The first clinical pig heart transplant: Was IVIg or pig cytomegalovirus detrimental to the outcome?

Abstract

The clinical course of the first patient to receive a gene-edited pig heart transplant was recently reported by the University of Maryland team. Although the pig heart functioned well for >40 days, serum anti-pig antibodies then increased, and the patient sadly died after 60 days. Because of his debilitated pre-transplant state, the patient never thrived despite excellent graft function for several weeks, and the cause of his demise continues to be uncertain. A few days before an increase in anti-pig antibodies was observed, the patient had received intravenous human immunoglobulin (IVIg), and whether this played a role in his cardiac deterioration has been discussed. Furthermore, mcfDNA testing indicated an increase in pig cytomegalovirus (CMV), and its possible role in the development of cardiac dysfunction has also been considered. On the basis of the limited data provided in the publication and on our previous investigations into whether IVIg contains anti-TKO pig antibodies and therefore might be deleterious to TKO pig organ xenografts, we suggest that the steady rise in anti-pig antibody titer was more consistent with the failure of the immunosuppressive regimen to prevent elicited anti-TKO pig antibody production, rather than from the passive transfusion of IVIg or the presence of pig CMV in the graft. Although the outcome of the Maryland experience was disappointing, valuable lessons were learned. Our attention was drawn to the potential risks of heart transplantation in a "deconditioned" patient, the administration of IVIg, the transmission of pig CMV, and of the difficulties in interpreting myocardial biopsy findings.

Keywords: IVIg; antibody-mediated; clinical; cytomegalovirus; genetically modified; heart; pig; rejection; xenotransplantation.

FIGURE 1

Photomicrograph of a wild-type pig heart that ceased functiong within an hour of being continually perfused by baboon ABO-compatible blood (in an experiment carried out in 1985). Interstitial hemorrhage and edema are promineny features of hyperacurte rejection (Hematoxylin and eosin, x150).The appearances are similar to those shown in Figure 4, panel B, of the Maryland report (Griffith et al., 2022, reference 1)