Early-Phase Clinical Trial: Pretransplant Infusion of Living Donor’s Immune Cells and Staged Immunosuppression Withdrawal in Living-Donor Liver Transplant Recipients

UPMC and University of Pittsburgh experts led a first-in-human phase I/IIa clinical trial demonstrating the safety, feasibility, and preliminary evidence supporting a novel pretransplant immune priming process and posttransplant staged immunosuppression withdrawal for adult, low risk living-donor liver transplant recipients. This approach could help reduce or eliminate the need for lifelong immunosuppression in a subset of liver transplant recipients.

"This trial is an important initial step in the evaluation of a very promising novel form of regulatory immune cell therapy in liver transplantation that has been developed at the Starzl Transplantation Institute,” says Angus W. Thomson, PhD, DSc, Distinguished Professor of Surgery and Immunology, professor, clinical and translational science, Department of Surgery, University of Pittsburgh School of Medicine, and study co-author. The study, titled “Donor-Derived Regulatory Dendritic Cell Infusion and Early Immunosuppressive Drug Withdrawal in Living-Donor Liver Transplantation: A Phase I/IIa Trial,” was published in Nature Communications in April 2026.

The living-liver donor’s regulatory dendritic cells (specialized cells that suppress immune response) were infused into the living-donor liver transplant recipient one week before their transplant. 12 months posttransplant, recipients whose liver biopsies did not show evidence of T-cell mediated rejection began staged immunosuppressant withdrawal. 3 of 8 (37.5%) eligible participants achieved complete immunosuppression withdrawal and remained off immunosuppressants without experiencing graft rejection three years post-withdrawal.

Long-term immunosuppression benefits liver transplant recipients by protecting graft function and preventing graft loss. But long-term immunosuppression use is also associated with a cascade of potential negative effects on cardiovascular and renal health, as well as high financial costs and increased risk of infection.

The transplant field has explored the role of regulatory immune cells in promoting allograft tolerance through animal studies and clinical observations. There have also been early-phase clinical trials of the regulatory T-cell as a tool to promote donor-specific tolerance in liver and kidney transplant recipients, but T-cell efficacy has not been confirmed. This clinical trial explores an alternative to regulatory T-cells: regulatory dendritic cells.

In the healthy steady state, regulatory dendritic cells circulate through the body’s tissue, collect antigens, and present them to T-cells. These cells manage the body’s immune response, promoting and suppressing T-cell activity against both self and non-self-antigens. Regulatory dendritic cells inherently express major histocompatibility complex (MHC) class II molecules which bind antigens, allowing them to be presented to T-cells. Regulatory dendritic cells also regulate memory T-cells which react to human leukocyte antigens (HLA) and undermine long-term allograft tolerance.

Prior to this trial, a primate kidney transplant model indicated that one pretransplant infusion of donor-derived regulatory dendritic cells could safely help to prevent allograft loss without leading to host sensitization to donor antigens.

Participants

16 donor-recipient pairs were initially enrolled in the study.

3 recipients were excluded from the study in its first year, either before and after donor-derived regulatory dendritic cells (ddDCreg) infusion.

• 1 recipient was excluded before ddDCreg infusion due to positive crossmatch.
• 2 additional recipients were excluded after ddDCreg infusion. 1 recipient was excluded due to the discovery of mucinous adenocarcinoma during transplant. The second recipient experienced spontaneous pontine hemorrhage and died 14 days posttransplant.

13 recipient-donor pairs were included in the clinical trial’s analysis and reporting.

The living-donor liver transplant recipients were adult patients deemed “low-risk.” Their mean Model for End-Stage Liver Disease score was 12 (interquartile range 8-16), indicating that this cohort has relatively low MELD scores, as MELD scores range from 6 to 40.

Alcohol-associated liver disease was the most common primary diagnosis (n=5), in addition to metabolic dysfunction-associated steatohepatitis (n=4), hepatocellular carcinoma (n=3), and hepatitis C virus (n=1).

Infusion of Donor-Derived Regulatory Dendritic Cells

2 to 4 weeks before the scheduled living-donor liver transplant, living donors underwent leukapheresis to collect monocytes from their blood. Then, the monocytes were used to manufacture regulatory dendritic cells. Donor-derived regulatory dendritic cells (ddDCreg) were infused into patients 7 days before their transplant. Patients also received daily half-doses of mycophenolate during these 7 days pretransplant.

Posttransplant Immunosuppression Protocol

For the first 7 days posttransplant, transplant recipients received a rapid steroid taper. This steroid taper was in addition to mycophenolic acid (MPA) and tacrolimus, the standard-of-care immunosuppression for solid organ transplantation.

Recipients continued standard-of-care immunosuppression through the first 12 months posttransplant.

At 12 months posttransplant, the 13 recipients underwent a protocol biopsy of their liver allograft to determine their eligibility for staged or tapered immunosuppression withdrawal. Biopsy evaluation criteria included T-cell mediated rejection, rejection activity index, fibrosis, antibody-mediated rejection, and C4d staining.

