Lymphatic Disruption After Transplant Drives Chronic Organ Rejection, Study Finds
When a surgeon removes a donor heart or lung for transplant, something invisible also gets severed: a fine web of lymphatic vessels that drain the organ's interstitial fluid. Those vessels grow back within a few weeks. But according to a study published February 25 in Science Translational Medicine, the damage done during that brief window can set chronic rejection in motion - without any help from the immune system at all.
The finding challenges a foundational assumption in transplant medicine. For decades, clinicians attributed long-term organ failure almost entirely to the recipient's immune response slowly attacking foreign tissue. Immunosuppression is therefore prescribed for life. Yet many patients develop progressive scarring - technically called fibrosis - anyway, and increasing immunosuppression does not stop it. That clinical puzzle is what led the Washington University School of Medicine team to look elsewhere.
A pattern in discarded tissue
Surgical resident Hailey Shepherd, MD, began by examining WashU Medicine's biorepository of human tissue collected from patients undergoing re-transplantation due to chronic failure. Looking at rejected lungs and hearts, she noticed that areas of fibrosis mapped almost exactly onto the lymphatic vasculature. The overlap was not subtle.
She then identified the likely culprit: hyaluronan, a sugar molecule normally cleared from tissues by the lymphatic system. When lymphatic drainage is disrupted, hyaluronan accumulates. In sufficient concentrations it drives fibrosis. The molecule had previously been associated with tissue damage in other contexts, but its role in transplant rejection had not been described.
To test whether this mechanism could operate independently of immune responses, the team turned to mouse models of lung and heart transplantation. Critically, they transplanted organs between genetically identical mice - meaning no immune reaction against foreign tissue was possible. Even so, chronic fibrosis developed. That result is direct evidence that lymphatic disruption alone is sufficient to cause the scarring that clinicians have been attributing to immunity.
Three interventions, all effective
The researchers then tested three separate strategies for preventing hyaluronan buildup during the critical post-transplant window. The first blocked HAS2, the protein responsible for manufacturing hyaluronan, keeping vessel capacity unimpaired while new lymphatics grew. The second stimulated the formation of new lymphatic vessels, expanding the system's drainage capacity. The third blocked the interleukin-1 signaling pathway that triggers specific cells to produce hyaluronan in the first place.
All three prevented fibrosis. In many treated animals, the transplanted organs were histologically indistinguishable from healthy tissue - a striking result for a model that reliably produces chronic rejection without intervention.
The most immediately translatable option is a compound called 4-methylumbelliferone, or 4-MU. It is already approved in Europe and Asia to treat biliary disorders affecting the gallbladder and has an established safety profile. The lymphatic-growth strategy could potentially be applied directly to an organ during cold storage before transplant, though its systemic side effects are less well characterized. The IL-1 pathway approach would require targeted delivery to specific cell types, making clinical translation more complex.
Why surgeons do not reconnect lymphatics
Transplant surgeons meticulously reconnect blood vessels during the procedure. Lymphatic vessels, by contrast, are too fine to see with the naked eye even under magnification, and they were long assumed to regenerate harmlessly on their own. They do regenerate - but this study shows that the 2-to-3-week gap before reconnection carries lasting consequences.
Senior author Daniel Kreisel, MD, PhD, noted that chronic rejection currently has no effective treatment short of re-transplantation, which many patients cannot undergo. "We are excited about this study because it reveals a previously unknown cause of chronic rejection that is independent of the immune response against foreign tissue, and our data show it may be treatable," he said.
Scope and limitations
The study combined analysis of human tissue from the biorepository with mouse models of both lung and heart transplantation. Because lymphatic vessels are present in every organ in the body, the researchers suggest blocked lymphatic drainage could contribute to chronic rejection across all transplanted organs - not only lungs and hearts.
Important caveats apply. The mouse experiments used genetically identical animals, which eliminates immune rejection but does not replicate the full complexity of clinical transplantation. Human transplants involve ongoing immunosuppression, immune mismatches, and variable donor organ quality. The human tissue analysis was observational and drawn from a single institutional biorepository. Prospective clinical studies will be needed to establish whether these interventions benefit patients.