Microtubule‐stabilizing agents delay the onset of EAE through inhibition of migration

Abstract

We have shown previously that microtubule-stabilizing agents (MSA), a class of anti-proliferative compounds, can delay disease onset and reduce cumulative disease in an experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To explore how MSA could alter EAE disease processes, we compared the effect of administering MSA before or after peak antigen-specific proliferation and found that treatment before proliferation completely inhibited antigen-specific responses in the spleen; whereas administration of an MSA such as paclitaxel or docetaxel after peak proliferation did not. Despite the presence of antigen-specific responses in mice treated at the later time point, both treatment periods resulted in similar protection against EAE, suggesting that the protective effect of MSA in EAE could not be solely attributed to anti-proliferative activity. Instead, using in vivo migration assays, it was shown that MSA inhibit immune cell infiltration into the central nervous system (CNS). Furthermore, we found that the efficacy of an MSA could be enhanced by administering low doses of two different MSA together, such as peloruside A and ixabepilone, indicating that these MSA synergize in vivo to suppress disease. Taken together, these data suggest that MSA can suppress EAE by at least two distinct mechanisms of action--prevention of proliferation and inhibition of migration into the CNS. Finally, we have shown that a combination treatment with synergizing MSA may provide enhanced protection at lower therapeutic doses.

Enhanced disease reduction using clozapine, an atypical antipsychotic agent, and glatiramer acetate combination therapy in experimental autoimmune encephalomyelitis

“…13,16 All flow data was collected on a FACSCanto II (Becton Dickinson, Franklin Lakes, NJ, USA) and analyzed using FlowJo v6.1 & 10.1r7 (Tree Star Inc., Ashland, OR, USA).…”

Peloruside A Inhibits Growth of Human Lung and Breast Tumor Xenografts in an Athymic nu/nu Mouse Model

“…Paclitaxel and docetaxel as chemotherapeutic drugs, although directed at a target found in both cancer cells and normal cells, have been hugely successful in treating solid tumors (4) but have several drawbacks. These include dose-limiting toxicities (3-5) and problems with vehicle (31). Synergistic interactions between peloruside and the taxane site drugs have been previously described in vitro in cultured cancer cell lines (32,33).…”

Amelioration of experimental autoimmune encephalomyelitis by clozapine is not associated with defective CD4 T cell responses

“…EAE is induced by immunization with a myelin self-peptide such as MOG 35-55 , which causes a rapid expansion of antigen-specific CD4 + T cells that initiate inflammation in the CNS [15]. Given the requirement for CD4 T cell expansion, defects in T cell proliferation can reduce the severity of EAE [16, 17], and in contrast, failure to suppress proliferation exacerbates EAE as seen in IFN-γ [18] or Treg-deficient mice [17]. A previous study reported that the atypical antipsychotic agent, quetiapine, reduced disease in EAE by impairing CD4 T cell proliferation [11].…”

“…Given that CD4 T cells express dopaminergic receptors (data shown in Additional file 1) as well as other neurotransmitter receptors targeted by atypical antipsychotic agents [19, 20], we investigated whether clozapine had affected MOG 35-55 -specific T cell expansion. To address this, we used an established in vivo model of proliferation [16]. We show that clozapine-treated mice maintained robust CD4 + T cell expansion as assessed by the percentage of cells that proliferated and the proliferative index in the peripheral blood (Fig.…”