Immunosuppressive Drugs

Immunosuppressants are drugs that lower or prevent an immune response. They are used extensively in the treatment of some autoimmune diseases such as Uveitis, Behcet’s and SLE as well as to prevent rejection during transplantation. Immunosuppressants have been classified by the WHO into six main categories. These are 1) the Selective Immunosuppressants, 2) TNF alpha inhibitors, 3) Interleukin inhibitors, 4) Calcineurin inhibitors 5) Glucocorticoids and 6) ‘Other’ immunosuppressants.  Another group of drugs classified as hormones by the WHO but which also have immunosuppressive properties are the Glucocorticoids.

 


1.    Selective Immunosuppressants


Selective immunosuppressants are immunosuppressants which are selective in their action as opposed to the pan reactive immunosuppressants which act globally.  Selective immunosuppressants include Anti-Lymphocyte Globulin (ALG), Anti-Thymocyte Globulin (ATG), Eculizumab, Everolimus, Mycophenolic acid (MMF) and Sirolimus.

 

Anti-Lymphocyte Globulin (ALG)

Anti-Lymphocyte Globulin (ALG) is an anti-human T cell antibody immunosuppressive used in the prevention and treatment of acute rejection in kidney transplantation. It has also been used to induce remission in Aplastic Anaemia. ALG use is less common than ATG use.

 

Anti-Thymocyte Globulin (ATG)

Anti-Thymocyte Globulin (ATG) is an anti-human T cell antibody immunosuppressive used in the prevention and treatment of acute rejection in kidney transplantation and in the prevention and treatment of GvHD in stem cell transplantation. It is also used to induce remission in Aplastic Anaemia.

 

ATG depletes T cells by direct complement action and by cell mediate cytotoxicity. Side effects include activation of the T cells and release of IL-2 before the T cells are destroyed thus potentially causing a cytokine storm. For this reason, anti-IL-2 receptor antibodies such as Basiliximab and Daclizumab are increasingly being used in place of ATG.

 

Eculizumab

Eculizumab is a monoclonal antibody directed against the complement component C5 which is a component on the final common Complement pathway leading to the formation of Membrane Attack Complex (MAC). Eculizumab blocks the cleavage of C5 and thus halts the process of Complement mediated cell destruction.

 

Everolimus

Everolimus is used as an immunosuppressant to prevent rejection in heart and kidney transplants and for treatment of advanced kidney cancer. Everolimus is a derivative of Sirolimus and is an mTOR (mammalian Target of Rapamycin) inhibitor. mTOR is a serine-threonine protein kinase that regulates cell growth, proliferation, motility, survival, protein synthesis and transcription.

 

Mycophenolic acid (MMF)

Mycophenolic acid is the active derivative of Mycophenolate mofetil or MMF. It is an antiproliferative immunosuppressant which inhibits purine synthesis thus suppressing T and B cell responses. MMF inhibits primary antibody responses more efficiently than secondary responses.

 

MMF is indicated for the prophylaxis of acute rejection in kidney and cardiac transplant patients. It is increasingly utilized as a steroid sparing treatment. MMF can be used concomitantly with cyclosporine and corticosteroids.

 

Sirolimus

Sirolimus (also known as Rapamycin) is an mTOR (mammalian Target of Rapamycin) inhibitor used in the prevention of rejection in heart and kidney transplants. Unlike the Calcineurin inhibitors which block the synthesis of IL-2, the mTOR inhibitors block cell responses to IL-2. For this reason, Calcineurin nephrotoxicity is often reduced by use of Sirolimus, allowing a reduction in the dose of Cyclosporin/Tacrolimus.

 


2.    TNFα Inhibitors


An example of a TNFα inhibitor is Infliximab.

Infliximab

Infliximab is an anti TNFα monoclonal antibody used in the treatment of many autoimmune diseases including Psoriasis, Crohn’s disease, Ankylosing Spondylitis, Psoriatic Arthritis, Rheumatoid Arthritis and Ulcerative Colitis.

 


3.    Interleukin Inhibitors


Interleukin inhibitors include Basiliximab and Daclizumab.

Basiliximab

Basiliximab is a chimeric mouse-human monoclonal immunosuppressive antibody to the α chain (CD25) of the IL-2 receptor of T cells. Basiliximab binds to CD25 thus blocking IL-2 from binding to activated lymphocytes. Basiliximab is used in the prevention and treatment of acute rejection in kidney transplantation.

 

Daclizumab

Daclizumab is, like Basiliximab, a monoclonal immunosuppressive antibody to the α chain (CD25) of the IL-2 receptor of T cells. Daclizumab binds to CD25 thus blocking IL-2 from binding to activated lymphocytes. Daclizumab is used in the prevention and treatment of acute rejection in kidney transplantation. Daclizumab is often used in combination with Glucocorticoids and Cyclosporine.

 


4.    Calcineurin Inhibitors


Calcineurin inhibitors include Cyclosporin and Tacrolimus.

Cyclosporin

Cyclosporin-A is a Calcineurin inhibitor. Calcineurin is a protein phosphatase also known as protein phosphatase 3. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate Calcineurin. Calcineurin then activates NFAT (Nuclear Factor of Activated T-cells) by dephosphorylating it. Upon activation, NFAT is translocated into the nucleus where it upregulates the expression of IL-2 which, in turn, stimulates the growth and differentiation of T cell response. Cyclosporin binds to the cytosolic protein Ciclophilin and the resulting complex binds to and inhibits Calcineurin.

 

Tacrolimus

Tacrolimus is a Calcineurin inhibitor which is similar in action to cyclosporin. Tacrolimus prevents NFAT dephosphorylation by complexing with the immunophilin FK binding protein 12 (FKB12) creating a new complex which interacts with and inhibits Calcineurin, thereby inhibiting the expression of IL-2 which, in turn, inhibits the growth and differentiation of T cell response.

 


5.    Glucocorticoids


Glucocorticoids (GC) are steroid hormones that bind to and activate the glucocorticoid receptor (GR), which is expressed on almost every cell and regulates genes controlling the development, metabolism and immune activity of the cell. Activation of the glucocorticoid receptor up-regulates the expression of anti-inflammatory proteins and down-regulate the expression of pro-inflammatory proteins. Glucocorticoids include Cortisone, Hydrocortisone (Cortisol), Meprednisone, Methylprenisolone, Prednisolone and Prednisone.

 


6.    Other Immunosuppressants


Other immunosuppressants include Azathioprine, Methotrexate and Thalidomide.

Methotrexate

Methotrexate (MXT) is a folic acid antagonist that inhibits dihydrofolate reductase, a key enzyme in the synthesis of the amino acids serine and methionine. Methotrexate is used in the treatment of some autoimmune diseases, including Psoriasis and Rheumatoid Arthritis as well as treatment of many types of cancer including ALL.

 


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3 Responses to Immunosuppressive Drugs

  1. Makaela says:

    Mighty usufel. Make no mistake, I appreciate it.

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