Chapter 44: Immunosuppressives

Immunopharmacology is the study of the use of drugs to modulate the immune response. The principal application of this field to clinical medicine is with drugs that suppress the immune response. These drugs are used in the treatment of autoimmune diseases (myasthenia gravis and rheumatoid arthritis) and in organ transplantation.

Ciclosporine (also cyclosporin) binds to cyclophilin (an intracellular protein of the immunophilin family), while everolimus (derivative of sirolimus), sirolimus, and tacrolimus bind to a protein called FKBP12, another immunophilin. For all of these drugs, the drug-protein complex then inhibits calcineurin phosphatase and T-cell activation. Nephrotoxicity is the major side effect of ciclosporine.

Mycophenolate mofetil is administered as a prodrug that is activated to mycophenolic acid—the active compound. It is a highly selective inhibitor of a crucial enzyme in the de novo synthesis of guanosine. Proliferating lymphocytes are dependent on the de novo pathway for purine biosynthesis. Most other cell lines can maintain function with the salvage pathway. Therefore, mycophenolic acid is a very specific lymphocyte inhibitor.

Azathioprine is thought to be immunosuppressive by interfering with DNA synthesis.

Muromonab is a mouse monoclonal antibody that binds to the CD3 protein complex on T lymphocytes, blocking antigen recognition. Its immunosuppressant activity reduces rejection after organ transplantation.

Basiliximab and daclizumab block the interleukin-2 (IL-2)–mediated activation of T lymphocytes by binding to CD25, which is the α chain of the interleukin-2 receptor. These antibodies were designed to selectively inhibit T-cell activation. Daclizumab is used in inflammatory multiple sclerosis and basiliximab is used to prevent rejection after organ transplantation.