IBD biobank: Annual checkup

In 2013, Mayo Clinic instituted an inflammatory bowel disease (IBD) serum biobank involving Mayo campuses in Arizona, Florida and Minnesota and the Mayo Clinic Health System. The goal was to use serologic samples from patients with diagnosed ulcerative colitis (UC) or Crohn's disease (CD) to advance biomarker research that might one day improve diagnosis, prognosis and treatment of IBD.

"The potential is enormous, both in terms of our ability to gather large amounts of patient data and to develop ongoing research projects that can further our understanding of this challenging disease," says Jonathan A. Leighton, M.D., who co-leads biobank research with Shabana F. Pasha, M.D., at Mayo Clinic's campus in Scottsdale, Arizona.

There, the focus is on the discovery of new antibodies against human proteins that can serve as potential serologic markers in the management of IBD. The hope is to improve on currently available markers such as anti-Saccharomyces cerevisiae antibodies and perinuclear-staining anti-neutrophil cytoplasmic antibodies. Although sometimes useful for differentiating between UC and Crohn's when clinical, endoscopic and pathological features are atypical or unclear, traditional biomarkers have limited diagnostic value due to low sensitivity and specificity.

To determine the feasibility of this line of research, Mayo investigators undertook a small pilot study with Arizona State University's Biodesign Institute, where Joshua LaBaer, M.D., Ph.D., one of the nation's foremost experts on protein biomarkers, directs the Virginia G. Piper Center for Personalized Diagnostics. Dr. LaBaer's laboratory has developed a novel protein microarray technology — the nucleic acid programmable protein array (NAPPA) — for biomarker discovery in cancer and autoimmune disease.

Dr. Pasha explains: "With the NAPPA technology, protein arrays are manufactured by printing cDNAs and then expressing the proteins at the time of the assay using a cell-free protein expression system. This allows the display of proteins without the need for prior protein purification."

Based on positive data from that study, Mayo researchers in Arizona are now actively working to identify antibodies against human proteins and to determine whether those biomarkers can differentiate between CD patients and healthy controls as well as between aggressive and nonaggressive CD phenotypes.

"NAPPA can generate all 20,000 proteins of the human genome. The samples for the current study will be screened on a set of NAPPA to assess the presence of antibodies against 2,000 randomly selected human proteins," Dr. Pasha explains.

If a noninvasive test could be found to differentiate between aggressive and nonaggressive CD, it would serve as a guide to earlier, more aggressive treatment for high-risk patients and spare those with a lower risk of severe disease the side effects and potential malignancies associated with immunobiological agents. Ideally, biomarkers would also help predict patient response to medications.

"When we look at trials, only about 70 percent of patients respond to any one drug, but we don't know which will work better in which patient. We know that patients with more aggressive disease should be on more aggressive therapy, but knowing which in that subgroup should be on a biologic or immunomodulator would be invaluable," Dr. Leighton says.

The current study phase should be complete by the end of 2015, with a robust set of data expected. "When we have enough patients and enough blood samples, we can begin doing large-scale prospective studies," Dr. Leighton says.

Other collaborations

Mayo biobank samples are also helping advance other projects. In conjunction with Yale University, Arizona researchers are investigating the TAM receptor tyrosine kinases, which affect inflammation and are activated by protein S. Both TAM and protein S appear to down-regulate the immune system and may play a role in the pathogenesis of IBD.

"We're continuing to try to understand the role of protein S in the inflammatory pathway and the progression of IBD. The hope would ultimately be to manipulate this pathway as a therapeutic strategy for inhibiting or enhancing the immune response," Dr. Leighton says. Recent Mayo Clinic research was published in the July 2013 issue of Immunity.

A complex interplay of genetic, environmental and immunological factors leads to the variable phenotypes that present as IBD. This heterogeneity is the primary challenge in IBD research, Dr. Pasha points out. But, she says, it also presents an opportunity for more individualized treatment, the first step toward which is serologic biomarker discovery.

"We have been recruiting for about a year and now have almost 250 patients with Crohn's or ulcerative colitis who have come to our clinic and consented to have blood samples drawn," she says. "I would say the project has been very successful to date. Patients are enthusiastic and look forward to participating because they're excited about the potential of a diagnostic test and new treatments for IBD."

Other biobank investigators

Leading the biobank program at Mayo Clinic's campus in Florida are John R. Cangemi, M.D., and Michael F. Picco, M.D.

In Minnesota, biobank investigators include William A. Faubion, M.D., and Laura E. Raffals, M.D.

Michael D. Van Norstrand, M.D., Ph.D., heads the Mayo Clinic Health System biobank program.

For more information

Carrera Silva EA, et al. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. 2013;30:160.