Despite advances in the field of organ transplantation, long-term organ rejection that can become apparent a decade or more after a heart or lung transplant remains a common problem for patients. This chronic organ failure has long been attributed exclusively to the recipient's immune system attacking the foreign organ over time.
Now, a study led by researchers at Washington University School of Medicine in St. Louis shows that chronic organ rejection may instead be triggered by the disruption of lymphatic vessels — an important drainage system throughout the body — from the donor organ rather than an attack by the patient's immune system.
The study is published Feb. 25 in Science Translational Medicine. It includes analyses of transplanted human organs with chronic rejection and mouse models of lung and heart transplantation.
The research suggests that disrupted lymphatic drainage starting at the time of the organ's removal from the donor can set off a chain of events that leads to a harmful process called fibrosis, in which scar tissue slowly replaces healthy tissue in the transplanted organ. The study also found that preventing the buildup of sugar molecules in the transplanted organ that are normally drained through lymphatics or restoring lymphatic drainage as quickly as possible after transplant — including with drugs already approved to treat other conditions — could head off the fibrosis before it starts.
Ongoing immunosuppression is necessary to prevent rejection of a donor organ after transplant. Still, many patients develop chronic organ rejection anyway, sometimes after many relatively healthy years. In response, doctors often increase the immunosuppression, but this has proven ineffective — an observation that has long puzzled the field, according to senior author Daniel Kreisel, MD, PhD , the G. Alexander Patterson, MD/Mid-America Transplant Endowed Distinguished Chair in Lung Transplantation at WashU Medicine.
"We have no effective treatment for chronic organ rejection short of re-transplantation, which many patients are not eligible for," said Kreisel, who is also a professor and the vice chair for research in the WashU Medicine Department of Surgery . "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."
Unlike blood vessels, for example, that must be reconnected after transplant, surgeons do not reconnect the donor organ's lymphatic vessels in part because they are not visible to the naked eye, even under magnification. Also, the severed lymphatic vessels are known to heal a few weeks after a transplant.
"Even though the vessels grow back, we now see that the two-to-three-week period of disruption after the transplant is a critical window that can lead to long-term detrimental consequences for the organ," said first author Hailey Shepherd, MD , a WashU Medicine surgical resident who conducted the research in Kreisel's lab. "But this window also creates an opportunity to intervene to help the lymphatics heal and perhaps prevent the chronic damage we see in these rejected organs."
Tracking down the culprit
Seeking clues to chronic rejection, Shepherd took advantage of WashU Medicine's biorepository of human organ samples collected from patients experiencing chronic rejection who went on to receive a second organ. In studying the rejected tissue, Shepherd noticed a pattern: the areas of fibrosis overlapped almost exactly with the lymphatic vasculature. She found evidence that the fibrosis in the human tissue is driven by a damaging buildup of a sugar molecule called hyaluronan. This molecule accumulates in the transplanted organ because of inadequate drainage due to the damaged lymphatic vessels, leading to the fibrosis characteristic of chronic organ failure.
In mouse models of lung transplantation, the researchers identified three possible strategies to help clear the lymphatic vessels of hyaluronan. One strategy blocked the protein responsible for manufacturing hyaluronan, helping keep the vessels unclogged while they were healing. A second strategy stimulated the growth of new lymphatic vasculature, thereby improving hyaluronan drainage by creating more vessels. And a third approach blocked the signal telling specific cells to manufacture more hyaluronan.
All three interventions stopped hyaluronan accumulation and prevented chronic fibrosis in the transplanted mouse lungs. In many cases, the treated transplanted organs were indistinguishable from healthy organs, according to the researchers.
Kreisel and Shepherd emphasized that the team conducted these transplants among genetically identical mice, whose tissues could not generate an immune response against one another. This provides evidence that the fibrosis is independent of immunity against foreign tissues and instead can be caused by the mechanical disruption of the lymphatic vessels alone. While this study was focused on transplanted lungs and hearts, the fact that lymphatic vessels are common to all organs raises the possibility that blocked lymphatic drainage could be a factor in the chronic rejection of any transplanted organ.
