What is immunosuppression?
Immunosupression may be caused by illness or it can be induced therapeutically. Drugs are used to suppress the immune system in organ transplant patients to keep their bodies from rejecting the new organ.
Immunosuppression compromises the immune system’s ability to fight infection. A healthy immune system protects the body by detecting and destroying harmful microbes and/or body cell changes that can cause diseases.
The immune system fights foreign organisms that enter the body with several types of white blood cells that circulate in the blood and the lymphatic system. Various proteins (cytokines) and enzymes act as signals to activate the immune cells. The body also develops specific antibodies to pathogens.
Most immune cells are produced in the bone marrow as stem cells and mature into different immune cells such as
- Lymphocytes
- Neutrophils
- Monocytes/macrophages (phagocytes)
The “complement cascade” is part of the immune system which enhances the ability of antibodies and phagocytes to attack and remove pathogens.
What can cause immunosuppression?
Immunosuppression can be caused by many factors such as:
- Age
- Malnutrition
- Chronic diseases
- Genetic conditions
- Certain cancers that affect immune cells
- Human immunodeficiency virus (HIV) infection
- Diseases that affect the immune system
- Chemotherapy or radiation therapy for cancer
- Drugs taken to induce immunosuppression in transplant patients
Why are immunosuppressive drugs given to transplant patients?
Organ transplant patients take immunosuppressive drugs to prevent the rejection of the transplanted organ (graft) by their own body’s immune system. The immune system considers the transplanted organ’s tissues as foreign bodies and attacks them, leading to organ rejection.
What are the immunosuppressive drugs?
Immunosuppressive drugs can be classified by the three phases in immunosuppression therapy which are:
- Induction: Start of therapy immediately after transplant.
- Maintenance: Lifelong maintenance medication to prevent rejection.
- Anti-rejection: Drugs to treat transplant rejection.
Corticosteroids for immunosuppression
Corticosteroids are anti-inflammatory and may be used in all three phases of therapy. Corticosteroids block the release of cytokines by immune cells. Common steroids used after transplantation are:
- Oral prednisolone
- Intravenous (IV) methylprednisolone
Side effects include:
- Osteoporosis (fragile bones)
- Cushing syndrome (symptoms such as a puffy face and/or a fatty lump in the neck from excess cortisol hormone)
- Avascular necrosis (bone tissue death due to lack of blood supply)
- Cataracts
- Glucose intolerance
- Infections
- Hyperlipidemia (high blood fats)
- Hypertension
- Peptic ulcer disease
- Pancreatitis
- Bowel perforation
- Weight gain
- Psychiatric disturbances
- Growth stunting
- Cleft palate and adrenal gland suppression in the fetus, when used during pregnancy
- Interaction with other drugs
Small molecule drugs
Small molecule drugs work by binding to a larger molecule and altering its activity.
Calcineurin inhibitors
Calcineurin inhibitors bind to and inhibit the calcineurin enzyme which activates T-cells, a type of lymphocyte.
Cyclosporine
Used for induction and maintenance of immunosuppression.
Side effects include:
- Nephrotoxicity (toxicity to kidneys)
- Hyperkalemia (high potassium)
- Hypomagnesemia (low magnesium)
- Nausea and vomiting
- Diarrhea
- Hypertrichosis (excessive hair growth)
- Hirsutism (male-pattern hair growth in women)
- Gingival hyperplasia (excessive gum tissue growth)
- Skin changes
- Hyperlipidemia
- Glucose intolerance
- Infection
- Malignancy
- Hyperuricemia (high uric acid level in blood)
- Hemolytic uremic syndrome (blood disorder that leads to low red blood cell and platelet levels, and kidney failure)
- Interactions with other drugs
Tacrolimus
Used for maintenance therapy and rescue therapy for refractory rejection with cyclosporine use.
Side effects are similar to cyclosporine with lower incidence of:
- Hirsutism
- Hyperlipidemia
- Hypertension
- Skin changes
- Gingival hyperplasia
Other side effects include:
- New-onset diabetes mellitus after transplantation
- Neurotoxicity
- Reversible alopecia
Mammalian target of rapamycin (mTOR) inhibitors
Rapamycin, also known as sirolimus, blocks the release of certain cytokines and inhibits the proliferation of two types of lymphocytes, T-cells and B-cells. Sirolimus also inhibits proliferation of cancerous nonimmune cells, and lowers the risk of malignancy after transplants. The mTOR inhibitor is used for maintenance immunosuppression and chronic rejection.
Side effects include:
- Hyperlipidemia
- Thrombocytopenia
- Anemia
- Pneumonitis (lung inflammation)
- Oral ulcers
- Diarrhea
- Low testosterone levels and infertility
- Poor wound healing
- Lymphoceles (collection of lymphatic fluid outside the lymphatic system)
- Thrombotic angiopathy (damage to small blood vessels in the organs such as brain and kidney)
- Worsening of kidney damage when used with calcineurin inhibitors.
- Interactions with other drugs
Inhibitors of nucleotide synthesis
Inhibitors of nucleotide synthesis impair the proliferation of B-cells and T-cells by inhibiting inosine monophosphate dehydrogenase (IMDH), an enzyme required for their synthesis.
Mycophenolate acid (Mycophenolate mofetil)
Mycophenolate mofetil is usually given with cyclosporine or tacrolimus for maintenance immunosuppression and chronic rejection.
