Indirect allorecognition can play an important role in the development of transplant arteriosclerosis

Stephan M. Ensminger, Bernd M. Spriewald, Oliver Witzke, Octavio E. Pajaro, Magdi H. Yacoub, Peter J. Morris, Marlene L. Rose, Kathryn J. Wood

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Background. Indirect allorecognition has been implicated in the initiation of chronic allograft dysfunction. Our aim was to develop an animal model that allowed the contribution of the direct and indirect pathway of allorecognition in the evolution of transplant arteriosclerosis, the main feature of chronic allograft rejection, to be evaluated. Methods. Aortic allografts mismatched for a single MHC class I antigen were transplanted into athymic NUDE or RAG-/- mice. Immunodeficient mice were reconstituted with either CD4+ (indirect) or CD8+ (direct + indirect) T cells in the presence or absence of depleting antibodies specific for the opposite T-cell subset. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of cytokine mRNA production. Donor-specific alloantibody production was measured by fluorescence-activated cell sorter analysis. Results. Reconstitution of athymic nude mice with 4 × 107 purified CD4+ T cells resulted in vascular rejection of MHC class I mismatched aortic grafts. Intimal proliferation was 24±8% and did not decrease when nude-derived endogenous CD8+ T cells were depleted from the nude recipients (intimal proliferation, 21±7%). Transplant arteriosclerosis initiated by T cells was associated with the presence of intragraft mRNA for interferon-γ, tumor necrosis factor-α, inducible nitric oxide synthase, and interleukin 12. Reconstitution of RAG-1-/- mice with 4 × 107 purified CD4+ T cells resulted in a similar degree of transplant arteriosclerosis (intimal proliferation, 20±9%) in MHC class I mismatched aortic grafts in the absence of alloantibody production. Conclusion. Indirect recognition of donor MHC class I molecules by CD4+ T cells can play an important role in the process of transplant arteriosclerosis. CD8+ T-cell effector function and alloantibody production in this model are dependent on CD4+ T-cell help after indirect allorecognition.

Original languageEnglish (US)
Pages (from-to)279-286
Number of pages8
JournalTransplantation
Volume73
Issue number2
StatePublished - Jan 27 2002
Externally publishedYes

Fingerprint

Arteriosclerosis
T-Lymphocytes
Transplants
Tunica Intima
Isoantibodies
Allografts
Nude Mice
CD4 Antigens
Messenger RNA
Histocompatibility Antigens Class I
T-Lymphocyte Subsets
Nitric Oxide Synthase Type II
Interleukin-12
Reverse Transcriptase Polymerase Chain Reaction
Interferons
Blood Vessels
Animal Models
Tumor Necrosis Factor-alpha
Fluorescence
Immunohistochemistry

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Ensminger, S. M., Spriewald, B. M., Witzke, O., Pajaro, O. E., Yacoub, M. H., Morris, P. J., ... Wood, K. J. (2002). Indirect allorecognition can play an important role in the development of transplant arteriosclerosis. Transplantation, 73(2), 279-286.

Indirect allorecognition can play an important role in the development of transplant arteriosclerosis. / Ensminger, Stephan M.; Spriewald, Bernd M.; Witzke, Oliver; Pajaro, Octavio E.; Yacoub, Magdi H.; Morris, Peter J.; Rose, Marlene L.; Wood, Kathryn J.

In: Transplantation, Vol. 73, No. 2, 27.01.2002, p. 279-286.

Research output: Contribution to journalArticle

Ensminger, SM, Spriewald, BM, Witzke, O, Pajaro, OE, Yacoub, MH, Morris, PJ, Rose, ML & Wood, KJ 2002, 'Indirect allorecognition can play an important role in the development of transplant arteriosclerosis', Transplantation, vol. 73, no. 2, pp. 279-286.
Ensminger SM, Spriewald BM, Witzke O, Pajaro OE, Yacoub MH, Morris PJ et al. Indirect allorecognition can play an important role in the development of transplant arteriosclerosis. Transplantation. 2002 Jan 27;73(2):279-286.
Ensminger, Stephan M. ; Spriewald, Bernd M. ; Witzke, Oliver ; Pajaro, Octavio E. ; Yacoub, Magdi H. ; Morris, Peter J. ; Rose, Marlene L. ; Wood, Kathryn J. / Indirect allorecognition can play an important role in the development of transplant arteriosclerosis. In: Transplantation. 2002 ; Vol. 73, No. 2. pp. 279-286.
@article{b227762590d748d19b54c255f0f3c198,
title = "Indirect allorecognition can play an important role in the development of transplant arteriosclerosis",
abstract = "Background. Indirect allorecognition has been implicated in the initiation of chronic allograft dysfunction. Our aim was to develop an animal model that allowed the contribution of the direct and indirect pathway of allorecognition in the evolution of transplant arteriosclerosis, the main feature of chronic allograft rejection, to be evaluated. Methods. Aortic allografts mismatched for a single MHC class I antigen were transplanted into athymic NUDE or RAG-/- mice. Immunodeficient mice were reconstituted with either CD4+ (indirect) or CD8+ (direct + indirect) T cells in the presence or absence of depleting antibodies specific for the opposite T-cell subset. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of cytokine mRNA production. Donor-specific alloantibody production was measured by fluorescence-activated cell sorter analysis. Results. Reconstitution of athymic nude mice with 4 × 107 purified CD4+ T cells resulted in vascular rejection of MHC class I mismatched aortic grafts. Intimal proliferation was 24±8{\%} and did not decrease when nude-derived endogenous CD8+ T cells were depleted from the nude recipients (intimal proliferation, 21±7{\%}). Transplant arteriosclerosis initiated by T cells was associated with the presence of intragraft mRNA for interferon-γ, tumor necrosis factor-α, inducible nitric oxide synthase, and interleukin 12. Reconstitution of RAG-1-/- mice with 4 × 107 purified CD4+ T cells resulted in a similar degree of transplant arteriosclerosis (intimal proliferation, 20±9{\%}) in MHC class I mismatched aortic grafts in the absence of alloantibody production. Conclusion. Indirect recognition of donor MHC class I molecules by CD4+ T cells can play an important role in the process of transplant arteriosclerosis. CD8+ T-cell effector function and alloantibody production in this model are dependent on CD4+ T-cell help after indirect allorecognition.",
author = "Ensminger, {Stephan M.} and Spriewald, {Bernd M.} and Oliver Witzke and Pajaro, {Octavio E.} and Yacoub, {Magdi H.} and Morris, {Peter J.} and Rose, {Marlene L.} and Wood, {Kathryn J.}",
year = "2002",
month = "1",
day = "27",
language = "English (US)",
volume = "73",
pages = "279--286",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Indirect allorecognition can play an important role in the development of transplant arteriosclerosis

