The immunobiology of pig-to-nonhuman primate islet xenotransplantation: insights, innovation, and impact

Previous studies of pig‐to‐non‐human primate (NHP) islet xenotransplantation have provided important insights into the immune recognition and effector pathways operative in this relevant preclinical model. The specifics of the xenograft product, microenvironment at the implantation site, and the imm...

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Published in:Xenotransplantation (Københaven) 2013-01, Vol.20 (1), p.50-50
Main Authors: Graham, Melanie L., Hennessy, Emily A., Wang, Shusen, Martins, Kyra V., Suarez-Pinzon, Wilma L., Bansal-Pakala, Pratima, Flanagan, Brian F., Murtaugh, Michael P., Azimzadeh, Agnes M., Hancock, Wayne H., Miller, Stephen D., Luo, Xunrong, Hering, Bernhard J.
Format: Article
Language:English
Subjects:
Allografts
CD4 antigen
CD8 antigen
Cell proliferation
Cell survival
CTLA-4 protein
CXCL10 protein
Diabetes mellitus
Foxp3 protein
gamma -Interferon
Graft rejection
Immunological memory
Immunoregulation
Immunosuppressive agents
Immunotherapy
Interleukin 10
Interleukin 12
IP-10 protein
Islets of Langerhans
Lymphocytes B
Lymphocytes T
Macrophages
Memory cells
Pancreas
Primates
Rapamycin
Tacrolimus
Transforming growth factor- beta
Vaccination
xenoantigens
Xenografts
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Summary:Previous studies of pig‐to‐non‐human primate (NHP) islet xenotransplantation have provided important insights into the immune recognition and effector pathways operative in this relevant preclinical model. The specifics of the xenograft product, microenvironment at the implantation site, and the immunosuppressive regimen significantly influence the mechanisms underlying the rejection of xenogeneic islets. Our current understanding of the immunological barriers to survival of pig islets in NHPs is largely based on studies on intraportal islet xenografts and on comparisons with islet allografts. The demonstration of cell‐mediated rejection of intraportal porcine islet xenografts at about 1 month posttransplant in monkeys immunosuppressed with the same protocols that prevent monkey islet allograft rejection indicates that islet xenograft rejection involves cellular mechanisms that are not present in acute islet allograft rejection. While these mechanisms remain poorly defined the demonstration of long‐term diabetes reversal after intraportal islet xenotransplantation in non‐human primates immunosuppressed with anti‐CD40L but not with anti‐CD40 antibody‐based protocols suggests that the therapeutic efficacy of anti‐CD40L in this transplantation setting likely involves the depletion of donor‐reactive, activated T cells besides CD40:CD40L costimulation blockade. Rejection of intraportal islet xenografts in NHPs immunosuppressed with CTLA4‐Ig and rapamycin was mediated largely by IL‐15‐primed, CXCR3+CD8+ memory T cells recruited by IP‐10 (CXCL10) positive pig islets and macrophages that showed staining for IL‐12 and iNOS. Adding basiliximab induction and tacrolimus maintenance therapy to this protocol prevented rejection in 24 of 26 recipients followed for up to 275 days. Comparison of both groups suggests, though by no means conclusive, that prolongation of graft survival in this large cohort was associated with reduced direct T cell responses to xenoantigens, reduced proportion of intrahepatic (intragraft) B cells and IFN‐γ+ and IL‐17+ CD4 and CD8 T cells, and increased local production of immunoregulatory molecules linked with Tregs, including TGF‐β, Foxp3, HO‐1, and IL‐10. Anti‐pig non‐Gal IgG antibody elicitation was suppressed in both groups. We are currently exploring the concept of negative vaccination to markedly minimize the need for immunosuppression in islet xenotransplantation. Peritransplant administration of donor apoptotic cells extended pig‐to‐mo
ISSN:0908-665X
1399-3089
DOI:10.1111/xen.12014_8