Immune mapping in first patient with a gene-edited pig kidney reveals barriers to overcome for long-term transplant hopes

A study has traced immune activity at high resolution in the first living recipient of a gene-edited pig kidney and has reported that – even after clinicians suppressed T-cell rejection – persistent innate immune activation in monocytes and macrophages still threatened graft health

Researchers have reported the most detailed molecular portrait so far of how a human immune system responded after clinicians transplanted a gene-edited pig kidney into a living patient, as xenotransplantation research has continued to seek options to ease chronic organ shortages.

The study combined transcriptomic, proteomic, metabolomic and spatial analyses to track both adaptive and innate immune responses across time and tissue. The results underlined a central problem for the field, being the suppression of early T-cell-mediated rejection did not silence a broader immune response that can erode long-term graft survival.

Xenotransplantation refers to the transplantation of organs, tissues or cells from one species into another, most often from pigs into humans because porcine organs match human anatomy reasonably well and because pig genomes can undergo extensive editing.

Gene editing has enabled donor pigs to carry multiple changes with the aim of reducing human immune incompatibility and dampening inflammatory triggers. Even so, rejection has remained a principal obstacle, with immune pathways differing in important ways from those seen in human-to-human transplantation.

The case at the centre of the study took place at Massachusetts General Hospital in Boston, USA, which is affiliated with Harvard Medical School, Cambridge, Massachusetts, USA. Surgeons performed the transplant in March 2024 in a 62-year-old man with end-stage kidney disease, using a pig kidney that carried 69 genetic modifications intended to increase immune compatibility. However, the patient died two months later with the probable cause of death attributed to pre-existing chronic myocardial fibrosis.

The study’s corresponding authors included Brazilian nephrologist Dr. Leonardo Riella and immunologist Dr. Thiago Borges at Massachusetts General Hospital. Their team set out to define – in a living recipient – how the immune system reacted as clinicians adjusted immunosuppression and as the graft encountered both early and persistent immune pressure. To do so, the researchers aligned conventional clinical tests with multiomic measurements. Transcriptomics assessed which RNA transcripts cells produced, proteomics measured proteins, and metabolomics quantified small molecules such as sugars, lipids and amino acids. Spatial analyses helped the team to locate cell populations and inflammatory signals within tissue, rather than treat the graft as a homogeneous sample.

The investigators detected early T-lymphocyte-mediated rejection within the first week after surgery. The paper linked this episode to subtherapeutic immunosuppression and to residual cytotoxic T cells that persisted in lymph nodes despite profound depletion of circulating T cells prior to the surgery being undertaken. Intensified immunosuppression reversed the T-cell rejection episode, and the researchers did not detect antibody-mediated rejection, which can damage blood vessels within a transplanted organ.

What followed, however, was the cautionary tale. After treatment, adaptive immune activity remained suppressed, but innate immune activation persisted. The analysis described sustained monocyte and macrophage activity alongside inflammatory signalling consistent with ongoing tissue stress. These findings suggested that immune control strategies that succeed in human allografts may still leave a substantial residual response in xenografts, particularly within the innate arm of immunity that acts as the body’s immediate threat detector.

“The main finding of the study was the detailed, unprecedented, high-resolution characterisation of the human immune response following the transplantation of a genetically modified pig kidney into a living patient.

“The results show that, for xenotransplantation to become a safe and lasting clinical option, controlling only adaptive immunity, as we traditionally do in transplants between humans, is insufficient.

“Specific strategies must also be developed to modulate the innate immune response and ensure the prolonged survival of xenogeneic grafts in humans,” Borges said.

The study also highlighted a monitoring gap. Standard blood tests did not detect this pattern of graft injury clearly, yet signs of damage emerged through measurement of donor-derived cell-free DNA, which consists of DNA fragments that enter the bloodstream when cells in the transplanted organ sustain injury.

In this case, changes in circulating pig donor-derived cell-free DNA tracked with graft stress and response to treatment. The researchers proposed that this approach could offer a sensitive, non-invasive biomarker to monitor xenograft health in near real time.

“We demonstrated that DNA fragments from the pig kidney circulating in the patient’s blood can be used as a sensitive and non-invasive marker of rejection. This opens up the possibility of monitoring the graft in real time which potentially reduces the need for biopsies,” Borges said.

The authors argued that xenotransplantation will likely require combination approaches that target both immune arms. In practical terms, that means continued work to refine immunosuppressive regimens that can prevent early T-lymphocyte-mediated rejection, alongside therapies that can modulate macrophages and other innate pathways that sustain inflammation even when adaptive activity stays low.

The paper also pointed to the value of further genetic engineering in donor pigs, with edits that can reduce the innate immune triggers that human myeloid cells recognise as danger signals. It also recommended more sensitive monitoring strategies to detect graft injury before conventional clinical tests can do so.

Brazilian researchers contributed substantially to the integrated analysis. Dr. Helder Nakaya, a senior researcher at Hospital Israelita Albert Einstein in São Paulo, Brazil, and a professor at the University of São Paulo’s School of Pharmaceutical Sciences, said that the breadth of the dataset could inform more effective immunosuppression choices because it captured molecular and cellular changes over time.

“This study was important because it provided a broad view of all the molecular and cellular changes that occurred during the transplant. This can help guide and improve the efficiency of immunosuppression,” Nakaya said.

In severe disease, dialysis can provide temporary renal replacement by removing waste products and excess fluid from the blood when kidneys no longer function adequately. Even with dialysis, long-term outcomes often depend on access to transplantation, which leaves a persistent gap between clinical need and organ supply.

Taken together, the findings have strengthened the case that xenotransplantation has moved beyond proof of surgical feasibility. The next phase will require clinicians and researchers to tame the innate immune response, rather than treat it as a secondary concern.

For further reading please visit: 10.1038/s41591-025-04053-3