AU - Ensminger, Stephan M.

AU - Spriewald, Bernd M.

AU - Witzke, Oliver

AU - Pajaro, Octavio E.

AU - Yacoub, Magdi H.

AU - Morris, Peter J.

AU - Rose, Marlene L.

AU - Wood, Kathryn J.

PY - 2002/1/27

Y1 - 2002/1/27

N2 - Background. Indirect allorecognition has been implicated in the initiation of chronic allograft dysfunction. Our aim was to develop an animal model that allowed the contribution of the direct and indirect pathway of allorecognition in the evolution of transplant arteriosclerosis, the main feature of chronic allograft rejection, to be evaluated. Methods. Aortic allografts mismatched for a single MHC class I antigen were transplanted into athymic NUDE or RAG-/- mice. Immunodeficient mice were reconstituted with either CD4+ (indirect) or CD8+ (direct + indirect) T cells in the presence or absence of depleting antibodies specific for the opposite T-cell subset. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of cytokine mRNA production. Donor-specific alloantibody production was measured by fluorescence-activated cell sorter analysis. Results. Reconstitution of athymic nude mice with 4 × 107 purified CD4+ T cells resulted in vascular rejection of MHC class I mismatched aortic grafts. Intimal proliferation was 24±8% and did not decrease when nude-derived endogenous CD8+ T cells were depleted from the nude recipients (intimal proliferation, 21±7%). Transplant arteriosclerosis initiated by T cells was associated with the presence of intragraft mRNA for interferon-γ, tumor necrosis factor-α, inducible nitric oxide synthase, and interleukin 12. Reconstitution of RAG-1-/- mice with 4 × 107 purified CD4+ T cells resulted in a similar degree of transplant arteriosclerosis (intimal proliferation, 20±9%) in MHC class I mismatched aortic grafts in the absence of alloantibody production. Conclusion. Indirect recognition of donor MHC class I molecules by CD4+ T cells can play an important role in the process of transplant arteriosclerosis. CD8+ T-cell effector function and alloantibody production in this model are dependent on CD4+ T-cell help after indirect allorecognition.

AB - Background. Indirect allorecognition has been implicated in the initiation of chronic allograft dysfunction. Our aim was to develop an animal model that allowed the contribution of the direct and indirect pathway of allorecognition in the evolution of transplant arteriosclerosis, the main feature of chronic allograft rejection, to be evaluated. Methods. Aortic allografts mismatched for a single MHC class I antigen were transplanted into athymic NUDE or RAG-/- mice. Immunodeficient mice were reconstituted with either CD4+ (indirect) or CD8+ (direct + indirect) T cells in the presence or absence of depleting antibodies specific for the opposite T-cell subset. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of cytokine mRNA production. Donor-specific alloantibody production was measured by fluorescence-activated cell sorter analysis. Results. Reconstitution of athymic nude mice with 4 × 107 purified CD4+ T cells resulted in vascular rejection of MHC class I mismatched aortic grafts. Intimal proliferation was 24±8% and did not decrease when nude-derived endogenous CD8+ T cells were depleted from the nude recipients (intimal proliferation, 21±7%). Transplant arteriosclerosis initiated by T cells was associated with the presence of intragraft mRNA for interferon-γ, tumor necrosis factor-α, inducible nitric oxide synthase, and interleukin 12. Reconstitution of RAG-1-/- mice with 4 × 107 purified CD4+ T cells resulted in a similar degree of transplant arteriosclerosis (intimal proliferation, 20±9%) in MHC class I mismatched aortic grafts in the absence of alloantibody production. Conclusion. Indirect recognition of donor MHC class I molecules by CD4+ T cells can play an important role in the process of transplant arteriosclerosis. CD8+ T-cell effector function and alloantibody production in this model are dependent on CD4+ T-cell help after indirect allorecognition.

UR - http://www.scopus.com/inward/record.url?scp=0037180932&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037180932&partnerID=8YFLogxK

M3 - Article

VL - 73

SP - 279

EP - 286

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 2

ER -