Multiple sclerosis affects 3,500 New Zealand families.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system.
It is characterised by immune-mediated nerve degeneration, leading to impaired vision, coordination and paralysis.
There is no cure, and while disease-modifying drugs are available, they are often effective in only a subset of individuals with MS.
Malaghan Institute Research Associate Dr Anne La Flamme, an Associate Professor in the School of Biological Sciences at Victoria University of Wellington, leads a research programme investigating different strategies for optimising currently available MS treatments, as well as the development of novel agents for future therapies.
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
Monocytes are a type of white blood cell that move quickly to sites of infection to stimulate inflammatory responses. They are also capable of suppressing inflammation in certain disease contexts.
Previously our researchers had demonstrated that the ability of blood monocytes to suppress inflammation and thus protect against the development of autoimmunity, is impaired in a murine model of human multiple sclerosis.
Their latest research now suggests that the solution to reactivating the suppressor function of these monocytes could lie in a modified superantigen, coupled to a myelin-derived peptide (MOG). This conjugate has been shown to alleviate the symptoms of disease in experimental models, however the mechanism of protection was unknown at the time.
“Our research has revealed that the reduced disease-mediating T cell activity observed in experimental MS models following treatment with the superantigen conjugate, correlates with a restoration of blood monocyte suppressor function,” says Dr Jacquie Harper. “Importantly, when we transferred blood monocytes isolated from conjugate-treated mice into naïve mice, the cells were able to protect the recipient mice from developing MS symptoms. This is significant because it suggests that the effects we observe with the superantigen conjugate can be traced back to a change in monocyte function.”
“This research has identified a new therapeutic approach that has the potential to control the inappropriate inflammation that occurs in autoimmune diseases such as MS.”
Slaney CY, Toker A, Fraser JD, Harper JL, Bäckström BT (2013) A modified superantigen rescues Ly6G-CD11b+ blood monocyte suppressor function and suppresses antigen-specific inflammation in EAE. Autoimmunity, 46:269-78
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.
Glatiramer acetate (GA) is an immunomodulator drug approved by the Food and Drug Administration (FDA) for treating relapsing-remitting multiple sclerosis (MS). Although previous studies have shown that GA relieves clinical symptoms in patients with MS and suppresses experimental autoimmune encephalomyelitis (EAE – an animal model of MS) in mice, its mechanism of action is not yet fully understood.
To expand our understanding of the suppressive mechanisms of GA, and elucidate whether GA targets specific subsets of immune cells, Masters student Aras Toker investigated the association between GA treatment and blood monocyte function. Monocytes are a type of white blood cell that moves quickly to sites of infection to stimulate inflammatory responses. They are also capable of suppressing inflammation in certain disease contexts.
"Aras’ research showed that GA enhances the ability of blood monocytes to suppress the inappropriate inflammatory responses of the T cells that damage the central nervous system,” says Dr Jacquie Harper. “Our findings identify additional mechanisms involved in GA-dependent suppression of autoimmune reactivity and illustrate that the different routes of GA administration could be used to engage multiple immunosuppressive pathways in the treatment of MS.”
This study highlights the potential for utilising alternative routes for GA administration to enhance its therapeutic efficacy. Dr Harper says they will also look to expand their understanding of the immunosuppressive effects of the monocytes identified in this research, to determine if they can be specifically targeted to develop a therapy for treating MS and other autoimmune conditions.
Toker A, Slaney CY, Bäckström BT, Harper JL (2011) Glatiramer acetate treatment directly targets CD11b+Ly6G- monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis. Scand J Immunol, 74:235-43