Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report.
In the first compassionate-use genetically engineered pig-to-human cardiac xenotransplant, the graft functioned well until diastolic heart failure on postoperative day 47; detailed studies implicated endothelial injury with features of antibody-mediated rejection, IVIG binding to donor endothelium, and reactivation of latent porcine cytomegalovirus/roseolovirus.
Background
A genetically engineered pig cardiac xenotransplantation was performed on January 7, 2022, in a non-ambulatory 57-year-old man with end-stage heart failure on veno-arterial extracorporeal membrane oxygenation support who was ineligible for a human allograft. This case report details the factors thought to be important to the xenotransplantation outcome.
Study design
Physiological and biochemical parameters were collected through extensive intensive-care monitoring. To ascertain the cause of xenograft dysfunction, investigators performed immunological and histopathological studies including electron microscopy, quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) by DNA PCR and RNA transcription, intravenous immunoglobulin (IVIG) binding assays to donor cells, and single-cell RNA sequencing of peripheral blood mononuclear cells.
Key findings
Hyperacute rejection was avoided, and the graft functioned well until postoperative day 47, when diastolic heart failure occurred. Endomyocardial biopsy on day 50 revealed damaged capillaries with interstitial edema, red cell extravasation, rare thrombotic microangiopathy, and complement deposition; by day 56 biopsy showed fibrotic changes consistent with progressive myocardial stiffness. Increased anti-pig antibodies (mainly IgG) were detected after IVIG administration, IVIG bound strongly to donor endothelium, and microbial cell-free DNA testing showed rising PCMV/PRV titres.
Clinical implications
The authors identified potential mediators of the observed endothelial injury: widespread endothelial injury indicating antibody-mediated rejection, IVIG binding to donor endothelium possibly causing immune activation, and reactivation of latent PCMV/PRV potentially initiating a damaging inflammatory response. These findings point to specific measures, such as more sensitive donor screening for latent pathogens, to improve future xenotransplant outcomes.
Category
Transplant
Source
Lancet
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