• 8/13 recipients whose biopsies were indeterminate or negative for T-cell mediated rejection, as defined by Banff 2022 criteria, were eligible for staged immunosuppression withdrawal.
• 5/13 recipients whose biopsies were positive for T-cell mediated rejection were not eligible for staged immunosuppression withdrawal. These recipients continued their baseline immunosuppression through the end of the study.

Staged Immunosuppression Withdrawal

Recipients’ immunosuppressants, specifically mycophenolic acid and tacrolimus, were withdrawn by reducing doses in stages over time.

For the 8 recipients who were eligible for immunosuppression withdrawal, complete mycophenolic acid (MPA) withdrawal occurred at 12.1 months (+/- 1.4 months) posttransplant. Staged tacrolimus withdrawal occurred 12 to 24 months posttransplant.

• During this period, 4 of the 8 eligible recipients failed immunosuppression weaning after T-cell mediated rejection was detected through “for-cause” biopsies. These recipients returned to their baseline level of immunosuppression
• 4 of the 8 recipients reached complete immunosuppression withdrawal 11.4 months (+/- 2.2 months) after their 12-month protocol biopsy (approximately 2 years posttransplant).

The 4 recipients who achieved complete immunosuppression withdrawal continued without immunosuppression. At 34 months posttransplant, 1 of the 4 recipients experienced suspected immune system re-activation two weeks after their COVID-19 vaccination. The recipient’s for-cause biopsy revealed moderate T-cell mediated rejection. They returned to their baseline immunosuppression and remained stable through the end of the study.

The 3 other recipients who achieved complete immunosuppression underwent another liver graft biopsy 12 months post-immunosuppression withdrawal (3 years posttransplant). Their biopsies showed no positive evidence of T-cell mediated rejection after 1 year without immunosuppression, meaning that they were operationally tolerant. These 3 recipients continued without immunosuppression through the end of the study (54 months posttransplant).

Takeaways

A pretransplant infusion of ddDCregs was associated with changes in the recipient’s immune response to the liver graft. The recipient’s antigen-presenting cells acquired donor exosomes. Exosomes are key to activating or suppressing the recipient’s immune response. The acquisition of donor exosomes was associated with a suppression of T-cell activity against donor antigens.

Additionally, the pretransplant infusion of ddDCregs was associated with a reduction in pro-inflammatory plasma mediators, which promote inflammation, part of the body’s immune response.

Limitations

The trial’s limitations include its small sample size and lack of a randomized control group. However, these study design choices reflect the authors’ prioritization of participant safety. In addition, this trial was open label, conducted at a single transplant center, and included recipients who were considered low risk. These factors limit the generalization of the study’s results across living-donor liver transplant recipient subgroups.

Next Steps

Study coauthors are currently engaged in a new single-center, open-label trial (ID: NCT04208919) to examine the efficacy of a posttransplant ddDCreg infusion for transplant recipients’ immunotolerance and allograft function and survival. Participants in this trial are 1-3 years posttransplant. They receive a posttransplant ddDCreg infusion and begin staged immunosuppression withdrawal 1 week after infusion.

Study Co-Authors

Study co-authors include:

• Abhinav Humar, MD, chief, UPMC Division of Transplantation Surgery and clinical director, Thomas E. Starzl Transplantation Institute
• Yannis Hadjiyannis, MD, Department of Pathology, University of Pittsburgh School of Medicine
• Camila Macedo, MD, director, Thomas E. Starzl Transplantation Institute Biorepository and research professor of surgery, Department of Surgery, University of Pittsburgh School of Medicine
• Lillian M. Tran, MD, now fellow, Division of Vascular Surgery, Duke University School of Medicine
• Beth D. Elinoff, MPH, nurse coordinator, clinical research, Thomas E. Starzl Transplantation Institute
• Christopher B. Hughes, MD, surgical director, UPMC Liver Transplant Program
• Swaytha R. Ganesh, MD, director, UPMC Living Donor Program
• Alan Zahorchak, research specialist, Thomas E. Starzl Transplantation Institute
• Erin M. Ables, biostatistician, Biostatics Consulting Center, Indiana University Bloomington School of Public Health
• Mindi A. Styn, PhD, clinical trial manager
• Douglas Landsittel, PhD, chair, Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo
• Adriana Zeevi, PhD, ABHI (D), Department of Pathology, University of Pittsburgh School of Medicine
• Fadi G. Lakkis, MD, now professor of medicine, Stanford University
• Diana M. Metes, MD, professor, Department of Surgery and Department of Immunology, University of Pittsburgh School of Medicine
• Angus W. Thomson, PhD, DSc, Distinguished Professor of Surgery and Immunology and professor, clinical and translational science, Department of Surgery, University of Pittsburgh School of Medicine

Study Reference

Humar A, Hadjiyannis Y, Macedo C, et al. Donor-derived regulatory dendritic cell infusion and early immunosuppressive drug withdrawal in living-donor liver transplantation: a phase I/IIa trial. Nature Communications. 2026;17(1). doi:https://doi.org/10.1038/s41467-026-71280-8