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Rheumatoid Arthritis: Future Therapies

If you look in the textbooks most autoimmune diseases have high affinity antibodies and auto-reactive T cells that are directly against a specific cell antigen. Yet, despite many many years of trying no diagnostic hike in the autoantibodies have been discovered. Nor have there been T cells found that are specific to patients and not present in normals. Certainly there is no transfer of IgG across the placenta, no evidence that the disease could be mediated. Finally, there is, despite some evidence - maybe one way or another - relative in that inadequacy of depleting anti-T cell therapies, and I actually spent a long time working on this myself with a drug that we had developed, which was very effective in leukemia, but in rheumatoid arthritis really had no clinical effect.

Now the second aspect: one would expect that this massive activation of the antigen-presenting cells and a prolonged activation and imprinting would certainly be a predisposition to stimulation of both T and B cells if those cells go into the joints. Iím going to talk now about how rheumatoid factor can do exactly the same thing. We now know is that genes and coding this autoantibody are not disease-specific but are present in everybody and they are actually conserved in all the different ethnic groups around the world. They are expressed at very high frequency - for instance in fetal spleen - the first trimester of life. And the cells that bear the specificity are very frequent among the mantle zone B cells in normal people who do not secrete the autoantibody. Their main function is in antigen presentation. Each one of these genes has an antibody against its gene product, which is called an idiotype. This is the basis for the idiotypic antigens. So an idiotypic marker can be used in pathological studies of people to determine the gene expression and presumably the autoantibody expression.

This is differences in normal consult from a child, and the red spots are the idiotype reactivity identifying rheumatoid factor cells. You will notice that they are in this mantle zone region. This is where draining lymphatics deposit antigen during infection. In fact, in experiments done a long time ago, if you just immunize a subject with tetanus toxoid, thatís a recall antigen so they will form small amounts of immunocomplex.

Mucosal vaccination, I still think has a role. The fact that we see these very robust responses to these bacterial and viral antigens in the joints, mean that the antigen is accessible to the systemic immune system and I think one idea of mucosal vaccination is not to induce some magic suppresser cell or something but simply to prevent access of the antigen to the systemic immune system by stimulating local antibody production. As I told you, most normal people have abundant antibodies to these proteins but they donít have T cell responses. So if you could increase that antibody production, presumably you would prevent the antigen from getting access to T cells and that might prevent the continued activation on those reactive follicles. By giving patients with rheumatoid arthritis a DNA-J protein peptide and looking at T cell proliferative responses. And it certainly has shown, particularly at higher doses of the peptide, you can reduce the proliferation. That is indicated here. There are different times after the initiation of therapy, at two different doses and this is just proliferation. Whether or not this will translate into clinical improvement is not clear. I certainly would not believe that this could ever be used alone again as a single agent to treat patients. But certainly limited the access of antigens to these reactive joints is something that is fairly harmless and could be of additional benefit.

Not much work has been done on agents that perturb the migration of the bone marrow-derived antigen-presenting cells and inflammatory cells into the joints. This is probably how the TNF antibody primarily works. But there may be a lot of other approaches to this, and I am particularly interested in maybe small molecules that alter the homing properties of leukocytes, because just a small change in the ability of cells to migrate across the endothelium and into the joint would probably have a very very marked effect on disease.

Finally, I think, as far as I know there is nothing being done with agents that interfere with the function of the immature fibroblasts like mesenchymal cells. I think the use of anti-proliferative agents in this situation is counter productive because the more you kill these cells, the more immature cells grow in and make things worse. What we need to do is create a barrier. To cause cells to differentiate but not die and this should then feed back and prevent the further expansion of the pannus. This could perhaps be done by neutralization or antagonism of mesenchymal growth and activation factors and perhaps by drugs and hormones that induce terminal differentiation. In fact, we donít know what will induce terminal differentiation of these cells.

In one system at least in proliferating neuroma cells the P-16 senescence marker, shown here, could be induced by a combination of vitamin D and retinoic acid without killing the cells, but leading to their terminal differentiation and enabling them to survive but without growing. These are not the agents that induce the terminal differentiation of the immature mesenchymal stem cells, but one would certainly think that this kind of approach would be feasible and the efficacy of the P-16 and the P-21 gene therapy in animal models of arthritis is a biological verification of this approach.

So I tried to give you an overview of what I understand as rheumatoid arthritis, as a disease of abnormal activation of the joints that go through several stages, each of which require different approaches to treatment. I think the future is actually very bright for treatment of disease, not by one magic bullet but by a combination of drugs.