Side effects include:
- Nausea and vomiting
- Diarrhea
- Leukopenia (low white cell levels)
- Anemia
- Thrombocytopenia
Enteric-coated mycophenolate sodium (EC-MPS)
EC-MPS, a derivative of mycophenolate mofetil has fewer reports of gastrointestinal side effects, compared to mycophenolate mofetil.
Mizoribine
Mizoribine inhibits T-cell proliferation and is usually given with tacrolimus.
Side effects include:
- Kidney damage due to elevation of uric acid levels
Leflunomide
Leflunomide has immunosuppressive and antiviral properties, but it is not FDA-approved for use in transplant patients. It has been used off-label in kidney transplant patients with resistant cytomegalovirus (CMV) or BK virus infection, or graft kidney dysfunction.
Side effects include:
- Liver toxicity
- Hemolytic anemia
Azathioprine
Azathioprine is used for immunosuppression maintenance and may be used with cyclosporine or tacrolimus.
Side effects include:
- Leukopenia
- Thrombocytopenia
- Liver toxicity
- Interaction with other drugs
- Congestive heart failure
- Atrial arrhythmia (irregular rhythm of atrium)
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Protein drugs (biologic agents)
Biologic agents are protein drugs prepared by injecting human immune cells into animals such as rabbits or horses. The antibodies that result in the animals are harvested and purified.
Polyclonal antibodies (antithymocyte globulins)
Polyclonal antibodies are prepared from different B-cell lineages, which can recognize and bind to multiple sites (epitopes) in an antigen. Antithymocyte globulins are used for induction, and treatment of rejection due to antibodies or corticosteroid-resistant rejection.
Side effects include:
- Fever and chills
- Thrombocytopenia
- Leukopenia
- Hemolysis (destruction of red cells)
- Respiratory distress (rare in adults)
- Serum sickness (immune response to the antibodies)
- Anaphylaxis (severe allergic reaction)
- Bleeding disorder
- Increased risk of
- CMV infection
- Non-Hodgkin lymphoma
Monoclonal antibodies
Monoclonal antibodies target specific t-cells with specific antigens to minimize side effects. The drug molecules bind with the T-cells, knocking them out of action.
Muromonab-CD3 (OKT3)
Muromonab-CD3 is a monoclonal antibody prepared in mice, which binds to the CD3 receptor of T-cells and leads to T-cell depletion. Muromonab-CD3 is used for induction and acute rejection. Approximately 50% patients develop antibodies to Muromonab-CD3, which reduces its efficacy.
Side effects include:
- Cytokine release syndrome which cause symptoms such as:
- Pulmonary edema
- Lymphoproliferative disorders (excessive lymphocyte production)
Alemtuzumab (Campath-1H)
Alemtuzumab is a humanized monoclonal antibody that binds to CD52 receptor, which is present in all immune cells. The use of alemtuzumab with tacrolimus for immunosuppression induction is in the clinical trial stage.
Side effects include:
- Cytokine release syndrome
- Neutropenia
- Anemia
- Idiosyncratic pancytopenia (low levels of all types of blood cells)
- Autoimmune disorders
- Thrombocytopenia
- Thyroid disease
Basiliximab (Simulect)
Basiliximab is a humanized monoclonal antibody that acts against CD25 receptor in T-cells and inhibit their activation. Basiliximab is used for induction and has negligible side effects, except for rare hypersensitivity reactions.
Rituximab
Rituximab is a monoclonal antibody that is anti-CD20 receptor found in B-cells. Rituximab is FDA-approved for treatment of post-transplantation lymphoproliferative disease.
Eculizumab
Eculizumab is a monoclonal antibody that inhibits C5, a component of the complement cascade. Eculizumab is used for treatment of antibody-mediated rejection which does not respond to conventional treatments.
Bortezomib
Bortezomib is a protease inhibitor targeted at plasma cells in the blood. Bortezomib is also for treatment of antibody-mediated rejection which does not respond to conventional treatments.
Belatacept (LEA29Y)
LEA29Y is a second-generation fusion protein immunosuppressive drug under development for blocking T-cell activation.
QUESTION
Lupus is an infection.
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What are the immunosuppressive therapies for transplant patients?
Immunosuppressive therapy is individualized based on the needs of the transplant patient. Immunosuppressive therapy during the three phases of treatment use different strategies, medicines and dosages.
Induction
Two strategies of therapy are followed during the induction phase:
- Aggressive immunosuppression: Use of high dosage of immunosuppressive drugs to achieve the strongest effect to prevent early acute rejection.
- Antibody-based therapy: Use of biologic agents such as monoclonal or polyclonal antibodies to suppress the immune cells, along with immunosuppressive drugs.
Maintenance
Maintenance therapy involves lifelong intake of immunosuppressive drugs at doses adjusted to optimize immunity suppression and minimize side effects. Maintenance therapy is essential to prevent transplant rejection.
Rejection treatment
Acute rejection: Acute rejection soon after the transplant is treated with
- Steroids
- Antithymocyte globulin
- Muromonab-CD3
Chronic rejection: Making changes in the immunosuppressive therapy has not been successful in reversing chronic rejection. Currently the main treatment is management of blood pressure, blood fats and blood sugar levels.
Studies on complications from immunosuppression
Research continues to find ways to improve the efficacy and survival rate after transplants. The major points of concern include the following:
- Effects of long-term use of steroids
- Risk of nephrotoxicity (kidney problems) with calcineurin inhibitors
- Length of immunosuppressive treatment after transplant
- Safety of treatment during pregnancy
- Balancing risks of transplant rejection and susceptibility to severe infections because of immunosuppression