Read more about our recent MS research.
MIS416 is a novel microparticle derived from Propionibacterium acnes comprising a minimal cell wall skeleton rich in immunostimulatory muramyl dipeptide (MDP) and bacterial single stranded DNA, which signal through the innate immune receptors, NOD2 and TLR9, respectively.
While originally developed as a vaccine adjuvant, interest has grown around the potential use of MIS416 as a standalone immunomodulatory agent for the treatment of inflammatory disorders when administered systemically.
“Based on positive anecdotal findings from a compassionate-use program in secondary progressive MS patients, a formal Phase 2A trial has just been completed to evaluate the safety, tolerability and initial impact of MIS416 in progressive MS,” says Dr La Flamme. “The results from this trial have met or exceeded expectations and a larger-longer Phase 2B trial in patients with SPMS is planned to commence in 2013.”
“In parallel at the Malaghan Institute, we are investigating MIS416’s mechanism of protection using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE).”
“Previously, we found that MIS416 significantly reduced neurological disease when administered before or after the onset of neurological symptoms in both progressive and relapsing-remitting models of MS,” says Dr La Flamme.
“Furthermore, we found that MIS416 modulated the systemic immune response to dampen down inflammatory responses, and preliminary results show that these alternations in turn reduced CNS inflammation.”
These findings have just been submitted for publication.
Macrophages are multifunctional immune cells and are key mediators of the inflammatory process. As such, these cells are a significant focus of Associate Professor Anne La Flamme’s MS research.
Macrophages can become activated by a variety of different products and signals. The type of activation signal they receive determines whether the macrophages release pro-inflammatory (Th1) or anti-inflammatory (Th2) mediators.
“Our previous work has shown that the type II activation state of macrophages is protective in experimental MS models, and this protection is dependent upon the Th2 cytokine IL-4,” says Associate Professor La Flamme. “However, it was unknown how the Th2 environment promoted by type II activated macrophages is induced or how it affects macrophage function.”
To address this question, Associate Professor La Flamme investigated if and how signalling through the major Th2 cytokine receptor IL-4R affected type II macrophage activation.
“Overall, our results are the first to indicate that type II activation induces production of low but significant levels of IL-4 by macrophages and that this production is common to all type II-inducing agents tested,” says Associate Professor La Flamme. “This IL-4 in turn may play an important role in shaping adaptive immune responses and Th2 response development.”
This work thus reveals another mechanism by which innate cells may direct and shape adaptive responses and opens up a new target for therapies designed to regulate the dysfunctional immune responses observed in diseases such as MS.
La Flamme AC, Kharkrang M, Stone S, Mirmoeini S, Chuluundorj D, Kyle R (2012) Type II-activated murine macrophages produce IL-4. PLoS ONE, 7:e46989