2013 - IXA 2013 Congress


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IXA Plenary Session 2: Update on Preclinical Cell Xenotransplantation

26.3 - Bone Marrow Xenotransplantation

Presenter: David H., Sachs, Padua, United States
Authors:

Since mixed chimerism has been shown in mouse and humanized mouse models to have the ability not only to induce central T cell tolerance, but also to prevent new antibody responses and turn off existing antibody responses, the establishment of xenogeneic mixed chimerism remains an attractive means for achieving xenograft tolerance.  Before GalT-KO miniature swine were available, the failure of attempts to achieve mixed chimerism across the pig-to-primate barrier was attributed to high levels of primate natural antibodies to the Gal antigen.  However, despite the absence of the Gal antigen on the cell surface of GalT-KO hematopoietic cells (HSC), we have found that these cells are rapidly cleared from the circulation of baboons shortly after infusion, potentially inhibiting the establishment of mixed chimerism.  We have investigated what we believe to be two of the major factors playing a role in this clearance: 1) natural antibodies to non-Gal determinants, which are variably present in baboons;  and 2) species incompatibility of the cell membrane protein CD47, which is required to inhibit the innate immune system from rapidly clearing cells from the circulation. 

In order to avoid or overcome the effects of natural anti-non-Gal antibodies on establishment of mixed xenogeneic chimerism, we have tested three approaches: 1) a search for baboons with little or no natural anti-non-Gal antibodies as recipients; 2) absorption of anti-non-Gal antibodies by organ perfusion prior to HSC administration; and 3) treatment of recipients with regimens directed toward decreasing production of anti-non-Gal antibodies prior to HSC administration.  To date, these approaches have met with limited success.

We have adopted a genetic engineering approach to the potential role of CD47 as an inhibitor of HSC engraftment. Our initial studies demonstrated that transduction of a porcine cell line with a human CD47 (hCD47) expression vector led to diminished clearance from the circulation after injection into a baboon.  We have subsequently developed an hCD47 transgenic pig on the background of our GalT-KO miniature swine.  Cytokine mobilized peripheral blood stem cells from the first transgenic animal were infused into a baboon subjected to a non-myeloablative conditioning regimen similar to that which we have previously utilized for xenogeneic bone marrow transplantation.  Results will be presented elsewhere at this meeting demonstrating that, unlike previous recipients of non-transgenic HSC, this animal demonstrated clear evidence of mixed xenogeneic chimerism in the peripheral blood for several days after the infusion.  Furthermore, two subsequent infusions of mobilized cells from the same donor, at 7 and 10 weeks following the initial infusion, also led to several days of mixed xenogeneic chimerism in the peripheral blood, indicating absence of sensitization. Finally, a skin graft from the donor showed markedly prolonged survival, suggesting an important systemic effect.

These results are encouraging with regard to the possibility of inducing transplantation tolerance in a pig-to-primate model through a mixed chimerism approach.


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