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Date: 27.05.2010
From: maz.aust

Subject: Research into RA by the Garvin Institute

Inflammation is a key process in the development of rheumatoid arthritis, and it is this mechanism that Garvan scientists are working on to further understand rheumatoid arthritis. Inflammation is a sign that the bodyâs protective mechanisms are at work: nearby blood capillaries are swelling, and fluid and immune cells are moving into damaged tissue in an effort to contain infection. However, when immune cells become overactive, such as with rheumatoid arthritis, too many move from the suffererâs blood into the damaged tissue, exacerbating the condition.

Our researchers are dissecting the immune cellsâ signalling pathways, to find points of intervention that may help control inflammatory conditions, such as rheumatoid arthritis. Professor Charles Mackay and team recently developed an antibody that blocks the action of one of the most important inflammatory molecules, called C5a, from guiding inflammatory cells into tissue by binding to the cell surface receptor, called C5aR. It is anticipated that a therapy based around C5aR will be a significant improvement over current anti-inflammatory therapies, such as TNF-alpha blockers, because it acts at a different and earlier point in the inflammatory process. Garvanâs C5aR antibody has already been used to completely reverse disease in mice with rheumatoid arthritis. In addition to treating rheumatoid arthritis, the new therapy may also be beneficial for psoriasis, sepsis, heart attack and transplant patients. A research, development and licensing agreement with Danish healthcare company Novo Nordisk will enable the therapy to proceed to human clinical trials.

In another project, we have discovered an enzyme that is part of the MAP kinase (MAPK) pathway and which is made only by immune cells. Investigating the role of this enzyme may deepen our understanding of numerous inflammatory conditions, including rheumatoid arthritis, asthma and multiple sclerosis. The MAPK pathway is one of the most important Îsensorsâ found in our body cells. It transmits danger and environmental signals to cells, such as the presence of bacteria, and these signals are turned into actions. For example, the cell may be told to undergo apoptosis (self destruction that helps to eliminate harmful cells) or to release inflammatory factors. The chief regulators of the MAPK pathways are enzymes called dual specificity phosphatases (DUSPs). Different tissues contain different DUSPs, allowing cells to have specific responses. More than ten DUSPs have been discovered in various tissues but our enzyme, Pac-1, is the only one restricted to the immune system. The clue to its importance comes from the fact that it is found in very high levels in immune cells and its production is tightly regulated. We want to know what happens when Pac-1 is prevented from acting in immune cells. We will study this using mice that are genetically deficient in Pac-1.

Garvanâs Autoimmunity Research Unit, lead by Professor Fabienne Mackay, is investigating the role of the B cell activating factor (BAFF) in rheumatoid arthritis. Without BAFF, humans are unable to make antibodies and are therefore immuno-suppressed. When there is too much BAFF, dangerous types of B cells live longer than they should and can damage healthy tissue. There are high levels of BAFF in inflamed tissue and serum from patients with autoimmune diseases, including rheumatoid arthritis. BAFF blockers, some of which are in clinical trials, have been shown to be effective in rheumatoid arthritis.

Another area of research relates to T cells and how they are affected when people are stressed. A collaboration with the Garvan Neuroscience program has enabled autoimmunity researchers to dissect the link between nerve signalling molecules released during stress, the function of T cells and the impairment of the immune system. When the body is stressed, nerves release much more neuropeptide Y (NPY) than normal. NPY gets into the bloodstream, where it inhibits the cells in the immune system that look out for and destroy pathogens (bacteria and viruses) in the body. Under normal conditions, circulating immune cells produce small amounts of NPY, enabling the immune cells to operate. However, too much NPY means the T cells are prevented from destroying pathogens. Understanding the connection between NPY and the immune system enables the exploitation of the T cell inhibitory mechanism to prevent immune responses getting out of control, as in inflammatory and autoimmune diseases such as rheumatoid arthritis, Crohnâs disease, multiple sclerosis, type I diabetes and lupus. Many other receptors (and the molecules that bind to them) may also play a part in regulation of the immune system. Our next challenge is to fully understand the circumstances of NPY release and its effect on immune cells.
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