The treatment that blocked the protein responsible for manufacturing hyaluronan is called 4-methylumbelliferone (4-MU). It is approved for use in Europe and Asia to treat biliary disorders, conditions that affect the gallbladder. According to the researchers, it has an excellent safety profile and is therefore a promising potential route to evaluating this approach in transplant patients. The strategy to increase growth of lymphatic vessels could be applied locally to the organ before and during transplant, but side effects are not as well known. And the strategy that blocks the signal that triggers the production of hyaluronan would need to be targeted to a specific cell type, making it a more challenging intervention to bring to patients.
In addition to treating the patient after transplant, these strategies could be explored as treatments to administer to the organ itself, when it's stored in solution and awaiting transplant. Unlike immunosuppressive drugs, which must be taken for life, such lymphatic-related treatments should theoretically be able to end after healthy lymphatic drainage is restored.
Kreisel is a leading surgeon-scientist and expert in lung transplantation and in particular in understanding immune responses after lung transplantation. He and Shepherd credited their WashU Medicine colleagues with providing the additional expertise required to put all the pieces of this discovery together. Co-author Gwendalyn J. Randolph, PhD , the Emil R. Unanue Professor of Pathology & Immunology, is a world leader in immunobiology and lymphatic system research and provided expertise on the lymphatic elements of the study; and Kory J. Lavine, MD, PhD , the Alan A. and Edith L. Wolff Professor of Cardiology, is a leading heart transplant cardiologist and cardiac immunologist who provided expertise in evaluating the heart transplantation elements of the study. The study used advanced techniques of lung and heart transplantation in mice, many of which have been developed or refined by co-author Wenjun Li, MD , a professor of surgery and the director of the microsurgery core.
"WashU Medicine provides an extraordinary environment for collaboration — none of these discoveries would have been possible had any of our colleagues and their expertise been absent," Shepherd said.
Added Kreisel: "Dr. Shepherd took a lot of initiative on this study, bringing these key people and analyses together. Our challenge now is to define the best next step to take it to the clinical setting for our patients."
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Shepherd HM, Li W, Kopecky BJ, Terada Y, Liu CR, Liu Z, Lee DD, Mineura K, Dun H, Yokoyama Y, Wong BW, Kurtoglu GK, Amrute JM, Scozzi D, Bai YZ, Bery AI, Bernadt CT, Ritter JH, Brody SL, Byers DE, Krupnick AS, Nava RG, Patterson GA, Puri V, Gelman AE, Lavine KJ, Randolph GJ, Kreisel D. Lymphatic disruption drives lung transplant fibrosis through interleukin-1-mediated hyaluronan accumulation. Science Translational Medicine. Feb. 25, 2026. DOI: 10.1126/scitranslmed.adu0358
This work was supported by National Institutes of Health (NIH), grant numbers P01AI116501, R01HL094601, T32HL007081, DP1DK130660, P30AR073752, R35HL161185, R01HL166402 and R01AI145108; a Cystic Fibrosis Foundation grant, number KREISE24AB0-CLAD; a Department of Veterans Affairs grant, number 1I01BX002730; the Foundation for Barnes-Jewish Hospital; a Leducq Foundation Network grant, number 20CVD02; the Burroughs Wellcome Fund, grant number 1014782; and the Children's Discovery Institute of Washington University and St. Louis Children's Hospital, grant number PM-LI-2019-829. Support was also provided by Chuck and Mary Meyer; the Lopker Family Foundation; Scott Ornstein; Richard and Eibhlin Henggeler; Joseph and Lisa Martin; and the UMB Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
About WashU Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with more than 3,000 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 83% since 2016. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently among the top five in the country, with more than 2,000 faculty physicians practicing at 130 locations. WashU Medicine physicians exclusively staff Barnes-Jewish and St. Louis Children's hospitals — the academic hospitals of BJC HealthCare — and Siteman Cancer Center , a partnership between BJC HealthCare and WashU Medicine and the only National Cancer Institute-designated comprehensive cancer center in Missouri. WashU Medicine physicians also treat patients at BJC's community hospitals in our region. With a storied history in MD/PhD training, WashU Medicine recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
