Experimental MS Therapy: Gift with no Strings Attached
September 18, 2009
Potential MS Therapy Uses Body's Own Cells
Researchers at McGill University in Montreal have developed a novel treatment for experimental autoimmune encephalomyelitis (EAE) in mice, a model of multiple sclerosis (MS), that produces virtually no side effects (Rafei et al. 2009). The treatment works by converting naive B cells into potent suppressive regulatory cells. If proven successful in humans, the treatment promises to be highly personalized — converting a person's own B cells into autoimmune suppressors.
A Surprise GIFT
The treatment depends on the action of GIFT15, a "fusokine" comprised of two artificially fused proteins: granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 15 (IL15). Separately, these two proteins stimulate the immune system; as a fusokine, they suppress it. The research team discovered GIFT15's effects serendipitously. Originally, GIFT15 was engineered to stimulate the immune system and induce tumor rejection in mice; however, proof-of-concept analysis revealed that GIFT15 is a powerful immune suppressor. Rafei and colleagues (2007) demonstrated that the GM-CSF moiety physically alters GIFT15's IL15 domain, leading to aberrant signaling downstream of the IL15 receptor (IL15R).
Gifted Mice Cured of EAE
The researchers wanted to know if the immunosuppressive properties of GIFT15 could stop or reverse autoimmunity. They chose to focus on MS and enlist the help of a bunch of rodents - specifically, JAX® Mice. They found that GIFT15-treated splenic B cells collected from C57BL/6J (B6, 000664) mice generate a novel immunosuppressive population of B cells, which the investigators called GIFT15Breg cells. They found that these cells express major histocompatibility complex class II (MHCII), surface IgM and IgD, secrete interleukin 10 (IL10), and downregulate PAX5 expression (as a result, CD138 is upregulated, and CD19 is suppressed).
Dr. Jacques Galipeau, leader of the team that developed GIFT15 (Photo courtesy of McGill University). |
The research team speculates that GIFT15 might be effective against other autoimmune disorders, including Crohn's disease, lupus, and arthritis. It might also be effective in controlling immune responses to organ transplants. Dr. Jacques Galipeau, leader of the research team that designed GIFT15, states: "Naturally-occurring immune-suppressing B cells, unlike their better-known T cell cousins, are almost unknown in nature, and the notion of using them to control immunity is very new. Although the mice showed no significant side-effects, and the treatment was fully effective with a single dose, GIFT15 must be tested in clinical studies before it is considered safe and effective in humans. It's easy to collect B cells from a patient. It's just like donating blood. We purify them in the lab, treat them with GIFT15 in a petri dish, and give them back to the patient. That's what we did in mice, and that's what we believe we could do in people. It would be very easy to take the next step. It's just a question of finding the financial resources and partnerships to make this a reality" (McGill University 2009).
References
Rafei M, Hsieh J, Zehntner S, Li MY, Forner K, Birman E, Boivin MN, Young YK, Perreault C, Galipeau J. 2009. A granulocyte-macrophage colony-stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties. Nat Med Aug 9. [Epub ahead of print].
Rafei M, Wu JH, Annabi B, Lejeune L, Francois M, Galipeau J. 2007. A GMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex. Blood 109:2234-42.
McGill University. 2009. Multiple sclerosis successfully reversed In mice: new immune-suppressing treatment forces the disease into remission. Science Daily. Retrieved August 14, 2009.
