Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection

Abstract

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5'-monophosphate dehydrogenase, has several immunosuppressant actions. MPA depletes guanosine and deoxyguanosine nucleotides preferentially in T and B lymphocytes, inhibiting proliferation and suppressing cell-mediated immune responses and antibody formation, major factors in acute and chronic rejection. MPA also can induce T-lymphocyte apoptosis. MPA suppresses dendritic cell maturation and can induce human monocyte-macrophage cell line differentiation, decreasing the expression of interleukin (IL)-1 and enhancing expression of the IL-1 receptor antagonist. In addition, MPA inhibits adhesion molecule glycosylation and expression and lymphocyte and monocyte recruitment. Activated macrophages produce nitric oxide (NO) and superoxide, which combine to generate tissue-damaging peroxynitrite. MPA depletes tetrahydrobiopterin and decreases NO production by inducible NO synthase without affecting constitutive NO synthase activity. By these mechanisms, MMF exerts anti-inflammatory activity, which could attenuate both acute and chronic rejection. Unlike calcineurin inhibitors, MMF is nonnephrotoxic and does not induce transforming growth factor-beta production, which is fibrogenic. MMF inhibits arterial smooth muscle cell proliferation, a contributor to graft proliferative arteriopathy, and does not increase blood pressure, cholesterol, or triglyceride levels. By decreasing high-density lipoprotein oxidation and macrophage recruitment, MMF also may delay onset/progression of graft atherosclerosis. Thus, MMF may prevent chronic rejection by several mechanisms. MMF activity is synergistic with that of other agents such as valganciclovir for treating cytomegalovirus infection. MMF also has synergistic activity with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists in the treatment of some nephropathies in experimental animals. This combination may prevent progression toward end-stage renal disease in humans with chronic allograft, lupus, and diabetic nephropathies.