2003/2004 General Immune System Function
With his Novel Research Grant from the LRI, Dr. Raman set out to test whether interventions to block a protein on the surface of T cells—CD5—can wipe out autoreactive cells and stem disease in mice. He also examined whether T cells from people with lupus are susceptible to this treatment, and will try to develop better drugs for blocking CD5 in humans.
Over the course of his LRI grant, Dr. Raman discovered that CD5 actually does keep T cells alive. In lupus, T cells kick off a 'cascade' of immune reactions that allows the body to 'attack' itself. But, Raman says, “we have discovered that if you block CD5's ability to deliver survival signals, the cell dies and you can re-program the immune system.”
The new research builds on studies in another autoimmune disease, multiple sclerosis, for which Dr. Raman and colleagues found that mice with multiple sclerosis recover if you block CD5.
Blocking CD5 shuts off the over- or auto-reactive immune system and stops the inflammatory response. “In early studies of lupus mouse models, we have seen the same exact results and now we are going to test this in human cells to see if it works out,” he said.
CD5 represents not just a new target but also a new class of drugs. And not just for lupus or multiple sclerosis. “It can absolutely play a role in other autoimmune disease in which T-cell activation is involved,” Dr. Raman explained.
In the future, doctors may be able to give a drug that blocks CD5 “during the course of active disease and it should prevent further organ-damage and maybe then the organ can recover and regenerate,” Dr. Raman said. The new drug may also be useful in combination with other lupus medications to enhance their effects.
“The LRI funding initiated our entrance into active lupus research. My lab is currently active in lupus research as one of the two diseases of focus. The other is multiple sclerosis, another chronic inflammatory autoimmune disease.” – Dr. Raman, 2010
In a 2010 Nature Medicine paper (see below), Dr. Raman and colleagues describe the first biomarker discovered for any chronic inflammatory autoimmune disease that would allow a physician to predict therapeutic approach.
“We believe such a model will be applicable is SLE and is one of the goals of the lab,” Dr. Raman said. “The discovery of the Nature Medicine [also] has the potential to revolutionize treatment for MS. Interferon beta is currently the therapy of first choice in about 60% of MS patients and about a 1/3rd of them do not respond to therapy. The non-responders go through significant discomfort, worsening of disease and unnecessary cost. The discovery will enable physicians to pre-select patients who are most likely to respond to interferon beta therapy. This perhaps is a first step to personalized medicine.”
CD5-CK2 Binding/Activation deficient mice are resistant to EAE: Protection is associated with diminished subpopulations of IL-17 expressing T-cells in the CNS. Axtell, R. C., Xu, L, Barnum, S. R., and Raman, C. 2006. J. Immunol. 177: 8542-8549.
T-helper types 1 and 17 determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis. Axtell, R. C., de Jong, B. A., Boniface, K., van der Voort,, L. F., Bhat, R., De Sarno, P, Naves, R., Han, M., Zhong, F., Castellanos, J. G., Mair, R., Christakos, T., Kolkowitz, I., Katz, L., Killestein, J., Polman, C. H., de Waal Malefyt, R., Steinman, L and Raman, C. 2010. Nat. Medicine. 16:406:412.
Dr. Raman has won both an NIH grant of $1.25 million and a National Multiple Sclerosis Society grant of $450,000 to continue the work that he began with his LRI funding.
Rev. July 2010