Costimulatory Blockade-Mediated Lung Allograft Acceptance Is Abrogated by Overexpression of Bcl-2 in the Recipient

Mikio Okazaki, Seiichiro Sugimoto, J. Lai, C. G. Kornfeld, R. S. Hotchkiss, S. B. Richardson, W. Li, F. H. Kreisel, H. J. Huang, G. A. Patterson, A. S. Krupnick, A. E. Gelman, D. Kreisel

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Lung allografts are considered to be more immunogenic than other solid organs. Little is known about the effectiveness of immunosuppressive regimens after lung transplantation. Herein, we describe a novel model of murine vascularized orthotopic lung transplantation we used to study the effects of costimulatory blockade on lung rejection. Transplants were performed in the Balb → B6 strain combination. Recipients were either not immunosuppressed or received perioperative CD40/CD40L and CD28/B7 costimulatory blockade. Nonimmunosupressed Balb/c → B6 lung transplants had severe acute rejection 7 days after transplantation and CD8 + T cells outnumbered CD4 + T cells within the allografts. Alternatively, B6 recipients that received perioperative costimulatory blockade had minimal inflammation and there were nearly equal numbers of CD8 + and CD4 + T cells in these grafts. Approximately one third of graft-infiltrating CD4 + T cells expressed Foxp3. CD4 + T cells isolated from these grafts induced apoptosis of alloreactive CD8 + T cells that were stimulated with donor splenocytes in vitro. In contrast with wild-type B6 recipient mice, we observed severe rejection of Balb/c lungs 7 days after transplantation into Bcl-2 transgenic B6 recipients that had received costimulatory blockade. CD8 + T cells outnumbered CD4 + T cells in these immunosuppressed Bcl-2 transgenic recipients and, compared with immunosuppressed wild-type B6 recipients, a lower percentage of graft-infiltrating CD4 + T cells expressed Foxp3, and a higher percentage of graft-infiltrating CD8 + T cells expressed intereferon-γ. Thus, our results show that perioperative blockade of the CD40/CD40L and CD28/B7 costimulatory pathways markedly ameliorates acute rejection of lung allografts in wild type but not Bcl-2 transgenic recipients.

Original languageEnglish
Pages (from-to)385-387
Number of pages3
JournalTransplantation Proceedings
Volume41
Issue number1
DOIs
Publication statusPublished - Jan 2009
Externally publishedYes

Fingerprint

Allografts
T-Lymphocytes
Lung
Transplants
CD40 Ligand
Lung Transplantation
Transplantation
Immunosuppressive Agents
Apoptosis
Inflammation

ASJC Scopus subject areas

  • Surgery
  • Transplantation

Cite this

Costimulatory Blockade-Mediated Lung Allograft Acceptance Is Abrogated by Overexpression of Bcl-2 in the Recipient. / Okazaki, Mikio; Sugimoto, Seiichiro; Lai, J.; Kornfeld, C. G.; Hotchkiss, R. S.; Richardson, S. B.; Li, W.; Kreisel, F. H.; Huang, H. J.; Patterson, G. A.; Krupnick, A. S.; Gelman, A. E.; Kreisel, D.

In: Transplantation Proceedings, Vol. 41, No. 1, 01.2009, p. 385-387.

