Immune System Ruse Could Help Treat Multiple Sclerosis

HANOVER, NH � Dartmouth Medical School researchers have developed a promising approach against a spectrum of immune and inflammatory disorders in humans by disrupting a key communications link in the immune system.

In mice, blocking this molecular communicator, called CD40 ligand (CD40L), has prevented or cured multiple sclerosis (MS), arthritis and other autoimmune diseases and has prevented organ transplant rejection. In some cases only a brief treatment with this blocking agent appears to provide long-term protection.

A recent article in the Journal of Clinical Investigation reports the potential for applying the method in MS. The study, which combined efforts of researchers at Northwestern University and Dartmouth Medical School (DMS), found that treatment with an agent (anti CD40L) that blocks the target molecule can help prevent relapses as well as reduce the severity of symptoms in the mouse form of the disease.

One of the authors, Randolph Noelle, PhD, professor of microbiology at DMS, was among the first to identify this CD40 ligand (also known as gp39 or CD154). Noelle has been involved in engineering monoclonal antibodies that bind to this molecule and interfere with its actions.

CD40 ligand molecules serve as communications links in the two arms of the immune response. The ligand, found primarily on the surface of white blood cells known as helper T cells, instructs B cells to produce antibodies. This same ligand can instruct phagocytes, the immune system�s scavengers that engulf and ingest intruder or dead cells, to cause inflammation and tissue destruction.

Normally antibodies fight infections. However, when the checks and balances of the system go askew, these antibodies can destroy the body�s own tissues, resulting in autoimmune or inflammatory diseases. Similar damage can occur if this ligand overactivates phagocytes. Inhibiting this T and B cell interaction and the T and phagocyte interaction can reset the immune system and ameliorate the immune attack against the patient.

While it is unknown what triggers the onset of MS, the disease is considered an immune abnormality that appears to result from an inflammatory invasion of the central nervous system and the degeneration of the myelin sheath surrounding nerve fibers. Experimental autoimmune encephalomyelitis in mice mimics the nerve degeneration of MS and serves as a model for the human disease.

"Therapeutics that target the molecule represent a new generation of substances designed to selectively block the immune response and may initiate remission of MS and other autoimmune diseases," says Noelle.

While the studies in mice are extremely encouraging, Noelle stresses that what works in animal models does not always work in humans, and MS has proved particularly recalcitrant to definitive treatment. "The safety and effectiveness of this class of therapeutics must be rigorously tested before we can say more about their potential value."

The research at DMS has been supported by grants from the NIH and the National Multiple Sclerosis Society.

Dartmouth-Hitchcock Medical Center has begun a Phase I clinical trial to test the safety of a humanized anti-CD40 ligand antibody in patients with multiple sclerosis. Lloyd Kasper, MD, professor of medicine and of microbiology, and William Hickey, MD, professor and chair of pathology, head the trial, together with a team of neurologists and neuroradiologists. If shown to be safe, a Phase II trial is anticipated to begin sometime next year to test if the therapeutic can actually ameliorate MS.

In the recent MS study, mice treated with the monoclonal antibody against CD40L antibody had considerable improvement compared to the untreated controls. There were fewer relapses as well as delayed onset and severity in those that did relapse. The results, the authors said, may also provide clues to the mechanisms of the disease and help to understand how the myelin sheath of nerve cells is infiltrated and destroyed.

The antibody was produced by DMS in collaboration with IDEC Pharmaceuticals of San Diego. Noelle and Dartmouth College have technology licensing agreements with IDEC to develop antibodies for potential use in humans, based on findings in mice systems.

A nationwide study with the Dartmouth/IDEC antibody is also under way at several centers to investigate the antibody's safety and clinical efficacy in patients with active systemic lupus erythematosus. If this therapeutic proves successful in the management of MS and lupus, according to Noelle, it will provide the basis for the use of this drug in the treatment of other autoimmune diseases, like rheumatoid arthritis inflammatory bowel disease, as well as in the rejection of transplanted organs and tissue.

Hali Wickner

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