Preventing organ transplant rejection

March 17, 2026

Preventing organ transplant rejection

Surgeons perform tens of thousands of organ transplants in the U.S. each year. Many transplant patients experience organ rejection after the procedure. Rejection causes fibrosis, a form of scarring that impairs the new organ's function.

Scientists have long believed that rejection occurs because the transplant recipient's immune system recognizes the new organ as foreign tissue. As a result, the recipient's immune cells attack the new organ.

However, suppressing the immune system doesn't always prevent rejection. Rejection can occur even in organs transplanted between identical twins. In those cases, the transplant shouldn't provoke an immune response since the donor and recipient have the same genes.

An NIH-funded research team, led by Dr. Daniel Kreisel of the Washington University School of Medicine in St. Louis, investigated whether the body's lymphatic system could be a key contributor to organ rejection. Results were published on February 25, 2026, in Science Translational Medicine.

The lymphatic system plays an important role in fighting off infections. It also drains fluid and removes waste materials from our tissues. Unlike with blood vessels, surgeons don't reconnect transplanted organs to the body's lymphatic vessels.

The researchers began by examining transplanted hearts and lungs removed from people due to organ rejection. Those people received a new transplant in its place. The rejected organs showed areas of fibrosis in the same locations as the organs' lymphatic vessels. The team also saw this pattern in hearts and lungs transplanted between genetically identical mice.

Fibrotic areas had abnormal lymphatic vessel structure. They also featured buildup of a substance called hyaluronan, which is a vital part of connective tissues. Hyaluronan depends on the lymphatic system for removal, so it accumulates in places with poor lymphatic drainage.

Certain connective tissue cells in rejected hearts and lungs showed increased activity of the Has1 gene. Has1 produces an enzyme, hyaluronan synthase 1, that makes hyaluronan. The molecule interleukin-1β (IL-1β), produced by certain immune cells, spurred elevated Has1 expression. Blocking the receptor IL-1β binds to, or depleting the cells that make IL-1β, lowered Has1 activity in transplanted mouse lungs.

Transplanted lungs that lacked the IL-1 receptor exhibited less fibrosis and hyaluronan buildup. Blocking the activity of hyaluronan synthase 1 in transplanted lungs had similar effects. So did treatment with a molecule that accelerates growth of lymphatic vessels after transplantation.

The findings suggest that hyaluronan buildup due to poor lymphatic drainage is a cause of chronic transplant rejection. Therapies that reduce hyaluronan production might help prevent rejection. Organ transplants in mice differ in important ways from transplants in humans. Future work will be needed to corroborate the results in animal models that more closely resemble human transplants.

"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," Kreisel says.

- by Brandon Levy

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References

Lymphatic disruption drives lung transplant fibrosis through interleukin-1-mediated hyaluronan accumulation. 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. Sci Transl Med. 2026 Feb 25;18(838):eadu0358. doi: 10.1126/scitranslmed.adu0358. Epub 2026 Feb 25. PMID: 41739903.

Funding

NIH's National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Department of Veterans Affairs; Cystic Fibrosis Foundation; Foundation for Barnes-Jewish Hospital; Leducq Foundation Network; Burroughs Wellcome Fund; Children's Discovery Institute of Washington University and St. Louis Children's Hospital; Chuck and Mary Meyer; Lopker Family Foundation; Scott Ornstein; Richard and Eibhlin Henggeler; Joseph and Lisa Martin; and UMB Foundation.