Optimizing IVIg in Xenotransplantation: A Call to Action

Posttransplant hypogammaglobulinemia is associated with an increased risk for infections, including bacteremia, pneumonia, invasive fungal infections, and end-organ cytomegalovirus disease.1 Infection risk is particularly high in recipients with IgG levels of <400 mg/dL.1 Experimental genetically modified pig-to-human xenotransplantation involves multimodal immunosuppression, including multiple manipulations of the B-cell compartment to suppress antibody production, for the prevention of hyperacute and acute antibody-mediated rejection. The first pig-to-human heart xenotransplant recipient developed severe hypogammaglobulinemia with an IgG level of 185 mg/dL, for which he was treated with 2 doses of IVIg.2 The University of Maryland xenotransplant team hypothesized that IVIg administration may have contributed to the eventual failure of the xenograft. Mohiuddin et al2 reported that the second dose of IVIg was correlated with clinical deterioration and a marked increase in anti-pig xenoantibody concentrations. Postmortem, they found “…strong binding to the donor porcine aortic endothelial cells was observed with three different lots of the same brand and manufacturer of IVIg.”2 However, the investigators did not observe complement-dependent cytotoxicity.2 The authors commented that “The role of anti-pig antibodies in IVIg preparation and their role in endothelial damage might be more important in xenotransplantation than in allotransplantation and should be further investigated,” and in terms of future lessons for xenotransplantation, “…the use of IVIg … might need strong justification.”2 In contrast, Cooper et al3 cast doubt on the role of IVIg in the fate of the xenograft. Based on their previous work on anti-pig antibodies in IVIg and lack of associated cytotoxicity, Cooper et al3 suggested that it was more likely recipient production, rather than exogenous IVIg, that was responsible for the rise in anti-pig antibodies. They concluded that, although IVIg in this setting is likely safe, anti-pig antibody levels in IVIg preparations vary, and screening to select IVIg lots that have low anti-pig antibody levels would be prudent.3 Although opinions may vary, enough questions have been raised that xenotransplant clinicians may be reluctant to administer IVIg, even for severe hypogammaglobulinemia. Given the intensive immunosuppression required in xenotransplantation, severe hypogammaglobulinemia could contribute to a high risk for bacterial, viral, and fungal infections.1 In turn, infections could have an adverse impact on xenograft function and could affect the success of the xenotransplant. We advocate addressing this concern in 2 ways: (1) optimizing methods for screening commercially available IVIg products for anti-pig antibodies, and (2) it would be valuable to have an IVIg product available that has undergone removal of anti-pig antibodies. Advances in antibody screening of xenorecipient serum in a pig-to-baboon model have been described by Hisadome et al4 and might be applicable to the screening of IVIg. Regarding IVIg which has undergone removal of anti-pig antibodies, Liu et al5 reported methodologies for extracorporeal removal of anti-pig antibodies by immunoabsorption. If such methods could be applied to IVIg preparations, “Xenotransplant-modified-IVIg” could become a reality. We encourage the development and further study of IVIg screening methods and modified IVIg products to optimize the safety and outcomes of future xenotransplant recipients.