New method identifies key proteins that trigger harmful immune responses

Mayo Clinic researchers have developed a new method to identify which proteins are most likely to trigger an immune response - a discovery that could help improve transplant care, regenerative medicine and other areas where the immune system plays a critical role. The results, published in Biomaterials, challenge a common assumption in the field that all proteins are equally likely to provoke immune reactions.

Some proteins can trigger a very strong response even when only tiny amounts remain, while others are much less troublesome. That gives us a much clearer roadmap for designing safer, more durable biomaterials."

Leigh Griffiths, Ph.D., MRCVS, senior author of the study and researcher at Mayo Clinic

The team's approach combines two factors: how much of each protein is present and how strongly it activates the immune system. By integrating these measurements, researchers can rank proteins from the most immunogenic to the least, revealing which ones matter most.

The researchers call this measurement the Ratio of Immunogenicity, or ROI. Applying it across hundreds of proteins revealed patterns that had not been clearly recognized before.

One of the most striking findings involved mitochondria - structures inside cells best known for producing energy. The study found that mitochondrial proteins were far more likely to evoke strong immune responses than proteins from other parts of the cell, accounting for more than a quarter of the most immunogenic proteins identified. Mitochondria likely evolved from ancient bacteria, and that evolutionary history may help explain why the immune system appears especially sensitive to them when they are exposed.

"We think the body has never fully accepted mitochondria as part of itself - they're normally hidden inside the cell, and when they're exposed, the immune system may still recognize them as foreign," says Dr. Griffiths.

The implications extend beyond tissue engineering. The researchers say the same strategy could help identify the most important immune targets in organ transplantation, infectious diseases and cancer biology. In transplantation, for example, ranking the most immunogenic proteins could eventually help scientists develop better biomarkers to detect rejection earlier or guide more targeted therapies.

The work also aligns with Mayo Clinic's Genesis strategic initiative by advancing the science needed to create next-generation regenerative medicine products. Dr. Griffiths' laboratory is already using these insights to refine engineered tissues intended for clinical use, with the goal of removing the proteins most likely to cause harmful immune reactions while preserving the structure needed for healing and integration.

"This study fills a critical gap in knowledge," Dr. Griffiths says. "If we want to build regenerative therapies and implants that are truly safe and effective, we need to understand not just that the immune system is reacting, but what exactly it is reacting to. That understanding is what will help move better products to patients."