TY - JOUR
T1 - Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs
AU - Iwase, H.
AU - Ekser, B.
AU - Satyananda, V.
AU - Zhou, H.
AU - Hara, H.
AU - Bajona, P.
AU - Wijkstrom, M.
AU - Bhama, J. K.
AU - Long, C.
AU - Veroux, M.
AU - Wang, Y.
AU - Dai, Y.
AU - Phelps, C.
AU - Ayares, D.
AU - Ezzelarab, M. B.
AU - Cooper, D. K C
N1 - Funding Information:
Burcin Ekser, MD, was a recipient of NIH NIAID T32 AI 074490 training grant. Mohamed Ezzelarab, MD, was supported in part by the Joseph A. Patrick Fellowship of the Thomas E. Starzl Transplantation Institute. 2C10R4 was kindly provided by Keith Reimann of the NIH NHP Resource Center, Boston, MA. Work on xenotransplantation in the Thomas E. Starzl Transplantation Institute of the University of Pittsburgh is supported in part by NIH grants # U19 AI090959 , # U01 AI068642 , and # R21 A1074844 , and # PO1 HL107152 , and by Sponsored Research Agreements between the University of Pittsburgh and Revivicor, Blacksburg, VA. The baboons used in the study were from the Oklahoma University Health Sciences Center, Baboon Research Resources, which is supported by the Office of the Director, NIH, under Award Number P40OD010431 and P40OD010988. The authors thank Yuko Miyagawa and Dirk J van der Windt for technical help in performing in vitro assays.
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - Background: In the pig-to-nonimmunosuppressed baboon artery patch model, a graft from an α1,3-galactosyltransferase gene-knockout pig transgenic for human CD46 (GTKO/CD46) induces a significant adaptive immune response (elicited anti-pig antibody response, increase in T cell proliferation on MLR, cellular infiltration of the graft), which is effectively prevented by anti-CD154mAb-based therapy. Methods: As anti-CD154mAb is currently not clinically applicable, we evaluated whether it could be replaced by CD28/B7 pathway blockade or by blockade of both pathways (using belatacept + anti-CD40mAb [2C10R4]). We further investigated whether a patch from a GTKO/CD46 pig with a mutant human MHC class II transactivator (CIITA-DN) gene would allow reduction in the immunosuppressive therapy administered. Results: When grafts from GTKO/CD46 pigs were transplanted with blockade of both pathways, a minimal or insignificant adaptive response was documented. When a GTKO/CD46/CIITA-DN graft was transplanted, but no immunosuppressive therapy was administered, a marked adaptive response was documented. In the presence of CD28/B7 pathway blockade (abatacept or belatacept), there was a weak adaptive response that was diminished when compared with that to a GTKO/CD46 graft. Blockade of both pathways prevented an adaptive response. Conclusion: Although expression of the mutant MHC CIITA-DN gene was associated with a reduced adaptive immune response when immunosuppressive therapy was inadequate, when blockade of both the CD40/CD154 and CD28/B7 pathways was present, the response even to a GTKO/CD46 graft was suppressed. This was confirmed after GTKO/CD46 heart transplantation in baboons.
AB - Background: In the pig-to-nonimmunosuppressed baboon artery patch model, a graft from an α1,3-galactosyltransferase gene-knockout pig transgenic for human CD46 (GTKO/CD46) induces a significant adaptive immune response (elicited anti-pig antibody response, increase in T cell proliferation on MLR, cellular infiltration of the graft), which is effectively prevented by anti-CD154mAb-based therapy. Methods: As anti-CD154mAb is currently not clinically applicable, we evaluated whether it could be replaced by CD28/B7 pathway blockade or by blockade of both pathways (using belatacept + anti-CD40mAb [2C10R4]). We further investigated whether a patch from a GTKO/CD46 pig with a mutant human MHC class II transactivator (CIITA-DN) gene would allow reduction in the immunosuppressive therapy administered. Results: When grafts from GTKO/CD46 pigs were transplanted with blockade of both pathways, a minimal or insignificant adaptive response was documented. When a GTKO/CD46/CIITA-DN graft was transplanted, but no immunosuppressive therapy was administered, a marked adaptive response was documented. In the presence of CD28/B7 pathway blockade (abatacept or belatacept), there was a weak adaptive response that was diminished when compared with that to a GTKO/CD46 graft. Blockade of both pathways prevented an adaptive response. Conclusion: Although expression of the mutant MHC CIITA-DN gene was associated with a reduced adaptive immune response when immunosuppressive therapy was inadequate, when blockade of both the CD40/CD154 and CD28/B7 pathways was present, the response even to a GTKO/CD46 graft was suppressed. This was confirmed after GTKO/CD46 heart transplantation in baboons.
KW - Anti-CD40 monoclonal antibody
KW - Artery patch
KW - CTLA4-Ig
KW - Costimulation blockade
KW - Pig
KW - Xenotransplantation
UR - http://www.scopus.com/inward/record.url?scp=84926421257&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84926421257&partnerID=8YFLogxK
U2 - 10.1016/j.trim.2015.02.003
DO - 10.1016/j.trim.2015.02.003
M3 - Article
C2 - 25687023
AN - SCOPUS:84926421257
SN - 0966-3274
VL - 32
SP - 99
EP - 108
JO - Transplant Immunology
JF - Transplant Immunology
IS - 2
ER -