When I started my training, if you wanted to know whether one gene goes up or down, it would take at least a week to figure out for every gene. Now, in one afternoon a scientist in one shot take a look at level of expression of all known genes (about 30,000) of the human body! This revolution in science has allowed for the discovery of new molecular pathways without having to know what one is looking for. So in conditions such as multiple sclerosis, many scientists basically “go fishing” to try to find new genes whose expression correlates with disease. People have even taken it further by being able to assess not only all genes, but also proteins made by the genes (called proteomics), and more recently, like my friend Gabriela Cezar at Stemina does, look for all small molecules (called metabolomics).
These very powerful techniques are beginning to bear their fruits. A recent paper (Schulze-Topphoff et al. Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment tothe central nervous system. Nature Medicine. June 28, 2009) identified that patients with multiple sclerosis, as well as in animals bearing a disease similar to multiple sclerosis (experimental allergic encephalomyelitis) have increased expression of the kinin receptor B1. This receptor is activated by components of the kinin-kallikrein system, which are a group of proteins involved in pain, inflammation, and coagulation of blood.
The investigators found that giving mice developing experimental allergic encephalomyelitis (mouse model of multiple sclerosis) activators of the kinin receptor resulted in less disease, whereas administration of inhibitors of this receptor resulted in acceleration of disease onset. This was demonstrated when the compounds were given before disease onset, but in other experiments even after disease onset.
Manipulation of receptors using small molecules can be tricky business. In other words, it may be that the small molecule receptor activator/inhibitors may have been working through other biological pathways to alter disease course. Therefore, in order to know conclusively whether the kinin receptor B1 is responsible or not for alteration in disease process, the investigators used mice lacking the kinin receptor B1. These mice suffered from accelerated disease, thus suggesting that the receptor is normally involved in controlling the disease.
Expression of the receptor had to be on the T cells in order to mediate protection from disease. It was demonstrated that activation of the kinin receptor B1 selectively suppressed the infiltration of Th17 cells into the central nervous system. Most interestingly suppression of infiltration was limited to Th17, with Th1 cells still infiltrating. One intersting question is whether there is selective expression of the kinin receptor B1 associated with various TCR clonotypes that are expanded in multiple sclerosis progression, as seen in this video describing a paper by Eli Sercarz.
These data suggest a brand new molecule that can be targetted in multiple sclerosis. It also illustrates the power of using “discovery based” approaches. If indeed selective inhibition of Th17 entry into the CNS can be achieved in humans, this may be useful as a synergistic agent with bone marrow or fat stem cell approaches to multiple sclerosis.