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.

 

The University of Texas Health Science Center at San Antonio, one of the country’s leading health sciences universities, ranks in the top 3 percent of all institutions worldwide receiving National Institutes of Health funding. The university’s schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced more than 29,000 graduates. The $765 million operating budget supports eight campuses in San Antonio, Laredo, Harlingen and Edinburg. For more information on the many ways “We make lives better®,” visit www.uthscsa.edu.

WHAT:

See the wonder of science on high school students’ faces as they meet a living legend, a Nobel Prize winner whose contributions have changed studies of disease!

WHEN:

A dedicated time for media to cover the student-scientist interaction is 1 to 1:30 p.m. Friday, May 16 (tomorrow). Later in the afternoon, at 3:30, Dr. Chalfie will discuss his science and career in a lecture open to students, parents, teachers and other members of the public.

WHERE:

The Barshop Institute for Longevity and Aging Studies, a research institute of the UT Health Science Center at San Antonio. The Barshop Institute is located at 15355 Lambda Drive, San Antonio, Texas 78245-3207, in the Texas Research Park.

WHO:

Several high school students who participate in the Voelcker Biomedical Research Academy at the UT Health Science Center will have face time with Nobel Laureate Martin Chalfie, Ph.D., of Columbia University.

BACKGROUND:

Dr. Chalfie shared the 2008 Nobel Prize in Chemistry for the discovery and development of the green fluorescent protein, which was first observed in a type of jellyfish. Biologists now routinely use green fluorescent proteins to track the growth and fate of specific cells, such as nerve cells damaged by Alzheimer’s disease.

Voelcker Scholars are outstanding area students who participate in three summers of programming at the Health Science Center. The Voelcker Biomedical Research Academy, made possible by the Max and Minnie Tomerlin Voelcker Fund, places these young scholars in mentors’ laboratories, where they learn how to conduct research and present their own novel findings. It will be a thrill for these students to meet Dr. Chalfie, who is generously giving of his time to perpetuate the science education pipeline.

 

The University of Texas Health Science Center at San Antonio is one of the country’s leading health sciences universities. The university’s schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced more than 31,000 graduates. The $801.8 million operating budget supports six campuses in San Antonio and Laredo. For more information on the many ways “We make lives better®,” visit www.uthscsa.edu.

SAN ANTONIO (May 8, 2014) – Samy Bendjemil, an M.D./M.P.H. student at The University of Texas Health Science Center at San Antonio, has been awarded a 2014-2015 Fulbright U.S. Student Award to set up a community health club in Burkina Faso, a West African country north of Ghana.

The Fulbright Program is the flagship international educational exchange program of the United States. He will represent the United States as a cultural ambassador while he is overseas. Bendjemil said the Fulbright program is unique because it challenges applicants to design a project that brings together different cultures to share their unique skills in order to make a positive impact on the community.

The impetus for Bendjemil’s award and his upcoming work in Burkina Faso began in August 2012 when he attended the General Assembly of the International Federation of Medical Student Associations in Mumbai. At this assembly, Bendjemil met Dr. Moumini Niaone, a doctor with family living in the rural village of Dierma.

“We talked a lot about the health conditions in his country, and the effects that poor sanitation practices and a lack of education have on the burden of disease,” Bendjemil said. “I was deeply impressed with the selfless devotion that Dr. Niaone has to the future of his country and was inspired to take a year off from studies to develop a health education program for his village.”

He laid the groundwork for his Fulbright award last November and December during a global health program in Burkina Faso. With guidance from Ruth E. Berggren, M.D., director of the Center for Medical Humanities & Ethics (CMHE) at the UT Health Science Center, and Jason Rosenfeld, M.P.H., an assistant director at the center, he collected baseline data of hygiene and sanitation through a Knowledge Attitude and Practice Survey, which is an adaptation of surveys used by the CMHE for similar projects in Ethiopia, Haiti and Guatemala. Translations were made into French and Bissa.

Dr. Berggren, who is Bendjemil’s mentor, said, “Samy has worked closely with the Center for Medical Humanities & Ethics ever since he started medical school. It has been our joy to watch him flourish as a developing professional, and to work closely with him through global health, community service learning, and leadership activities in the center’s student advisory council.”
It was a natural for him to incorporate all that he has learned from the center about community engagement and community health clubs into his Fulbright application, she said.

“Samy’s Fulbright is a first for our center, and while his significant achievement will shape the direction of his medical career, it is also tangible evidence of the center’s success in catalyzing scholarship in global health. We are deeply proud of Samy and grateful to the philanthropists and faculty who helped us build the programs that made his achievement possible. We hope this award is the first of many for our global health education program,” Dr. Berggren said.

Through the center, Bendjemil traveled last year to Dierma, a rural village of 3,500. He met with community leaders and members who he found were motivated to learn how they can reduce the incidence of preventable disease.

“Our plan is to implement a community-led health and development program using a community health club model. This model has been successful in impoverished communities of other countries including Haiti, Rwanda and Zimbabwe,” he said. “We will use the survey results for the development of curriculum. We must identify barriers to education, brainstorm solutions to these barriers, and share the importance of education for community development and a better quality of life.”

Bendjemil visited approximately 70 of the 100 compounds in the village. He learned the residents had little knowledge of disease transmission, and there is no concept of proper sanitation and hygiene in Dierma.

“Almost all cooking areas were outside without any barrier from livestock or flies. It was very common to see animals defecating in the eating area. Residents drank and ate from pots with dozens of flies flying between them. Many compounds did not use a latrine, and those that did were used by more than 50 people,” he said.

Access to education, which is an essential component of community development and sustainability, is one of the biggest challenges in the village, Bendjemil said.

“Primary and secondary education in Burkina Faso is not free, and families often cannot afford to send their children to school. The vast majority of people have no concept of why education is important. Our project will blend education promotion into the existing community health club curriculum used by our CMHE and Africa AHEAD (Applied Health, Education and Development) so that participants can discuss the importance of education for their village and identify barriers and solutions.”

This project could not be successful without the support of the community leaders in Burkina Faso, Dr. Niaone and Dr. Nicolas Meda of the University of Ouagadougou, and from the UT Health Science Center, including Dr. Thomas Matthews, assistant dean for students, and Dr. Florence Eddins-Folensbee, vice dean for education, in the School of Medicine Dean’s Office as well as Dr. Berggren and Mr. Rosenfeld from the CMHE, he said.

Bendjemil believes the program will be a first experience in education for many of the village residents. He hopes they will begin to feel empowered by their increased knowledge and begin to recognize the importance of education.

“It has been demonstrated that community-led education and development programs are beneficial in creating sustainable change in rural, impoverished communities,” he explained. “We are all very excited about the potential the community health club model has to reduce the burden of infectious disease in Burkina Faso.”

 

The University of Texas Health Science Center at San Antonio is one of the country’s leading health sciences universities. The university’s schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced more than 31,000 graduates. The $801.8 million operating budget supports six campuses in San Antonio and Laredo. For more information on the many ways “We make lives better®,” visit www.uthscsa.edu.