Immunomodulators and Immunosuppressive Agents

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                        Immunomodulators & Immunosuppressive Agents


Welcome to this video tutorial on immunomodulators and immunosuppressive agents.

The body’s immune system is a normally occurring protective mechanism that helps the body defend itself against potentially harmful agents. However, sometimes the immune system perceives normally harmless substances, such as allergens or the person’s own body tissues, as harmful invaders and tries to eliminate them. This inappropriate activation of the immune response is a major factor in allergic and autoimmune disorders.

Let’s start with some definitions.

Immunomodulators are natural or synthetic substances that modulate or modify the immune response. They help regulate or normalize the immune system by either stimulating or suppressing the immune system. Immunostimulants, such as vaccines and interferons, enhance the body’s resistance against infections. Immunosuppressive agents are drugs that suppress the immune system to reduce the risk of rejection of foreign bodies with organ transplant or in autoimmune diseases.

Immunosuppressant drugs are used to decrease the immune response by interfering with the production or function of immune cells and cytokines. When foreign tissue or an organ is transplanted into the body, the body has an appropriate but undesirable immune response. If the immune response is not suppressed, the body reacts by attempting to destroy the foreign tissue. Immunosuppressant drugs are used to decrease this undesirable immune response with transplants and autoimmune disorders.

Drug induced immunosuppression is a major factor in tissue and organ transplantation. There is a fine balance to adequate immunosuppression for the body to accept the transplant, without suppressing the immune system too much where the patient develops serious infections and other adverse effects.

Immunosuppressant drugs are also given for autoimmune disorders to decrease the undesirable immune response of the body. Autoimmune disorders occur when a person’s immune system attacks the healthy cells in the body by mistake – the body has lost its ability to differentiate between antigens on its own cells (self-antigens) and antigens on foreign cells. Generally, all autoimmune disorders share inflammation as a major mechanism of tissue damage. There are many autoimmune diseases; we’ll take a look at a few common ones.


             In multiple sclerosis (MS), the immune system attacks nerve cells, causing 
             symptoms that can include muscle spasms, weakness, poor coordination, 
             pain, and blindness.

             Rheumatoid arthritis occurs when the immune system produces antibodies 
             that attach to the linings of joints, which get attacked by immune system 
             cells, causing inflammation, swelling, and pain. 

             In lupus (SLE), autoimmune antibodies attach to tissues throughout the body, 
             affecting the lungs, nerves, blood cells, joints, and kidneys.

             Type 1 diabetes mellitus occurs when the immune system antibodies attack 
             and destroy insulin-producing cells in the pancreas.

             Inflammatory bowel disease (IBD) occurs when the immune system attacks 
             the lining of the intestines, causing episodes of abdominal pain, 
             diarrhea, urgent bowel movements, fever, and weight loss. There are 
             two forms of IBD - Crohn’s disease and ulcerative colitis.

             In psoriasis, overactive immune system T-cells collect in the skin, 
             stimulating the skin cells to reproduce rapidly, forming scaly plaques 
             on the skin.

             In myasthenia gravis, antibodies bind to nerves and make them unable to 
             stimulate muscles properly, seen as weakness that gets worse with 
             activity.

             Graves’ disease occurs when the immune system produces antibodies that 
             stimulate the thyroid gland to release excess amounts of thyroid hormone, 
             causing hyperthyroidism.

             Hashimoto’s thyroiditis occurs when antibodies produced by the immune 
             system attack the thyroid gland, slowly destroying the cells that produce 
             thyroid hormone, leading to hypothyroidism.

Immunosuppressant drugs are diverse agents with often overlapping mechanisms and sites of action. Older drugs are generally nonspecific and depress the entire immune response to all antigens, greatly increasing the risk of serious infections and other side effects.

Immunosuppressants include:
     Corticosteroids	
     Cytotoxic, antiproliferative agents
     Conventional antirejection agents

Corticosteroids are strong anti-inflammatory drugs that suppress the immune response at multiple levels. They do have numerous side effects, so the duration of therapy should be as short as possible. Examples include prednisone, dexamethasone, hydrocortisone, betamethasone, and methylprednisolone.

Cytotoxic, antiproliferative drugs damage or kill cells that are able to reproduce, and are primarily used in cancer chemotherapy. However, in small doses, some are also used to treat autoimmune disorders and to prevent organ transplant rejection. Examples include methotrexate and azathioprine.

