By Randolph Fillmore
When Martin Trapecar, Ph.D., an assistant professor in the Division of Endocrinology, Diabetes and Metabolism at the Johns Hopkins University School of Medicine, established The Laboratory of Human Biomimetics at Johns Hopkins All Children’s Hospital in 2021, his first task was to build a dedicated research team to explore the fundamental origins of immune-metabolic diseases.
Now in place, that team is focused on unraveling the causes behind inflammatory bowel disease (IBD), a term used to describe disorders that involve chronic inflammation of the digestive tract and include ulcerative colitis and Crohn's disease, both of which are characterized by inflammation of the lining of the digestive tract and its deeper layers.
Because IBD is increasingly affecting children and adolescents, Trapecar said there is a strong motivation at Johns Hopkins All Children’s for solving some of the biological mysteries behind IBD and its influence on overall health beyond the intestine.
“Many patients develop IBD in childhood or early adolescence, which also significantly affects their well-being into adulthood. There is a strong and urgent motivation to discover why this is happening and, hopefully, find better ways to treat or prevent it,” Trapecar explains.
A $2 million NIH Grant has ‘Opened Doors’
Help in reaching these goals recently arrived when Trapecar and his colleagues received a competitive “Maximizing Investigator’s Research Award” (MIRA) to help facilitate their research. The five-year, $2 million federal grant came from the National Institutes of Health’s (NIH) National Institute of General Medical Sciences (NIGMS), which offers grants to promising early-stage investigators (ESI) conducting research on basic biological processes.
While the full title of the grant — NIH NIGMS ESI MIRA Grant — may sound like “alphabet soup,” the important funding will help them continue to build advanced models of human multi-organ physiology and organ-to-organ “cross-talk.”
Organ ‘Cross-talk’ and the ‘Human-on-a-Chip’ Concept
For some time, to look for possible pathways related to the development of IBD and other inflammatory diseases, Trapecar has been investigating the “gut-liver axis” as it interacts with the immune system under both disease and normal conditions.
To aid in this effort, researchers in the Trapecar lab create models of diseases using a tool called a “human-on-a-chip.” In more technical terms, the technology is called a “microphysiological system” (MPS). Trapecar says MPSs are built using donated human tissue and cells to recreate, in miniature, aspects of complex human biology that are influenced by inter-tissue communication. This technique allows the researchers to re-engineer and apply simplistic versions of disease under highly controlled conditions, then examine how tissues and cells react.
“The MPS technology offers insight into how disruption in the cross-talk between tissues and the immune system can lead to the early emergence of autoimmune disease, such as inflammatory bowel disease and degenerative disorders,” Trapecar explains. “When we recreate disease conditions, we can better understand biology unique to humans as well as stresses and environmental conditions that also can affect tissues and cells.”
MPSs have the potential to revolutionize preclinical research that historically have relied on studies conducted using animal models.
Investigating the World of ‘Unconventional’ T-Cells
Trapecar’s immediate research effort is focused on the role of what he calls a “unconventional T-cell.” He refers to the more recently discovered adaptive immune system cells called “MR1-restricted lymphocytes.” MR1-restricted lymphocytes seem to play a role in a wide variety of immune-related diseases such as autoimmunity and how we respond to pathogens, yet we only recently became aware of their existence.
The immune system’s “conventional” T-cells — perhaps best known to the non-clinical public through their demise in patients with HIV-AIDS — were known only for their ability to bind and respond to peptides (small pieces of proteins). However, MR1 T-cells recognize a completely new class of antigens. Among these are small organic molecules derived from metabolic reactions in our bodies called metabolites that are produced both by our own cells or by bacteria that live within us.
“Until they were discovered, MR1-restricted lymphocytes were hiding in plain sight, with up to 40 percent of all conventional T cells in the liver actually being restricted to MR1. These cells share many of the same characteristics by which we identify them thus it was only with advances in other fields of science that we learned about their existence,” explains Trapecar.
According to Trapecar, unlike conventional T-cells, MR1-restricted lymphocytes have the unique ability to recognize and bind to a number of metabolites.
The discovery of MR1 T-cells has led to their implication in a wide range of disorders, including ulcerative colitis, type 1 diabetes and multiple sclerosis. Because MR1-restricted lymphocytes are found in mucosal and liver tissues, the researchers are interested in the role they might play in IBD and autoimmune liver diseases.
“MR1 lymphocytes are quite diverse, and they comprise several subpopulations that assume different roles in our bodies. Previous studies have discovered connections between their migration and proliferation in several autoimmune disorders but also in tissue repair for example,” Trapecar says. “However, their exact function remains to be established. We are interested in the role they might play in inflammatory disorders of the gut-liver axis. We are also interested in the possible therapeutic potential for engineered MR1-restricted lymphocytes and how these could be harnessed to modulate progression of diseases.”
Building Models of Disease: A ‘Passion with a Purpose’
Supported by the MIRA grant, Trapecar and his colleagues are continuing to develop the next generation of multiorgan microphyisiological systems (MOMPS) using human donor-matched tissue samples to search for relationships between MR1-restricted lymphocytes and the tissues.
“We are passionate about understanding how disruption in tissue-tissue and tissue-immune “cross-talk” leads to the early emergence of immune-metabolic disorders such as IBD,” Trapecar explains.
However, using MOMPS under controlled laboratory conditions, the researchers can better understand the behavior of organ systems and investigate them without the “noise” of uncontrolled factors, such as those from the environment.
“Our goal is to find targets as well as new cell-based approaches for better understanding the fundamental origins of complex diseases,” he adds. “By using these advanced models of human multiorgan physiology— but under controlled conditions — we can reconstruct patients and track the progression of inflammatory diseases that affect multiple organ systems.”
The researchers’ recent work on the gut-liver-brain axis and its relationship to inflammatory diseases such as IBD and Parkinson’s disease suggests that organ systems act differently when interacting with each other as opposed to how they act in isolation, primarily because of metabolic changes and tissue-immune interactions.
“Our model of the gut-liver-cerebral axis offers the opportunity to better understand relationships between systemic alteration of metabolism, immunity and neurodegenerative disease,” Trapecar concludes. “By identifying and understanding these relationships, we can open a wider window for developing therapeutic interventions, regenerative medicine, and tissue engineering.”