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Mycophenolate mofetil

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.

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Mycophenolate mofetil

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  1. Mycophenolate mofetil A suppression tale ד"ר יוסי רימר

  2. Mycophenolate mofetil

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

  4. Mechanism of action

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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.

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

  14. 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

  15. 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.

  16. Adhesion molecules production is tempered in multiple cellular levels

  17. 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.

  18. MMF suppresses NO production in human

  19. 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

  20. 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.

  21. PMA and human disorders

  22. 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.

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

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

  25. Renal disaease - SLE

  26. 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”

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