Mycophenolate mofetil A suppression tale ד " ר יוסי רימר

Mycophenolate mofetil

History MPA, a product of a Penicillium fungus, was originally isolated in 1896 MPA has anti-neoplastic, anti-viral, anti- fungal and immunosuppressive activity

Mechanism of action

MMF prevents T and B cell proliferation by inhibiting the metabolic pathway needed for cell division. Two major pathways lead to purine synthesis : de-novo & salvage T and B cell depend selectivly on the de- novo pathway

Mechanism of action The action of MPA on IMPDH and its ability to inhibit nucleic acid synthesis was established in There are two types of IMPDH type I & type II. MPA inhibits both types. The inhibition is selective reversible and non-competitive

Mechanism of action – regulation of purine synthesis Purine synthesis is regulated by the balance of of adenosine to guanosine nucleotides. IMPDH inhibition causes reduction in guanosine nucleotides and excess of adenosine nucleotides.

Mechanism of action – regulation of purine synthesis in human lymphocytes AMP excess cause feedback inhibition of PRPP synthetase. Excess of d ATP inhibits ribonucleotide diphosphatase reductase. So no substrates for DNA and RNA are available. The de-novo pathway is shuts down

Other metabolic effects Glycoprotein (selectines,integrines) synthesis requires GTP for manose and fructose transfer. MPA interfere with adhesion molecules synthesis. Depletion of GTP interfrer with G prot. Signal transduction

T and B lymphocytes MPA inhibits generation of Tc. MPA prevents Ab production by polyclonal activated B cells. MPA has no effect on cytokine production.

Clinical trials MMF has FDA approval since 1995 MMF is equel to AZA when 1 year survivel is measured MPA inhibits response to PHA,PWM, Protein A. MPA also inhibits late MLR MPA inhibits proliferation of T and B cells

Cytokine production CsA and FK-506 inhibits early T activation and IL-2 production MPA has no primary effect on IL-2 Long term treatments inhibits allmost all cytokines production. Meaning – MPA has no influence on early activation.

Antibody production Ab production is inhibited Mostly primary response is inhibited MMF inhibits primary humoral response but not secondary response

Apoptosis in T lymphocutes MPA doubles the amount of apoptotic cells after CD3 activation. MOLT-4 cells showed 82-98% apoptosis With MPA. MPA can eliminate T cells responding to TCR activation and possibly Ag stimulation

Inhibition of adhesion molecules GTP depletion inhibits fucose and manose transfer to glycoproteins. Adhesion molecules are one class of those glycoproteins. The transfer through the golgi apparatus is impaired due to incorrect glycosylation GTPase regulate secretory pathways – no GTP no regulation.

Adhesion molecules production is tempered in multiple cellular levels

Say NO to MPA NO a multifunctional biological mediator NO is synthesized from guanidino nitrogen of L-arginine by NO-synthase iNOS is the enzyme that regulates NO No iNOS makes apoptosis inefficient Acute graft rejection is also NO mediated.

MMF suppresses NO production in human

HIV HIV replicates in lymphocytes where GTP is depleted. It is logical to find some anti-HIV activity when usinf MPA. MPA has synergistic anti-HIV effect with Abacavir (Margolis 1999) Abacavir is a guanosine analog RT inh. When no dGTP Abacavir works better

Other infection Hsv – MPA potentiates acyclovir and gancyclovir EBV – MPA inhibits cellular prolifaration of EBV infected cells HCV – MPA given to hcv+ liver transplanted had better long term surviv.

PMA and human disorders

Rheumatoid Arthritis 2 DB studies preformed. Improvement seen in some patients not responding to any treatment before. RF titers were lower Peak effect started after 8-12 weeks and lasted 36 weeks.

Myasthenia gravis 1 report about successful treatment of a severe refractory MG.

Skin disease MMF efficacy in treating Psoriasis is well proven Other diseases treated are: Pemphigus Dishidrotic eczema Idiopathic nodular panniculitis

Renal disaease - SLE

SLE “We found that the regimen of mycophenolate mofetil and prednisolone induced complete remission in 81 percent of patients and partial remission in 14 percent within 12 months. These results were similar to those obtained with our sequential regimen but were better than the response rates reported by other investigators”