The immune system is responsible for protecting the host organism against pathogens and tumour cells. It is composed of two main branches: the innate (natural) immune system and the adaptive immune system. The adaptive immune system is further bifurcated into the humoral and the cell-mediated systems. Before we delve deep into the pharmacology of immunosuppressant drugs, it is worth investing some time on these different branches – understanding their differences is key to understanding how immunosuppressant drugs work.
The Immune Response
Here, we’ll offer a brief introduction to the major components of the immune system. It is by no means intended to be an exhaustive account, as the subject itself is considerably more complex. Nonetheless, for the sake of brevity the principal actors include:
- : As the name suggests, this is part of our genetic fabric – hence why it is sometimes referred to as natural immunity. Processes associated with innate immunity include:
- Physiochemical barriers: Skin and mucous membranes.
- Complement activation: As the name suggests, the complement system ‘complements’ the innate response. It achieves this by enhancing the ability of antibodies and phagocytic cells to liquidate pathogens from the body. It is non-adaptable.
- Attraction: Immune cells can be delivered to inflammatory sites due to their attraction to cytokines.
- Phagocytosis: The process of breaking bacteria and parasites down, typically performed by granulocytes such as neutrophils, monocytes, and macrophages.
- Assisting adaptive response: Macrophages and dendritic cells phagocytose pathogenic material to produce antigens, which remain on display on their surfaces. These ‘antigen-presenting cells’ present the antigen to T-lymphocytes to trigger the adaptive response.
- Fever: Antigens can bind to the IgE antibody on mast cells and basophils.
It’s worth remembering that, unlike the adaptive immune response, the innate response does not offer long-term immune protection after initial exposure to a particular pathogen.
- : This type of immunity is superimposed onto the initial innate response. From an evolutionary point of view, the adaptive immune response is considerably more recent – offering long-term protections that the innate response fails to provide.
Two populations of cells are particularly relevant to the adaptive response: T-lymphocytes and B-lymphocytes.
- T-lymphocytes are produced in the bone marrow and migrate to the thymus, where they mature. Those chosen, on the basis of their avidity, have the potential to combat a number of pathogens.
- B-lymphocytes comprise about 10 percent of the total lymphocyte population. They mature in the bone marrow. B-lymphocytes mainly operate in the humoral component of the adaptive response, secreting antibodies in the process.
Within the adaptive immune response, there are two main components: the cell-mediated response and the humoral response. What are the major differences?
- Cell-mediated immunity refers primarily to T-cells – deploying Th1 and cytotoxic T-cell (Tc) subtypes. The response is chiefly involved in combating viral infections, graft rejections, chronic inflammation, and tumour immunity.
- In humoral immunity, the pathogen is identified by immunoglobulin molecules (or by specific receptors to that antigen on the surface of B-cells). This eventuates in the secretion of IL-4 – which causes B-cell proliferation. In turn, B-cells are converted into active plasma cells which secrete antibodies (IgG, IgM, IgA etc.) to kill the pathogen.
This is the fundamental architecture of the immune system, and segways neatly onto the next section on the pharmacology of immunosuppressant drugs. It is only through understanding the basics of the immune response that one can comprehend how immunosuppressant drugs work.
Pharmacology of Immunosuppressant Drugs
The complexity of the immune system offers a wide range of actual and potential therapeutic targets. Immunosuppressant drugs of today tend to be non-specific in effect, thereby increasing the risk and occurrence of unwanted effects. There are five main classes of immunosuppressant drugs:
- Drugs acting on immunophilins
- Miscellaneous agents
Let’s go through each of these categories in turn, assessing not only the mechanistic pharmacology of immunosuppressant drugs, but also their indications, notable adverse effects, and drug interactions.
Glucocorticoids (such as dexamethasone and prednisone) are highly effective anti-inflammatory drugs, which can also be used to suppress type 4 hypersensitivity reactions (you’ll recall that type 4 reactions are cell-mediated, delayed-type hypersensitivity reactions), autoimmune diseases, and graft rejection, among other indications. They suppress both cell-mediated immunity and humoral immunity – whose most relevant effect is the suppression of IL-2.
