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Posted: Thu Oct 11, 2007 2:26 am Post subject: Biogen's drugs for MS
Lots of presentations by Biogen on its various MS products at the ECTRIMS conference which starts today. Most are being presented at the weekend so I'll try to post them when I see them. This is a taster:
Joined: May 04, 2006 Posts: 3403 Location: Mid-Michigan
Posted: Thu Oct 11, 2007 7:15 am Post subject:
Thanks for the reminder and links Ian. It does seem there are going to be at least a couple of interesting presentations at ECTRIMS this year:
Quote:
Immunology 1
Friday, October 12, 2007, 15:30 - 17:00
IL-25, a cytokine up-regulated in parasitic infections, prevents T-cell-mediated neurotoxicity
R. Kinsey, D. Pasychnik, F. Giuliani (Edmonton, CAN)
Objective: to determine whether IL-25 can prevent T cell-mediated neurotoxicity.
Background: Multiple Sclerosis(MS)is an autoimmune inflammatory disease of the Central Nervous System(CNS)and is characterized by demyelination and axonal loss. More recent evidences strongly suggest that axonal and neuronal degeneration underlies the development of permanent disability in MS. The cause of tissue loss in MS is uncertain but inflammation likely plays a role since there is good correspondence between the frequency of axonal transection/disruption and the degree of inflammation within a given lesion. T cells play a major role and they represent one of the main populations in the inflammatory infiltrates of MS lesions and we have previously shown that human neurons are extremely vulnerable to T cell-mediated injury in culture (Giuliani et al., 2003). Both Th1 and Th17 cells are considered as key mediator of MS pathogenesis where Th2 induced anti-inflammatory environment is thought to be protective. Parasitic infections can induce a Th2 cell immune bias and recently, a decrease in the progression of disability has been described in MS patients with parasite infection (Correale and Farez, 2007). IL-25, a recently discovered cytokine, has been found to be up-regulated in parasitic infections and has been shown to amplify Th2 responses.
Methods and results: Human fetal neurons were co-cultured with unactivated, anti-CD3 activated or IL-25 (50 mcg) treated activated T cells. In addition, neurons were also co-cultured with ovalbumin specific T cell-lines untreated or IL-25 treated. Neurons were then stained for MAP-2 and counted for percent of survival. In both antigen (viability 40% for untreated and 72% for IL-25 treated) and non-antigen (viability IL-25+anti-CD3:78%; 38% for anti-CD3 activated only) specific systems IL-25 treatment was able to significantly prevent neuronal killing. The IL-25 treatment did not alter the cytokine secretion profile for IFN-g and IL-4, the proliferation, the CD/CD8 ratio, the IL-17 production or the expression of FasL of T cells. In contrast, IL-25 treatment induced a decrease in TNF-alpha production and decreased expression of CD40L.
Conclusions: the prevention of T cell-mediated killing of human neurons suggests IL-25 as a mediator of the observed protective effect of parasitic infections on MS progression. Further studies are necessary to explore IL-25 as a potential neuroprotective treatment for MS.
Quote:
MS and infections
Friday, October 12, 2007, 15:30 - 17:00
The role of regulatory B-cells during the course of parasite infections in multiple sclerosis patients
J. Correale, M. Farez (Buenos Aires, AR)
B cells are typically characterized by their ability to produce antibodies (Abs). However, B cells possess additional immunological functions including cytokine secretion, and the ability to function as antigen presenting cells (APCs). In addition, regulatory B cells can also suppress autoimmunity in different murine models through IL-10 and TGF-beta production. Moreover, previous studies have demonstrated that cells from the immune system are able to produce neurotrophic factors, suggesting a neuroprotective role during inflammation. Recently, we demonstrated that parasite infected MS patients show a significantly lower number of relapses, reduced disability scores, and much less MRI activity compared to uninfected MS individuals.
To assess the importance of B cell control during parasite infections in MS patients, peripheral blood CD19+ B cells from 12 parasite infected MS patients, 12 MS patients without infection, and 12 healthy controls were purified using magnetic cell sorting. A significant increase in the production of IL-10 by B cells was observed in parasite infected MS patients, compared to uninfected MS subjects and healthy controls. No differences in IL-4, IL-6, TNF-alpha, TGF-beta, and TNF-beta production by B cells were observed between groups. To test which costimulatory interactions provided greater stimulus for IL-10 production by B cells, peripheral blood mononuclear cells were cultured in the presence of blocking mAbs specific for B7RP-1, CD80, CD86, and CD40L. The number of IL-10 producing cells was calculated using flow cytometry. ICOS-B7RP-1 blockade decreased the percentage of IL-10 producing B cells the most. IL-10 production by B cells closely correlated CD1d expression, a molecule linked to signaling cascades associated with IL-10 transcription. Finally, brain derived neurotrophic factor (BDNF), and nerve growth factor (NGF) secretion in culture supernatants from LPS stimulated B cells was significantly higher in cultures derived from parasite-infected MS patients compared to uninfected MS subjects and normal controls.
Overall, these data indicate that parasite infections in MS patients induce IL-10 producing B cells, dampening harmful immune responses through a mechanism mediated at least in part by the ICOS-B7RP-1 pathway. Moreover, B cells produced higher amounts of BDNF and NGF, raising the possibility that these cells may have a neuroprotective effect.
_________________ Wife diagnosed with MS in Feb. 2006 and is a participant in the Tovaxin IIb clinical trial.
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