The aim of this project is to develop immune-modulating peptides (small protein fragments) that will specifically inhibit immune responses against the most abundant myelin protein in the central nervous system, myelin proteolipid protein (PLP). Dr Greer and colleagues have recently found that PLP comes under immune attack in people whose MS affects the parts of the brain that control functions such as balance. Dr Greer believes that the immune-modulating peptides will be able to specifically prevent damage to these areas of the brain, without causing unwanted side-effects.
An optimal immunomodulatory therapy for MS would target only those cells that are causing the damage in MS and have no effect on other cells. None of the currently available therapeutic agents have this ability. A major limiting factor in the development of such therapies has been that to use them effectively requires knowledge of the appropriate antigens to target in different individuals. Dr Greer may be one step closer to being able to do this in people who carry particular versions of the immune system gene, HLA and who develop brainstem and cerebellar lesions. Dr Greer’s team have recently identified a particular peptide within PLP as a region under attack in these people with MS.
Dr Greer’s team have also developed a laboratory model whereby injection of certain peptides leads to development of lesions that are largely restricted to the brainstem and cerebellum. Because the self-directed activity of the immune system (autoreactivity) to this region of PLP appears to be tied closely to an easily recognizable clinical feature of MS, modified peptides have good potential for clinical use. They could easily be targeted for treatment of patients showing appropriate clinical signs, carrying the relevant HLA molecules and MRI brainstem or cerebellar lesions.
Dr Greer and her colleagues are developing new therapeutic agents that will specifically inhibit immune responses that target PLP. To use these therapeutic agents in a specific manner, the first step is to determine which particular part of the PLP protein is attacked in people who carry different HLA molecules. These HLA molecules regulate which parts of the protein can be recognized by a person’s immune system.
So far, Dr Greer has identified the HLA molecules that seem to be important in people with MS who develop lesions in the parts of the brain that control functions such as balance, and has found which parts of the PLP protein are targeted by the different HLA molecules. They then went on to use this information to develop experimental compounds that may be able to prevent the pro-inflammatory immune responses that normally occur when PLP comes into contact with the immune cells of a person with MS. The team have now started the thorough testing of these therapeutic peptides in pre-clinical assays.
In addition, using a laboratory model of MS, Dr Greer has developed a simple way to modify the therapeutic peptides to make them work much more effectively. Typically, peptides do not make very good therapeutic agents because they are quickly broken down in the body and do not get to the correct type of immune cells to induce a strong protective response. With the modification that has been developed during this project, the peptides last much longer in the blood and they are targeted directly to the correct type of immune cells. In the laboratory model of MS the modified therapeutic peptides are much better at reducing the signs of disease than are peptides that have not been modified. This knowledge can now be applied to the development of therapeutic peptides for testing in humans.
Dr Greer has two publications in scientific journals currently underway (please see below for details).
* Moxey NC, Trifilieff E, Beino W, Sauer ELC, Greer JM. Enhancing antigen-specific immunoregulatory effects of therapeutic peptides via thioacylation of the peptides.
* Sauer ELC, Moxey NC, Greer JM. Modified peptides as specific therapeutic agents for autoimmune diseases.
Updated: 06 January, 2009