Cytostatics, as their name suggests, inhibit cell division. They are used both in immunotherapy and cancer chemotherapy – though are administered in smaller doses for the former purpose. Cytostatic drugs work by disturbing the proliferation of T and B-cells. There are several cytostatic drug classes worth considering:
- Alkylating agents: These include cyclophosphamide, nitrosoureas, and platinum compounds. Cyclosphosphamide is the most potent immunosuppressant drug in this class, and can be used to treat systemic lupus erythematosus, autoimmune haemolytic anaemias, and other immune diseases.
- Antimetabolites: Examples include methotrexate, purine analogues (azathioprine and mercaptopurine), pyrimidine analogues (fluorouracil), and protein synthesis inhibitors. Methotrexate is one of the most commonly deployed antimetabolites, and can be used to treat rheumatoid arthritis, Behcet’s disease, and psoriasis. Methotrexate works by binding to dihydrofolate reductase and preventing tetrahydrofolate synthesis. Azathioprine is cleaved in vivo to the active compound 5-mercaptopurine – where it suppresses both cell-mediated and humoral immune responses, particularly for transplant rejection reactions. Dactinomycin is one of the most important cytotoxic antibiotics, and is extensively used in kidney transplantations. Other cytotoxic antibiotics include anthracyclines, bleomycin, and mitomycins.
- Monoclonal antibodies
These drugs are much more specific in effect. Muromonab-CD3 prevents T-cell activation and proliferation by binding to the T-cell receptor complex located on all differentiated T-cells. It is used in the therapy of resistant organ transplants – particularly for organs such as the kidney, heart, and liver. Interleukin-2 receptor antibodies – such as basiliximab and daclizumab – are also used to treat acute transplant rejection. These drugs may be used as a prophylactic against organ transplant rejection, unlike muromonab-CD3. Both basiliximab and daclizumab have very long half-lives – ranging from 1-3 weeks.
- Drugs acting on immunophilins
Ciclosporin and tacrolimus belong to the calcineurin inhibitor class of drugs. Ciclosporin is a fungal cyclic peptide (with 11 amino acids) which binds – in the cell cytoplasm – to the protein cyclophilin. This complex, in turn, inhibits calcineurin; a calmodulin-Ca2+-dependent phosphatase which is itself a key component of T-cell activation. Tacrolimus can be derived from the bacterium Streptomyces tsukubaenis – a macrolide lactone. It, too, inhibits calcineurin. Along with sirolimus, all three drugs can be used for organ transplant rejection. Sirolimus works by binding to intracellular FK-binding protein 12 – and this complex inhibits the actions of a cytoplasmic kinase called mTOR (target of rapamycin). This helps to inhibit T-cell proliferation by arresting the cell between the G1 and S phases of the cell cycle.
- Miscellaneous agents
There are several other immunosuppressant drugs worth mentioning, including:
- Fingolimod: This drug has greater immunomodulating effect, and is currently used in the treatment of multiple sclerosis. It is a sphingosine-1-phosphate receptor inhibitor.
- Mycophenolic acid: Reduces purine synthesis by reversible non-competitive inhibition of the enzymes inosine monophosphate (IMP) dehydrogenase and guanylyl synthase. Inhibition of these enzymes eventuates in the inhibition of cellular DNA synthesis. T-cells, B-cells, and monocytes rely on a regular supply of de novo purine nucleotide synthesis released from the breakdown of pre-formed nucleic acids (salvage pathway).
- TNF binding proteins: Examples include infliximab, etanercept, and adalimumab. These drugs prevent TNF-α from inducing the synthesis of IL-1 and IL-6. They are used in the treatment of Crohn’s disease, ankylosing spondylitis, rheumatoid arthritis, and psoriasis.
- Interferons: IFN-β suppresses production of Th1 cytokines and monocyte activation. It can be used to slow the progression of multiple sclerosis. IFN-γ is capable of inducing lymphocytic apoptosis.
The pharmacology of immunosuppressant drugs is a broad church. It’s comprised of many different drug classes, each of which is directed at a specific immunological target. Given the wealth of potential targets in the immune system, it’s only a matter of time – whether serendipitously or otherwise - before treatment becomes yet more specific and more effective.
Test your knowledge of the pharmacology of immunosuppressant drugs here – ten questions on all the material covered in this article.