Malaghan Institute of Medical Research

Targeting macrophage activation for the treatment of MS

Contributors: Dr Anne La Flamme, Sarrabeth Stone, Delgertsetseg Chuluundorj, DrScottHarding (CCDHB) collaborating with Dr Jacquie Orian (LaTrobe University)

Macrophages are multifunctional immune cells and are key mediators of inflammatory immune processes. During inflammation the immune 'climate' of an organism shapes the type of immune response that develops and directs immune cells such as macrophages to promote or resolve disease.
Malaghan Institute Research Associate Dr Anne La Flamme and colleagues have shown that treatments that alter a macrophage's state of activation, and thus alter the immune climate, can prevent central nervous system inflammation and progressive paralysis in the murine model of human MS - experimental autoimmune encephalomyelitis (EAE).
Identification of the pathway(s) by which these macrophage altering treatments prevent disease may uncover much-needed therapeutic targets to inhibit or reduce the severity of MS.

Investigating immune regulation of microglial function

Contributors: Sarrabeth Stone, Dr Anne La Flamme collaborating with Assoc Prof Bronwen Connor (University of Auckland)

Immune cells including T cells, macrophages, and microglia (brain-resident macrophages) are responsible for the damage to the nerves and subsequent clinical features of MS.
While many current MS treatments target T cells, because microglia are involved in controlling central nervous system inflammation and damage, microglia may also be a valuable target for new therapies.
Dr Anne La Flamme and colleagues are investigating the immune factors that regulate microglia function in the brain using the EAE model of MS, in the hope that targeting these factors will prevent central nervous system inflammation and damage.

Exploiting anti-cancer and immune-modulating drugs for the treatment of MS

Contributors: Marie Kharkrang (VUW), Dr Anne La Flamme, collaborating with Prof John Miller & Assoc Prof Peter Northcote (Victoria University of Wellington) and David O'Sullivan & Assoc Prof Bronwen Connor (The University of Auckland)

Current disease-modifying therapies used to treat individuals with MS have variable efficacy in reducing the neurological and physical disability associated with the disease.
Recently Dr La Flamme's research group have demonstrated that drugs that prevent cellular proliferation, such as those used to treat cancer patients or immune-modulatory drugs that work to suppress immune responses, are also effective at reducing the incidence and severity of MS in experimental disease models.
Dr La Flamme is currently investigating the potential of these classes of compounds for treating MS with the hope that the use of drugs that are already in clinical practice, or are in the process of gaining FDA approval for clinical use, will accelerate the path from drug design to clinical application.

A key role for blood monocytes in EAE

Contributors: Dr Clare Slaney, Aras Toker, Dr Anne La Flamme, Assoc Prof Thomas Bäckström, Dr Jacquie Harper, collaborating with Prof John Fraser (The University of Auckland)

Experimental autoimmune encephalomyelitis (EAE) is a well established murine model of multiple sclerosis (MS) that has been used by scientists at the Malaghan Institute to better understand the causes of MS, and to test the therapeutic potential of compounds designed to halt its progression. An important outcome of this work has been the identification of a key role for blood monocytes in maintaining immune tolerance in EAE.
The monocytes were shown to suppress inflammatoryT cell responses in naive mice but lost this function when EAE was induced.
The MS drug Glatiramer acetate was shown to be taken up by the monocytes and cells exposed to the drug demonstrated increased intrinsic T cell suppressor activity. Similar outcomes were obtained with an immune-modifying superantigen compound developed by Prof John Fraser.
These findings have important clinical implications for the design of novel immunotherapeutic agents that target specific cell types for the treatment of individuals with MS.