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

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 1969.

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 synthesisPurine 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 1995MMF is equel to AZA when 1 year

survivel is measuredMPA inhibits response to PHA,PWM,

Protein A.MPA also inhibits late MLRMPA 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-2Long term treatments inhibits allmost all

cytokines production.

Meaning – MPA has no influence on early activation.

Antibody production

Ab production is inhibitedMostly 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% apoptosisWith 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 mediatorNO is synthesized from guanidino

nitrogen of L-arginine by NO-synthaseiNOS 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 lowerPeak 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:PemphigusDishidrotic eczemaIdiopathic 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”