Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs

H. Iwase, B. Ekser, V. Satyananda, H. Zhou, H. Hara, P. Bajona, M. Wijkstrom, J. K. Bhama, C. Long, M. Veroux, Y. Wang, Y. Dai, C. Phelps, D. Ayares, M. B. Ezzelarab, D. K C Cooper

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)99-108
Number of pages10
JournalTransplant Immunology
Volume32
Issue number2
DOIs
StatePublished - Mar 1 2015

Fingerprint

Papio
Swine
Arteries
Transplantation
Transplants
Immunosuppressive Agents
Adaptive Immunity
Galactosyltransferases
Gene Knockout Techniques
Heart Transplantation
Therapeutics
Genes
Antibody Formation
Anti-Idiotypic Antibodies
Cell Proliferation
T-Lymphocytes
Abatacept

Keywords

  • Anti-CD40 monoclonal antibody
  • Artery patch
  • Costimulation blockade
  • CTLA4-Ig
  • Pig
  • Xenotransplantation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Transplantation

Cite this

Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs. / Iwase, H.; Ekser, B.; Satyananda, V.; Zhou, H.; Hara, H.; Bajona, P.; Wijkstrom, M.; Bhama, J. K.; Long, C.; Veroux, M.; Wang, Y.; Dai, Y.; Phelps, C.; Ayares, D.; Ezzelarab, M. B.; Cooper, D. K C.

In: Transplant Immunology, Vol. 32, No. 2, 01.03.2015, p. 99-108.

Research output: Contribution to journalArticle

Iwase, H, Ekser, B, Satyananda, V, Zhou, H, Hara, H, Bajona, P, Wijkstrom, M, Bhama, JK, Long, C, Veroux, M, Wang, Y, Dai, Y, Phelps, C, Ayares, D, Ezzelarab, MB & Cooper, DKC 2015, 'Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs', Transplant Immunology, vol. 32, no. 2, pp. 99-108. https://doi.org/10.1016/j.trim.2015.02.003
Iwase, H. ; Ekser, B. ; Satyananda, V. ; Zhou, H. ; Hara, H. ; Bajona, P. ; Wijkstrom, M. ; Bhama, J. K. ; Long, C. ; Veroux, M. ; Wang, Y. ; Dai, Y. ; Phelps, C. ; Ayares, D. ; Ezzelarab, M. B. ; Cooper, D. K C. / Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs. In: Transplant Immunology. 2015 ; Vol. 32, No. 2. pp. 99-108.
@article{7cf5e7a77f4a45b8b8739204cea94994,
title = "Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs",
abstract = "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.",
keywords = "Anti-CD40 monoclonal antibody, Artery patch, Costimulation blockade, CTLA4-Ig, Pig, Xenotransplantation",
author = "H. Iwase and B. Ekser and V. Satyananda and H. Zhou and H. Hara and P. Bajona and M. Wijkstrom and Bhama, {J. K.} and C. Long and M. Veroux and Y. Wang and Y. Dai and C. Phelps and D. Ayares and Ezzelarab, {M. B.} and Cooper, {D. K C}",
year = "2015",
month = "3",
day = "1",
doi = "10.1016/j.trim.2015.02.003",
language = "English (US)",
volume = "32",
pages = "99--108",
journal = "Transplant Immunology",
issn = "0966-3274",
publisher = "Elsevier",
number = "2",

}

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

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 - Costimulation blockade

KW - CTLA4-Ig

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

VL - 32

SP - 99

EP - 108

JO - Transplant Immunology

JF - Transplant Immunology

SN - 0966-3274

IS - 2

ER -