Does Xenotransplantation Offer a Large Benefit for Human Patients?—A Reply

Does Xenotransplantation Offer a Large Benefit for Human Patients?

In their comment to our review article,[1] the authors referred to the outcome of the first two clinical cases of cardiac xenotransplantation in Baltimore, Maryland (United States), that were limited by transmission of a porcine cytomegalovirus (PCMV) and rejection.

We agree with the authors that there are still remaining hurdles to be overcome before cardiac xenotransplantation may enter the clinical arena as a routine.

As stated by M. Mohiuddin, scientific head of the Baltimore group, in a New England Journal of Medicine Podcast,[2] in both Maryland patients, antibody-mediated rejection was the major culprit leading to endothelial cell damage and eventually cardiac failure. A major contributing factor was patient selection since both patients were in far advanced terminal heart disease, leading to kidney failure at the time of transplant. In addition, the first patient was on extracorporeal membrane oxygenation (ECMO) for 40 preoperative days and the second patient had a cardiac arrest the night before the transplant.

Postoperatively they did not tolerate well the immunosuppressive protocol applied. In the first patient, rejection may have been induced or aggravated by treating him with intravenous immunoglobulin (IVIG) containing antipig antibodies and various blood products. The second patient received an anti-CD40L monoclonal antibody (tegoprubart), which is successfully used in the first clinical trials after kidney and islet allotransplantation.[3] However, its effectiveness still needs to be proven in preclinical xenotransplantation.

The Munich group therefore is currently conducting these experiments, which will address the control of rejection by optimized donor modification (genetic engineering of the pig, high levels of human CD46 transgene overexpression) and immunosuppression. Organ overgrowth will be avoided by using Auckland Island (AI) minipigs instead of growth hormone receptor knockout pigs as applied in the two Maryland cases.

With regard to the transmission of potentially zoonotic (zoonotic means inducing a disease in the infected host) porcine viruses, which happened to the first Maryland patient, it has to be clarified that this was due to methods not sensitive enough to detect latent PCMV infection in the donor pig. This can easily be prevented by using the appropriate methods (as was done in the second Maryland patient).[4]

In the last several years, sensitive methods have been generated to detect numerous porcine viruses. Elimination programs have been developed to eradicate these viruses by antiviral drugs, vaccines, early weaning of the piglets, colostrum deprivation, or embryo transfer. Theoretically, all known viruses with the exception of porcine endogenous retroviruses (PERVs) can be eliminated by these methods. AI minipigs used by the Munich group are, however, PERV-C free to avoid potentially dangerous PERV-A/C recombinations—a strategy that has already been approved by the regulating authorities (Paul-Ehrlich-Institute).

The risk of transmission of unknown pathogens is relatively low since humans have lived together with pigs for 10,000 years. Therefore, xenotransplantation is expected to be safer compared with allotransplantation, where several viral diseases (HSV, CMV, EBV, HIV-1, hepatitis B/C, and rabies) have been transmitted during transplantation of human organs into human recipients in the past. In the xenotransplantation setting, the donor pigs are kept in a special designated pathogen free (DPF) unit, thus minimizing the risk of infection.

Xenograft recipients will have to submit to lifelong treatment with immunosuppressive drugs and surveillance to monitor rejection of their transplanted organ (as do allograft recipients). In parallel, infection and possible diseases (e.g., malignancies) can be detected. As long as an organ recipient is not infected, there is no need to screen “bystanders” such as partners, close relatives, or caregivers for virus infection.

In summary, xenotransplantation will be a safe method/technology if it is performed by experienced groups adhering to the above-mentioned prerequisites. Given the tasks still to be fulfilled, including the strict German/European regulations, we expect the first clinical trials in Germany not to start before 2026.

Publication History

Article published online:
13 February 2024

• References

• 1 Schmoeckel M, Längin M, Reichart B. et al. Current status of cardiac xenotransplantation. Thorac Cardiovasc Surg 2023; (e-pub ahead of print) DOI: 10.1055/a-2235-8854.
• 2 Gotbaum R, Gauzens C, Bennett Jr D, Mohiuddin M, Montgomery R. Is xenotransplantation ready for prime time?—ITT episode 22. N Engl J Med Podcast 2023; 389: e49
• 3 Anwar IJ, Berman DM, DeLaura I. et al. The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. Sci Transl Med 2023; 15 (711) eadf6376
• 4 Denner J. Xenotransplantation can be safe: a reply. Camb Q Healthc Ethics 2024; 33 (01) 148-149