Faculty Bibliography

HLA sensitization poses a major challenge to kidney transplantation for patients with end-stage kidney disease, especially for highly sensitized candidates. Attempts at antibody elimination (desensitization) have had inconsistent efficacy and have often failed to produce sustained reductions in anti-HLA antibodies in patients with the highest level of sensitization (calculated panel-reactive antibody score, ≥99.9%). We now report the results for the safety run-in cohort of a multicenter phase 1 clinical study evaluating the safety and efficacy of combined CD19-targeted and B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells in eliminating the cellular sources of preformed anti-HLA antibodies (ClinicalTrials.gov number, NCT06056102). Kidney transplantation was performed in two highly sensitized candidates after desensitization with the use of dual CAR T-cell therapy.

The inaugural Richard Slayman Clinical Xenotransplantation Workshop convened >140 participants from North America, Europe, and Asia to discuss emerging advances and challenges in translating xenotransplantation from bench to bedside. This report summarized key discussions spanning kidney, heart, and liver xenotransplantation, with an emphasis on clinical readiness and future directions. Core themes included the importance of patient selection, the role of genetic editing to reduce immune incompatibility, adaptive immunosuppressive strategies, novel molecular tools for immune and infectious surveillance, and the growing recognition of innate immune activation as a barrier to long-term graft survival. The workshop highlighted decedent models as a translational bridge, the use of machine perfusion in liver xenograft applications, and progress in living recipients. Notably, 1 patient achieved 9 mo of kidney xenograft function, underscoring the feasibility of extended survival in carefully selected candidates. Perspectives from patients and families, including a reflection honoring Richard Slayman, the first living recipient of a genetically edited pig kidney, framed the scientific dialogue within the broader human impact of this emerging field. The workshop marked a pivotal moment in aligning scientific, ethical, and regulatory efforts to advance safe and equitable access to xenotransplantation.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution^1-3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure⁴. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A6⁵, SPP1⁶ (Osteopontin), and COLEC11⁷, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

With U.S. Food and Drug Administration (FDA) clearance of clinical trials of kidney xenotransplantation (XTx) in living humans, understanding the recipient experience is critical. Semi-structured interviews with the three living XTx recipients identified core domains of the recipient experience, including quality of life (QoL), fears about XTx, and healthcare team communication and support. Transcribed interviews were analyzed by two qualitative researchers using an inductive thematic approach and were mapped onto the Warwick Patient Experience Model, a validated framework to assess key aspects of patient satisfaction with the healthcare experience. All three recipients (53-year-old female; 66-year-old male; 54-year old male) described a restoration of hope, contrasted with their poor quality of life on dialysis. They emphasized that access to XTx and graft survival requires mutual confidence and commitment between recipients and healthcare teams. XTx recipients use dialysis as a point of reference when describing changes in their post-transplant QoL and seemed well-situated to handle the possibility of graft failure. These insights may aid in the creation of decision aids and educational materials tailored to the specific needs of XTx recipients.

UNLABELLED:(N = 24 patients) among functioning grafts. DSA rebounded with levels progressively decreasing over time and no increase in DSA seen between 3 and 5 years. No AMR occurred between 3 and 5 years. Furthermore, no additional safety signals assessed as related to imlifidase were reported in this cohort. At 5 years, highly-HLA sensitized patients who underwent imlifidase desensitization prior to transplantation demonstrated excellent patient and graft survival, despite their high-risk immunological profile. Imlifidase offers a viable and effective treatment option for highly sensitized patients to achieve life-saving transplantation and continued optimism is warranted. CLINICAL TRIAL/UNASSIGNED:ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.