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 - 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
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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 -