Mycophenolate mofetil treatment accelerates recovery from experimental allergic encephalomyelitis.
Mycophenolate mofetil (MM) acts through its metabolite mycophenolic acid to inhibit inosine monophosphate dehydrogenase (IMPDH), an enzyme essential for purine synthesis in lymphocytes. Oral treatment with MM from the day of immunization for 2 weeks significantly delayed both the development of active experimental allergic encephalomyelitis (EAE) in Lewis rats and reduced the antibody response to myelin basic protein (MBP). MM did not deplete T and B cells, nor did it prevent induction of Th1 or Th2 cytokine in the regional nodes. Treatment of EAE with MM at the onset of clinical symptoms resulted in more rapid recovery from EAE than in control or cyclosporin A (CsA)-treated. MM-treated rats had less infiltration of T cells, B cells, macrophages and dendritic cells into brainstems than either the control or CsA-treated. MM-treated brainstems also had lower level of mRNA for Thl (IL-2, IL-12Rbeta2, IFN-gamma), Th2 (IL-4, IL-10) cytokines and TNF-alpha and TGF-beta compared to that in CsA and controls groups. This study shows MM was superior to CsA in the treatment of EAE and acted by reducing the inflammatory infiltrate, not by suppression of Ig response or by promotion of regulatory cells such as Th2 or Th3.
Tran
G T
GT
Department of Medicine, University of New South Wales, Liverpool Hospital, Australia.
Carter
N
N
Hodgkinson
S J
SJ
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D017403:In Situ Hybridization; D016131:Lymphocyte Subsets; D051379:Mice; D008815:Mice, Inbred Strains; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016572:Cyclosporine; D009173:Mycophenolic Acid