Research: Stopping immune cells talking prevents nerve damage

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].

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. 

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. 

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

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

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. 

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. 

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. 

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.

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