Epub: Hucke et al. Licensing of myeloid cells promotes central nervous system autoimmunity and is controlled by peroxisome proliferator-activated receptor γ Brain. 2012 Mar [Epub].
During central nervous system autoimmunity, interactions between infiltrating immune cells and brain-resident cells are critical for disease progression and ultimately organ damage. Here, we demonstrate that local cross-talk between invading autoreactive (sellf-reactive) T cells and auto-antigen-presenting myeloid cells (macrophages or microglia) within the central nervous system results in myeloid cell activation, which is crucial for disease progression during experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis.
This T cell-mediated licensing (what does this really mean?) of central nervous system myeloid cells triggered astrocytic CCL2- (monocyte chemotactic protein...that attracts macropahge forming cells) release and promoted recruitment of inflammatory CCR2(+)-monocytes (macrophages of the blood) , which are the main effectors of disease progression (In MS Yeah, but is this true in EAE?). By employing a cell-specific knockout model, we identify the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in myeloid cells as key regulator of their disease-determining interactions with autoreactive T cells and brain-resident cells, respectively.
LysM-PPARγ(KO) mice exhibited disease exacerbation during the effector phase of experimental autoimmune encephalomyelitis characterized by enhanced activation of central nervous system myeloid cells accompanied by pronounced local CCL2 production and inflammatory monocyte invasion, which finally resulted in increased demyelination and neuronal damage.
Pharmacological PPARγ activation (activation with PPAR-specific drugs) decreased antigen-specific T cell-mediated licensing of central nervous system myeloid cells, reduced myeloid cell-mediated neurotoxicity and hence dampened central nervous system autoimmunity (Inhibit the T cell bit and all the rest follow whether directly related to drug activity or not) . Importantly, human monocytes derived from patients with multiple sclerosis clearly responded to PPARγ-mediated control of proinflammatory activation and production of neurotoxic mediators.
Furthermore, PPARγ in human monocytes restricted their capacity to activate human astrocytes leading to dampened astrocytic CCL2 production. Together, interference with the disease-promoting cross-talk between central nervous system myeloid cells, autoreactive T cells and brain-resident cells represents a novel therapeutic approach that limits disease progression and lesion development during ongoing central nervous system autoimmunity.
Stopping damaging immune cells from "talking" to each over inhibits function of the immune system. This not an exactly a new concept and neither is targeting EAE/MS with PPAR gamma modulators. Indeed PPAR agonists have been used in preliminary studies, with a suggestion that if may affect MRI lesions formation, suggestive of neurodegeneration but it has not shown a clinical effect. However larger studies are needed to put some meat onto there ideas. Importantly, this has to be tempered with the side-effect profile (heart problems) of these types of drugs may have.
In fact a small phase 2 study was negative; this was published as an abstract at ECTRIMS 2005.
Miller et al. Efficacy of six months' therapy with oral rosiglitazone maleate in relapsing-remitting multiple sclerosis
Background: Peroxisomal proliferator-activated receptors (PPAR) are transcription factors that regulate metabolic pathways. PPAR gamma agonists such as rosiglitazone (Avandia) are used in the treatment of type II diabetes. Both in vitro and in vivo studies show that these drugs also possess anti-inflammatory or immunomodulatory properties on many cell types involved in neuroinflammation. They are also effective in the experimental autoimmune encephalomyelitis model in mice, an established model of multiple sclerosis. Rosiglitazone improves glycaemic control in diabetic patients. It is generally well-tolerated, and it also reduces inflammatory markers (e.g. C-reactive protein, interleukin-6) in diabetic and non-diabetic patients, suggesting it has potential anti-inflammatory activity in other diseases.
Methods: This was a double-blind, placebo-controlled, parallel-group study to investigate the utility of a PPAR gamma agonist, rosiglitazone (8 mg once daily) in the treatment of relapsing-remitting multiple sclerosis (RRMS). Subjects entered a 12-week run-in phase followed by 24-weeks on treatment, and then an 8-week follow-up. During the treatment period, subjects were randomised equally to active treatment or placebo. Sixty-one patients entered the run-in phase, with 51 randomised to treatment (26 to rosligitazone, 25 to placebo). The primary objective was to investigate the effect of six months' treatment on the number of new gadolinium enhancing lesions on magnetic resonance imaging (MRI) as recorded on monthly MRI scans. The secondary objectives were to explore additional MRI endpoints, clinical and immunological responses to treatment, safety and tolerability and pharmacokinetic data.
Results: The primary analysis was conducted comparing the MRI lesion number per month during the treatment phase to the run-in phase within the rosiglitazone group (for new gadolinium enhancing lesions, the difference was -0.20, 95% confidence interval was -0.82 to 0.42). Exploratory secondary analyses were conducted comparing within the placebo group and between the rosiglitazone and placebo groups. No statistically significant differences were observed in the analyses on any of the endpoints.
Conclusion: There was no evidence from this study to support the utility of rosiglitazone as a treatment for RRMS. Rosiglitazone was generally well-tolerated in RRMS patients with a similar safety profile to that seen in other patient populations.