Mayo Clinic researchers have developed a new method to identify which proteins are most likely to trigger an immune response. This discovery could help improve transplant medicine, regenerative medicine, and other fields in which the immune system plays an important role. The result is biomaterials, They challenge the field’s common assumption that all proteins are equally likely to trigger an immune response.
Some proteins can cause very strong reactions even when only small amounts are left, while others are less of a problem. This provides a clearer roadmap for designing safer and more durable biomaterials. ”
Dr. Lee Griffiths, MRCVS, senior author of the study, Mayo Clinic researcher
The researchers’ 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 most to least immunogenic and reveal which are most important.
Researchers call this measurement the immunogenicity ratio (ROI). Applying this to hundreds of proteins revealed patterns that had not been clearly recognized before.
One of the most impressive discoveries involved mitochondria, the structures within cells best known for producing energy. The study found that mitochondrial proteins are much more likely to trigger a strong immune response than proteins in other parts of the cell, accounting for more than a quarter of the most immunogenic proteins identified. Mitochondria likely evolved from ancient bacteria, and their evolutionary history may help explain why the immune system appears particularly sensitive when exposed to mitochondria.
“We believe that the body has never fully accepted mitochondria as part of itself. Normally, mitochondria are hidden within cells, and even when exposed, the immune system can still recognize them as foreign,” says Dr. Griffiths.
Its impact extends beyond tissue engineering. Researchers say the same strategy could help identify the most important immune targets in organ transplantation, infectious diseases, and cancer biology. In transplants, for example, ranking the most immunogenic proteins could ultimately help scientists detect rejection earlier or develop better biomarkers to guide more targeted treatments.
This effort also aligns with Mayo Clinic’s Genesis strategic commitment to advancing the science necessary to create the next generation of regenerative medicine products. Dr. Griffith’s lab is already using these insights to purify engineered tissues for clinical use, with the aim of removing proteins most likely to trigger harmful immune responses while preserving the structures necessary for healing and integration.
“This study fills an important gap in knowledge,” Dr. Griffiths said. “If we want to build truly safe and effective regenerative therapies and implants, we need to understand not just that the immune system is responding, but what exactly it is responding to. That understanding will help us deliver better products to patients.”
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Reference magazines:
NA Short Read, LG Griffiths (2026). Immunogenicity ratio: A quantitative metric to identify highly immunogenic protein antigens to improve tissue-engineered biomaterials. biomaterial. DOI: 10.1016/j.biomaterials.2026.124134https://www.sciencedirect.com/science/article/abs/pii/S0142961226001584?via%3Dihub