Conventional antirejection agents include drugs such as cyclosporine, tacrolimus, and sirolimus, which are fungal metabolites with strong immunosuppressive effects, used to prevent rejection reactions after organ transplants.

Extensive research has been done to develop drugs with a more specific immunosuppressive action, causing fewer or less severe adverse effects than older immunosuppressants. They are often referred to as biologic response modifiers or biologics. Biologics are antibodies made from biological proteins (human or animal based) that stop certain proteins in the body from causing inflammation. Biological products include a wide range of products such as blood and blood components, vaccines, allergenics, gene therapy, and recombinant therapeutic proteins. The biologics we will be discussing here are immunosuppressive drugs that have had a profound impact on the treatment of many diseases, which in most cases have had no effective therapies available. Biologics target overactive cells in the body, and are designed to block diseases in the immune system rather than waiting to treat the symptoms of the disease. Biologic therapies offer a distinct advantage in treatment of diseases because their mechanisms of action are more precisely targeted to the factors responsible for the disease, instead of affecting the whole body, as some immunosuppressants do. Biologics are used to treat many autoimmune diseases, however, their cost is significantly higher than other conventional medications.

Some of the newer biologic agents used for immunosuppression include:
     - Antibody preparations, which include polyclonal antibodies and 
       monoclonal antibodies.
     - Cytokine inhibitors, which include interleukin-blocking agent & 
       tumor necrosis factor (TNF)- alpha blocking agents


Antibody preparations are produced in the laboratory or derived from animals injected with human lymphoid tissue to stimulate an immune response. These drugs are used in inflammatory autoimmune disorders, transplant rejection reactions, and cancer. Monoclonal antibody drugs end in “mab,” such as basiliximab and daclizumab.

Cytokine inhibitors are biologic agents that inhibit cytokines that cause chronic, inflammatory autoimmune disorders, such as rheumatoid arthritis (RA), Crohn’s disease, and psoriasis. They suppress inflammation and promote tissue repair; however, they also increase the risks of serious infections, such as TB, pneumococcal infections, necrotizing fasciitis, and others. An example of an interleukin-blocking agent is anakinra (Kineret), used to treat moderate to severe RA.

Some examples of TNF-alpha blocking agents include adalimumab (Humira), infliximab (Remicade), and etanercept (Enbrel). These drugs are used to treat autoimmune diseases such as RA, Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis.

Other immunosuppressants used to treat RA include a biologic, abatacept (brand name Orencia), leflunomide (Arava), which is in a drug class called disease-modifying antirheumatic drugs (DMARDs). This class of drugs can decrease joint damage and disability caused by RA.

The general side effects of all immunosuppressive agents include increased risk of infection and cancer. Immunosuppressant drugs are used to treat serious illnesses, but thorough assessment must be done to verify that the benefits outweigh the risks.

Let’s go over some general patient teaching guidelines for patients taking immunosuppressant drugs:

   Wash hands often & thoroughly and practice meticulous personal hygiene - 
   this applies to patients and others around the patient. Avoid contact with 
   infectious people.

   To enhance immune defenses, practice healthy lifestyle habits, such as a 
   nutritious diet, adequate sleep, and avoiding tobacco and alcohol.

   Keep a list of drugs taken, dosage, provider’s information, and emergency 
   instructions with you in case of emergency.

   Report adverse drug effects to a health care provider, including signs/symptoms 
   of infection, such as sore throat or fever, easy bruising or bleeding if taking 
   methotrexate, or decreased urine output if taking cyclosporine.

   See the doctor regularly, for evaluation of drug responses, dosage changes, 
   adverse drug reactions, and blood monitoring tests that may be needed.

   Notify doctor if other drugs need to be taken - immunosuppressant drugs may 
   interact with other medications, decreasing therapeutic effects or increasing 
   adverse effects. Some vaccines should also be avoided while taking 
   immunosuppressants.

   Patients of reproductive age should practice effective contraception during 
   immunosuppressive therapy, due to the adverse effects of some of the drugs 
   on the fetus and mother.

   Protect skin from sunlight, as some drugs increase the risk of sensitivity 
   to the sun, sunburn, and skin cancer.


 

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