Mixed xenogeneic porcine chimerism tolerizes human anti‐pig natural antibody‐producing cells in a humanized mouse model. (26th April 2021)

• Record Type: Journal Article
• Authors: Waffarn, Elizabeth E.; Khosravi‐Maharlooei, Mohsen; Vecchione, Andrea; Shao, Steven; Vishwasrao, Paresh; HÖlzl, Markus A.; Frangaj, Kristjana; Sykes, Megan; Li, Hao Wei
• Is Part Of: Xenotransplantation. Volume 28:Number 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-26
• Subjects: B cells -- humanized mice -- Mixed Chimerism -- xenoantibody -- xenotolerance; Xenografts -- Periodicals; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/xen.12691
• Languages: English
• ISSNs: 0908-665X

Abstract

Abstract: Background: A major obstacle to the success of organ transplantation from pigs to humans, necessitated by the shortage of human organs, is robust humoral immune rejection by pig‐reactive human antibodies. Mixed xenogeneic hematopoietic chimerism induces xenoreactive B cell tolerance in rodents, but whether mixed pig/human chimerism could induce tolerance of human B cells to pig xenoantigens is unknown. Methods: We investigated this question using a humanized mouse model in which durable mixed (pig‐human) xenogeneic chimerism can be established. Results: Human natural anti‐pig cytotoxic antibodies, predominantly IgM, are detectable in non‐chimeric humanized mouse serum, and pig‐reactive antibodies were reduced in mixed chimeric versus non‐chimeric humanized mice. This difference required persistent mixed chimerism and was not due to the adsorption of antibodies on pig cells in vivo. Furthermore, human B cells from spleens of mixed chimeric mice produced lower levels of anti‐pig antibodies when stimulated in vitro compared with those from non‐chimeric mice. Conclusions: Our findings demonstrate that mixed chimerism reduces human natural antibodies to pig xenoantigens, providing the first in vivo evidence of human B cell tolerance induction by mixed xenogeneic chimerism and supporting further evaluation of this approach for inducing human B cell tolerance to xenografts.