Delaying the onset of experimental autoimmune encephalomyelitis with the microtubule-stabilizing compounds, paclitaxel and Peloruside A.
The hallmark of autoimmunity is the activation and proliferation of autoreactive lymphocytes. Therefore, one potential strategy to treat autoimmunity is to target the proliferating autoreactive lymphocytes with antimitotic drugs. Paclitaxel and peloruside are two microtubule-stabilizing drugs that halt cell proliferation by stabilizing microtubules in the G(2)/M phase of the cell cycle. C57BL/6 mice treated for 5 consecutive days with paclitaxel or peloruside had a reduced incidence and significantly delayed development of EAE, a mouse model of MS. Although paclitaxel and peloruside were effective at inhibiting T cell proliferation in vitro, paclitaxel was shown to be ineffective at preventing the proliferation of autoreactive T cells in vivo during the 5-day treatment period. However, after the 5-day treatment, the ability of splenocytes or LN cells to proliferate in vitro was reduced significantly, suggesting that drug treatment targeted late but not early proliferative events in the animal. Moreover, in paclitaxel-treated, MOG-immunized mice, there was a complete inhibition of the recruitment of myeloid cells (especially macrophages) to the peripheral lymphoid organs. These results indicate that microtubule-stabilizing drugs are effective at reducing disease but require a prolonged exposure to paclitaxel in vivo to alter proliferation in the myeloid and lymphoid cell compartments.
Crume
Kevin P
KP
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand 6140.
O'Sullivan
David
D
Miller
John H
JH
Northcote
Peter T
PT
La Flamme
Anne C
AC
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D016195:G2 Phase / Q000187:drug effects* / Q000276:immunology; D007783:Lactones / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000276:immunology*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D017239:Paclitaxel / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; D050257:Tubulin Modulators; C414085:peloruside A; D017239:Paclitaxel