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.
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:

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.

QUESTION

Lupus is an infection. See Answer

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:

Side effects include:

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:

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:

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:

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:

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:

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:

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.

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Hyperthyroidism Symptoms and Treatment See Slideshow

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

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Summary

Immunosuppression compromises the immune system’s ability to fight infection. 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.

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Medically Reviewed on 8/12/2020
References
Medscape Medical Reference
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