and suffix.


Introduction Monoclonal antibodies (mAbs) are a type of protein that is designed to bind to a specific target molecule. They are widely used in the diagnosis and treatment of various diseases. The nomenclature of mAbs is an important aspect of their identification, classification and use. In this chapter, we will discuss the nomenclature of monoclonal antibodies.

Name of Monoclonal Antibody The name of the monoclonal antibody can be divided into four parts. These include Prefix, Target subsystem, Origin subsystem, and Suffix.

Prefix: The prefix is different for each monoclonal antibody.

Target subsystem: The target is identified by specific letters. For example, vi is for virus, ci is for circulation, and so on. Previously, the target consisted of three letters, including the first consonant, second vowel, and third consonant. However, the third consonant can be deleted for ease of pronunciation. In 2009, new and shorter target subsystems were introduced.

Origin subsystem: Depending on the source of origin, various names are given. For instance, u stands for human, xi for chimeric, and so on.

Suffix: The suffix for all monoclonal antibodies is mab.

Examples: • Adalimumab – Prefix: Ada, Target subsystem: tu, Origin subsystem: hu, Suffix: mab • Trastuzumab – Prefix: Tra, Target subsystem: ce, Origin subsystem: hu, Suffix: mab

Co-Stimulation Inhibitors: Abatacept and Belatacept

Certain costimulatory molecules are present on the surface of T cells as well as antigen-presenting cells (APCs). Interaction of these molecules is necessary for the activation of T cells. Abatacept and belatacept act by inhibiting CD 80 and CD 86 costimulatory molecules present in APCs. Abatacept is used for the treatment of severe rheumatoid arthritis resistant to DMARDs. Belatacept is used to prevent the rejection of kidney transplants.

IL-1 receptor antagonist 

Macrophages and other mononuclear cells that have been stimulated produce IL-1, which activates helper T-cells and triggers the production of other substances such as ILs and metalloproteinases. An endogenous IL-1 receptor antagonist has been identified, and various versions of it have been created through genetic engineering for medical purposes.

Anakinra is an inhibitor of IL-1 being investigated for use in septic shock and RA.

IL-2 receptor antagonist

IL-2 receptor antagonist is a type of medication that works by blocking the CD-25 molecule, which is expressed on the surface of activated T-cells, from acting as a receptor for IL-2. This leads to the arrest of activated T-cells and prevents cell proliferation and differentiation. Two examples of IL-2 receptor antagonists are Daclizumab and Basiliximab.

Daclizumab is a highly humanized chimeric monoclonal anti-CD-25 antibody that binds to and acts as an IL-2 receptor antagonist. It has a long plasma half-life of 3 weeks and is often used in combination with other medications, such as glucocorticoids, calcineurin antagonists, and/or azathioprine/MMF to prevent transplant rejection reactions. Daclizumab is also used as a maintenance medication for grafts.

Basiliximab is another type of anti-CD-25 anti-CD-25 antibody that has a higher affinity for the IL-2 receptor but a shorter plasma half-life of 1 week. Its clinical use is similar to that of Daclizumab.

Other Drugs

Nintedanib is a small-molecule kinase inhibitor that blocks multiple pathways involved in the scarring of lung tissue. It is approved for oral treatment of idiopathic pulmonary fibrosis.

Apremilast is a phosphodiesterase-4 inhibitor indicated for severe plaque psoriasis and psoriatic arthritis.


Immunostimulants are agents that enhance the body’s immune response. They can be used to treat a variety of conditions, including cancer and infectious diseases.

  1. Levamisole

Levamisole is an anthelmintic drug that has immunostimulatory properties. It works by stimulating the production of white blood cells, which are important for fighting off infections and cancer cells. Levamisole is used along with 5-FU for the treatment of colorectal carcinoma after surgery. However, its major adverse effect is agranulocytosis. Levamisole is also used for the treatment of pediculosis.

  1. Bacillus Calmette Guerin (BCG)

BCG is a viable strain of Mycobacterium bovis that is used as intravesical therapy for superficial bladder cancer. It works by stimulating the immune system to attack cancer cells. BCG is also used as a vaccine against tuberculosis.

  1. Cytokines

Cytokines are proteins that play an important role in the immune response. They include interferons, colony-stimulating factors (CSF), and various interleukins. A recombinant form of IL-2 is Aldesleukin, which is useful in malignant melanoma and renal cell carcinoma. Filgrastim (recombinant G-CSF) and sargramostim (recombinant GM-CSF) are useful for chemotherapy-induced myelosuppression.

  1. Imiquimod

Imiquimod is an immune response modifier that is effective against external genital and peri-anal warts (i.e., condyloma acuminata) by topical route. It acts by releasing IFN-α and cytokines like IL-1, IL-6, and TNF α, etc. Imiquimod has also been approved for basal cell carcinoma and actinic keratosis of the face and scalp.

Disclaimer: This article is for informational purposes only and should not be taken as medical advice. Always consult with a healthcare professional before making any decisions related to medication or treatment.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

Leave a Reply

Your email address will not be published. Required fields are marked *