Drugs called epigenetic modulators hold promise in treating lupus
SAN ANTONIO (May 19, 2014) — Mechanisms of action in lupus by drugs called epigenetic modulators are the focus of a new three-year, $600,000 grant by the Alliance for Lupus Research to Paolo Casali, M.D., of the School of Medicine at the UT Health Science Center at San Antonio. Only six of these grants are awarded each year.
Systemic lupus erythematosus (SLE) is an autoimmune disease that debilitates half a million to 1.5 million people in the United States, mostly women in their fertile years. Epigenetic modulators, often used in the treatment of lymphomas, may turn out to be useful therapies for lupus, as well.
The body’s immune system usually mounts a defense against viruses, bacteria, parasites and other entities, including tumors. In SLE patients, however, it turns against the body’s own tissues, including the kidneys, lungs, heart, skin, brain and central nervous system. “It’s a generalized attack that systematically destroys the inner core of most cells of the body, including the DNA itself and other constituents of the cellular nuclei,” Dr. Casali said.
Dr. Casali has contributed to fundamental understandings about the immune system abnormalities that occur in SLE. These findings provide a scientific rationale for why epigenetic modulators might be effective in humans. In addition, the Alliance for Lupus Research grant will identify novel targets for new lupus therapeutics. “Our team of investigators has conducted basic science research that has found an immediate translational relevance to a disease, lupus,” Dr. Casali said. “For the first time, mechanisms important to the generation of autoantibodies (the antibodies that attack components of the body) have been identified. We outlined the mechanisms and then looked for drugs that may alter them.”
In a healthy person, infection-fighting cells called B lymphocytes or B cells react to foreign substances (antigens on viruses, bacteria, etc.) by producing antibodies. Such antibodies home in on and neutralize the threats. During an effective immune response, B cells initiate two changes:
• class-switch DNA recombination, which modifies the tail of an antibody to alter its biological effect for a targeted use, and,
• somatic hypermutation, which involves the fast-paced introduction of genetic mutations, enabling the antibody to speedily recognize antigens that it has not previously encountered. “Good vaccines induce both changes,” Dr. Casali said.
The self-aggressive, autoimmune response utilizes the same process, but far beyond healthy parameters. “When you analyze a blood sample from a woman with SLE, you find all kinds of antibodies and, more importantly, autoantibodies,” Dr. Casali said. “The antibody response is dysregulated and widespread.”
Dr. Casali’s studies focus on two enzymes. The first is called activation-induced cytidine deaminase (AID), which is critical for class-switch recombination and somatic hypermutation. The second is B lymphocyte-induced maturation protein-1 (Blimp-1), which is required for B lymphocytes to differentiate into antibody-secreting cells. AID and Blimp-1 are elevated in systemic lupus. Reducing AID and Blimp-1 expression in a mouse model of lupus decreases autoimmunity and improves health, Dr. Casali said. The hormone estrogen and epigenetic factors called microRNAs also play roles in AID and Blimp-1 expression.
“In the Alliance for Lupus Research grant, we will systematically test the ability of different epigenetic modulators to blunt the lupus autoantibody response and ‘prevent/cure’ the disease,” Dr. Casali said. This grant complements and expands the scope of two additional and larger National Institutes of Health research grants that Dr. Casali holds to address the basic molecular and cellular mechanisms of the antibody response in health and disease.
Dr. Casali’s laboratory is part of an integrated immunology research operation that also includes the laboratories of Hong Zan, Ph.D., and Zhenming Xu, Ph.D. Dr. Casali moved to San Antonio from the School of Medicine of the University of California, Irvine in January 2014 as the Zachry Foundation Distinguished Professor and Chairman of the Department of Microbiology and Immunology at the UT Health Science Center.
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