The immune system has a critical role in the pathology and clinical features of MS. Destruction of the insulating myelin sheath surrounding axons (nerve fibres) in the central nervous system is mediated by the immune system. As such, current treatments are often designed to suppress or modify the immune system to diminish inflammation. This can have significant side-effects and increase susceptibility to infections.
Strategies that more specifically target the immune response to one’s own body (autoimmune response), while maintaining normal immune function could therefore, have the potential to reduce these side-effects.
Associate Professoressor Alderuccio’s research over the past 20 years has focused on understanding the mechanisms associated with autoimmunity and how promoting immune tolerance to the body’s molecular targets (auto-antigens) can be used as a strategy for treating autoimmunity.
In this project he will test a strategy aimed at specifically alleviating the self-targeted immune response in MS. A natural mechanism that the body uses to control the immune system is regulatory immune cells. These cells have the capacity to suppress the action of other immune cells and are responsible for reducing the incidence of autoimmunity.
Associate Professoressor Alderuccio will use a gene therapy approach and exploit his laboratory’s expertise in manipulating the bone marrow from which all blood (and hence immune) cells are derived. By driving the activity of specific genes in bone marrow cells, he aims to generate regulatory T-cells that will specifically suppress the immune cells associated with the development of experimental autoimmune encephalomyelitis in mice.
If successful, this incubator grant will provide future impetus for the team to progress to preclinical models to determine if transplantation with bone marrow modified with the ability to generate regulatory T cells will be capable of reversing or preventing progression of MS.
Associate Professoressor Alderuccio successfully generated regulatory T cells in the animal models. Analysis of this population demonstrated that the cells did not display all the features of natural regulatory T cells, which raises the issue of the capacity of these cells to be able to suppress the autoimmune reaction. In particular, the generated cells had a much lower level of the signature gene activity (FoxP3) when compared to natural regulatory T cells. This implies there is more about the immune selection process of the cells within the thymus that is not fully understood.
The second part of the study tested whether the generated regulatory T cells were capable of suppressing MS-like disease in the animal models. An earlier experiment demonstrated that while the mice were not fully protected, 50% of a small cohort were resistant to MS-like disease while the control group all succumbed. This was repeated with a larger number of mice. Unfortunately, in the larger experiment, the mice were not protected and all mice developed disease. Therefore, the conclusion is that this method of bone marrow manipulation to produce T regulatory cells is not able to skew cells towards a regulatory function.
Associate Professor Alderuccio’s team are continuing to investigate methods to manipulate the immune system to control auto-immunity.
Updated: 13 June 2013
Updated: 03 January, 2012