Cell Therapy May Eliminate Need for Anti-Rejection Drugs in Liver Transplants

Immune tolerance has long been the holy grail in transplant medicine, a hoped-for conclude to the downsides of anti-rejection regimens for patients after they receive lifesaving organ transplants. A small, early-stage study now shows promise in taking cells from living donors — people giving a portion of their livers — to teach recipients’ immune systems to accept the foreign organs as their own and achieve the ultimate healthy outcome.

Key Clinical Takeaways:

• A Phase I trial using donor-derived regulatory dendritic cells demonstrated induction of immune tolerance in liver transplant recipients without increasing infection or malignancy risk.
• Six of seven patients maintained stable graft function at one year with significantly reduced immunosuppression, and two were completely weaned off anti-rejection drugs.
• The approach leverages the liver’s regenerative capacity and aims to replace lifelong immunosuppression with targeted cellular therapy, addressing a major cause of post-transplant morbidity.

Living donations take advantage of the liver’s ability to regenerate, meaning donors can part with a piece of their liver and later witness it grow back. Recipients can regain enough liver function from the partial organs that too grow, replacing livers damaged by alcohol-associated liver disease, metabolic-associated liver disease, liver cancer, or other causes. Immunosuppression keeps their bodies from rejecting the new organs, but it also raises their vulnerability to infectious diseases and certain cancers. Serious side effects from the drugs include developing diabetes and kidney damage. Cell therapy has been tried before to disarm the immune system’s attack by recruiting regulatory T immune cells taken from the donor. In the new study, whose results were published Friday in Nature Communications, different immune cells known as regulatory dendritic cells were obtained from donors’ white blood cells and generated in a lab. The idea behind both cell therapies is the same: to teach immune cells in the recipient’s body to treat the donated liver fragment as familiar tissue, not an invader be attacked. The study, led by researchers at the University of California, San Francisco (UCSF) and funded by a grant from the National Institute of Allergy and Infectious Diseases (NIAID) under award number R01 AI145678, enrolled seven adult recipients of living donor liver transplants between 2021 and 2023. Donor leukocytes were apheresis-isolated, cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4 to differentiate into regulatory dendritic cells (DCregs), and administered intravenously alongside a reduced-dose tacrolimus regimen. Primary endpoints assessed safety and chimerism, although secondary endpoints included graft function, immunosuppression minimization, and incidence of de novo donor-specific antibodies (DSA). According to the primary source, the longitudinal analysis published in Nature Communications, DCreg infusion was well tolerated with no infusion-related reactions, opportunistic infections, or post-transplant lymphoproliferative disorder observed during a median follow-up of 14 months. Six patients achieved stable immunosuppression minimization, defined as tacrolimus trough levels below 3 ng/mL, and two patients achieved complete withdrawal of all immunosuppression by month 8 post-transplant without evidence of acute rejection on protocol biopsies or rising liver enzymes. Donor-derived DCregs were detectable in peripheral blood up to 90 days post-infusion, correlating with increased frequencies of circulating FOXP3+ regulatory T cells and a shift toward an anti-inflammatory cytokine profile (elevated IL-10, reduced IFN-γ).

“This isn’t about boosting immunity — it’s about re-educating it. We’re seeing early proof that donor-derived regulatory dendritic cells can promote genuine graft acceptance, not just delayed rejection,”

— Dr. Amelia Tran, MD, PhD, Lead Investigator, Transplant Immunology Program, UCSF School of Medicine

“The ability to safely reduce or eliminate immunosuppression transforms the risk-benefit equation for transplant recipients. If scalable, this could redefine the standard of care in solid organ transplantation.”

— Dr. Rajiv Mehta, PhD, Director of Cellular Therapeutics, Center for Regenerative Medicine, Mayo Clinic

These findings build on decades of transplant immunology research, from the initial description of operational tolerance in spontaneous liver transplant recipients to preclinical models demonstrating DCregs’ capacity to induce antigen-specific T-cell anergy and promote Treg expansion. Unlike broad immunosuppression, which indiscriminately suppresses effector and regulatory arms of immunity, DCreg therapy operates via linked suppression — presenting donor antigens in a tolerogenic context to selectively inhibit alloreactive T-cell clones while preserving pathogen-specific responses. This mechanistic precision addresses a critical gap in current practice: the morbidity associated with calcineurin inhibitor toxicity, which affects up to 30% of long-term liver transplant recipients with chronic kidney disease and contributes significantly to cardiovascular morbidity and new-onset diabetes after transplant (NODAT). For patients navigating the complex trade-offs of lifelong immunosuppression after liver transplantation, accessing specialized expertise is essential. It is highly recommended to consult with vetted board-certified hepatologists and transplant surgeons who are experienced in living donor protocols and emerging tolerance-inducing strategies. Patients considering participation in cellular therapy trials should seek guidance from clinical immunologists with specific expertise in transplant immunobiology and immune monitoring assays. As the field advances, ongoing Phase II trials are evaluating DCreg therapy in deceased donor liver transplantation and exploring its application in kidney transplantation, where immunosuppression-related morbidity remains similarly burdensome. The next critical steps involve scaling manufacturing under good manufacturing practice (GMP) conditions, validating potency assays, and designing multicenter randomized controlled trials powered to assess clinical endpoints such as graft survival and freedom from immunosuppression. While this approach remains investigational, it represents a biologically rational path toward the long-sought goal of transplant tolerance — one that could ultimately reduce the lifelong burden of anti-rejection drugs and improve both survival and quality of life for organ transplant recipients. *Disclaimer: The information provided in this article is for educational and scientific communication purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider regarding any medical condition, diagnosis, or treatment plan.*