Sunday, 25 January 2015

What's SA237

ProfG made a post on UCLP trials and mentioned a trial of NMO using SA237. Whats is this?

It is monoclonal antibody that inhibited the interleukin 6 receptor

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. IL-6 is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. IL-6 also plays a role in fighting infection, IL-6' role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10.

IL-6 is an important mediator of fever. It is capable of crossing the blood-brain barrier and initiating synthesis of protaglandings in the hypothalamus, thereby changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs). These PAMPs bind to an important group of detection molecules of the innate immune system, called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These are present on the cell surface and intracellular compartments and induce intracellular signaling cascades that give rise to inflammatory cytokine production.IL-6 stimulate the production of neutrophils (a common cell in NMO) in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.

IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding IL-6Rα chain (CD126), and the signal-transducing component gp130 (also called CD130). CD130 is the common signal transducer for several cytokines including leukemia inhibitory factor (LIF), ciliary neurotropic factor, oncostatin M, IL-11 andcardiotrophin-1, and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the intracellular regions of gp130 to initiate a signal transduction cascade through certain transcription factors, Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs).

In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth and promote survival of neurons and, hence, may be important in nerve regeneration through remyelination.

ClinicSpeak: spinal fluid cells on natalizumab (Tysabri)

How much more do we have to learn about natalizumab? De-risking natalizumab. #MSBlog #MResearch #ClinicSpeak

"The study below shows that natalizumab (Tysabri) does not have the same effect on the immune system in everyone on the drug. It shows that levels of the drug vary between individuals and the effect on immune surveillance of the central nervous system differs depending on levels of natalizumab on the surface of cells. Should we be surprised? No. There is only one certainty about nature and it is that it is highly variable; so I am not surprised that a fixed dose of a drug, i.e. 300mg intravenously per month, will have different effects on different people. This study is important as it may tell us that there are a proportion of MSers on natalizumab who may have relatively intact CNS immune surveillance and are therefore at low risk of getting PML."

"What is CNS immune surveillance? There are several subsets of immune cells that literally go walk-about all over the body looking for infections and  cancers. The immunological equivalent of reconnaissance commandos in the military. If they find something amiss they will start fighting it and at the same time send signals to call in the army. Natalizumab is designed to stop trafficking of autoimmune cells into the CNS and because the autoimmune cells and surveillance cells use the same mechanism of trafficking natalizumab stops the vital function of immune surveillance. Imagine an army without surveillance or intelligence? This is why MSers on natalizumab are at high risk of PML and other CNS infections."

"Please note if you are on natalizumab and get another viral infection of the brain, for example herpes encephalitis, you will also be in trouble; PML is not the only infectious risk on natalizumab. Natalizumab-associated herpes encephalitis is very different to typical herpes encephalitis; the condition is initially more indolent and progresses slowly and mimics a tumour. This is why MSologists have to be very vigilant for atypical manifestation of other CNS infections in MSers on natalizumab."

"What this study shows that a proportion of MSers on natalizumab have higher CD8+ T-cells in their spinal fluid that is associated with lower levels of natalizumab on their surface. These cells are the ones that survey for infections and fight them. I suspect these MSers will have a lower risk of PML. The downside of this is these MSers may have a greater chance of breakthrough MS disease activity."

"Other observations and musings: I have been aware for sometime now that a subset of MSers (~20%) on natalizumab are aware when the natalizumab wears off before the next dose. These MSers describe non-specific symptoms of MS returning, particularly fatigue and feeling out of sorts, in the week or 2 before their next infusion. It's as if the immune system is trafficking back into the brain and setting-off a low grade immune response that is triggering sickness behaviour. Sickness behaviour is the brain's response to inflammation. Typical symptoms of sickness behaviour include fatigue, raised temperature, sleepiness, reduced appetite, low mood, poor concentration and attention and a mild systemic inflammatory response. Sickness behaviour is what it feels like when you have flu or another viral infection. Getting to the point of the argument; I would be interested to know if the small group of MSers who feel natalizumab wearing off are the ones with lower natalizumab saturation levels on their CD8+ T cells and are the ones at lower risk of PML."

"Why are these observation important? If the MSers with wearing-off have a lower, or no, risk of PML, but still have a excellent, or good, therapeutic response to natalizumab may be we could optimise the dose of natalizumab to de-risk natalizumab and prevent PML. You may be interested in reading my previous post on other strategies to de-risk natalizumab."

"For those of you interested in natalizumab and PML risk we have created a new app. We would appreciate your feedback on the app. Thanks."

Epub: Harrer et al. High interindividual variability in the CD4/CD8 T cell ratio and natalizumab concentration levels in the cerebrospinal fluid of patients with multiple sclerosis. Clin Exp Immunol. 2015 Jan. doi: 10.1111/cei.12590. .

Background: Strongly decreased leukocyte counts and a reduced CD4/CD8 T cell ratio in the cerebrospinal fluid (CSF) of natalizumab (NZB)-treated MSers may have implications on central nervous (CNS) immune surveillance.

Aims: With regard to NZB-associated progressive multifocal leukoencephalopathy we aimed at delineating a relationship between free NZB, cell-bound NZB, adhesion molecule (AM) expression, and the treatment-associated shift in the CSF T cell ratio. 

Methods: Peripheral blood (PB) and CSF T cells from fifteen NZB-treated MSers, and CSF T cells from ten patients with non-inflammatory neurological diseases and five newly diagnosed MSers were studied. Intercellular adhesion molecule-1 (ICAM-1), leukocyte function antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), NZB saturation levels, and T cell ratios were analyzed by flow cytometry. NZB concentrations were measured by ELISA. 

Results: Lower NZB saturation levels (P <.02) and a higher surface expression of ICAM-1 and LFA-1 (P <.001) were observed on CSF CD8 T cells. CSF T cell ratios (0.3-2.1) and NZB concentrations (0.01-0.42 µg/ml) showed a pronounced interindividual variance. A correlation between free NZB, cell-bound NZB, or AM expression levels and the CSF T cell ratio was not found. Extremely low NZB concentrations and a normalized CSF T cell ratio were observed in one case. 

Conclusion: The differential NZB saturation and AM expression of CSF CD8 T cells may contribute to their relative enrichment in the CSF. The reduced CSF T cell ratio appeared sensitive to steady-state NZB levels as normalization occurred quickly. Latter may be important concerning a fast reconstitution of CNS immune surveillance.

CoI: multiple

The centre of Immune tolerance

Safavi F, Li H, Gonnella P, Mari ER, Rasouli J, Zhang GX, Rostami A.c-kit plays a critical role in induction of intravenous tolerance in experimental autoimmune encephalomyelitis.
Immunol Res. 2015 Jan 15. [Epub ahead of print]

c-kit (CD117) is a tyrosine kinase receptor found in various types of immune cells. We examined the role of c-kit in autoantigen-induced i.v. tolerance in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our results show that induction of intravenous tolerance against EAE in B6 mice is characterized by increased numbers of CD117+ cells and altered mast cell-associated molecules in the periphery and in the CNS. W-sh (c-kit-deficient) mice were resistant to i.v autoantigen-induced tolerance, with increased proinflammatory cytokine production in the periphery. I.v. autoantigen in WT mice suppressed the production of proinflammatory cytokines IFN-γ and IL-6 and up-regulated the expression of FoxP3, a transcription factor of Tregs; however, in W-sh mice, IFN-γ and IL-6 were increased with a failure of FoxP3 induction upon i.v. autoantigen injection and is thus a mechanism for resistance to i.v. tolerance induction in these mice. We conclude that c-kit signaling has a regulatory role in i.v. tolerance and could be a target for potential immunotherapy in autoimmune disorders.

Not sure, what to say here, you can all read, if you can induce immune tolerance you can get rid of the problem with minimal effect on the rest of the immune system