Research output: Contribution to journalArticle

Okazaki, M, Sugimoto, S, Lai, J, Kornfeld, CG, Hotchkiss, RS, Richardson, SB, Li, W, Kreisel, FH, Huang, HJ, Patterson, GA, Krupnick, AS, Gelman, AE & Kreisel, D 2009, 'Costimulatory Blockade-Mediated Lung Allograft Acceptance Is Abrogated by Overexpression of Bcl-2 in the Recipient', Transplantation Proceedings, vol. 41, no. 1, pp. 385-387. https://doi.org/10.1016/j.transproceed.2008.10.068
Okazaki, Mikio ; Sugimoto, Seiichiro ; Lai, J. ; Kornfeld, C. G. ; Hotchkiss, R. S. ; Richardson, S. B. ; Li, W. ; Kreisel, F. H. ; Huang, H. J. ; Patterson, G. A. ; Krupnick, A. S. ; Gelman, A. E. ; Kreisel, D. / Costimulatory Blockade-Mediated Lung Allograft Acceptance Is Abrogated by Overexpression of Bcl-2 in the Recipient. In: Transplantation Proceedings. 2009 ; Vol. 41, No. 1. pp. 385-387.
@article{4322e841e01947389b603de23b361dda,
title = "Costimulatory Blockade-Mediated Lung Allograft Acceptance Is Abrogated by Overexpression of Bcl-2 in the Recipient",
abstract = "Lung allografts are considered to be more immunogenic than other solid organs. Little is known about the effectiveness of immunosuppressive regimens after lung transplantation. Herein, we describe a novel model of murine vascularized orthotopic lung transplantation we used to study the effects of costimulatory blockade on lung rejection. Transplants were performed in the Balb → B6 strain combination. Recipients were either not immunosuppressed or received perioperative CD40/CD40L and CD28/B7 costimulatory blockade. Nonimmunosupressed Balb/c → B6 lung transplants had severe acute rejection 7 days after transplantation and CD8 + T cells outnumbered CD4 + T cells within the allografts. Alternatively, B6 recipients that received perioperative costimulatory blockade had minimal inflammation and there were nearly equal numbers of CD8 + and CD4 + T cells in these grafts. Approximately one third of graft-infiltrating CD4 + T cells expressed Foxp3. CD4 + T cells isolated from these grafts induced apoptosis of alloreactive CD8 + T cells that were stimulated with donor splenocytes in vitro. In contrast with wild-type B6 recipient mice, we observed severe rejection of Balb/c lungs 7 days after transplantation into Bcl-2 transgenic B6 recipients that had received costimulatory blockade. CD8 + T cells outnumbered CD4 + T cells in these immunosuppressed Bcl-2 transgenic recipients and, compared with immunosuppressed wild-type B6 recipients, a lower percentage of graft-infiltrating CD4 + T cells expressed Foxp3, and a higher percentage of graft-infiltrating CD8 + T cells expressed intereferon-γ. Thus, our results show that perioperative blockade of the CD40/CD40L and CD28/B7 costimulatory pathways markedly ameliorates acute rejection of lung allografts in wild type but not Bcl-2 transgenic recipients.",
author = "Mikio Okazaki and Seiichiro Sugimoto and J. Lai and Kornfeld, {C. G.} and Hotchkiss, {R. S.} and Richardson, {S. B.} and W. Li and Kreisel, {F. H.} and Huang, {H. J.} and Patterson, {G. A.} and Krupnick, {A. S.} and Gelman, {A. E.} and D. Kreisel",
year = "2009",
month = "1",
doi = "10.1016/j.transproceed.2008.10.068",
language = "English",
volume = "41",
pages = "385--387",
journal = "Transplantation Proceedings",
issn = "0041-1345",
publisher = "Elsevier USA",
number = "1",

}

TY - JOUR

T1 - Costimulatory Blockade-Mediated Lung Allograft Acceptance Is Abrogated by Overexpression of Bcl-2 in the Recipient

AU - Okazaki, Mikio

AU - Sugimoto, Seiichiro

AU - Lai, J.

AU - Kornfeld, C. G.

AU - Hotchkiss, R. S.

AU - Richardson, S. B.

AU - Li, W.

AU - Kreisel, F. H.

AU - Huang, H. J.

AU - Patterson, G. A.

AU - Krupnick, A. S.

AU - Gelman, A. E.

AU - Kreisel, D.

PY - 2009/1

Y1 - 2009/1

N2 - Lung allografts are considered to be more immunogenic than other solid organs. Little is known about the effectiveness of immunosuppressive regimens after lung transplantation. Herein, we describe a novel model of murine vascularized orthotopic lung transplantation we used to study the effects of costimulatory blockade on lung rejection. Transplants were performed in the Balb → B6 strain combination. Recipients were either not immunosuppressed or received perioperative CD40/CD40L and CD28/B7 costimulatory blockade. Nonimmunosupressed Balb/c → B6 lung transplants had severe acute rejection 7 days after transplantation and CD8 + T cells outnumbered CD4 + T cells within the allografts. Alternatively, B6 recipients that received perioperative costimulatory blockade had minimal inflammation and there were nearly equal numbers of CD8 + and CD4 + T cells in these grafts. Approximately one third of graft-infiltrating CD4 + T cells expressed Foxp3. CD4 + T cells isolated from these grafts induced apoptosis of alloreactive CD8 + T cells that were stimulated with donor splenocytes in vitro. In contrast with wild-type B6 recipient mice, we observed severe rejection of Balb/c lungs 7 days after transplantation into Bcl-2 transgenic B6 recipients that had received costimulatory blockade. CD8 + T cells outnumbered CD4 + T cells in these immunosuppressed Bcl-2 transgenic recipients and, compared with immunosuppressed wild-type B6 recipients, a lower percentage of graft-infiltrating CD4 + T cells expressed Foxp3, and a higher percentage of graft-infiltrating CD8 + T cells expressed intereferon-γ. Thus, our results show that perioperative blockade of the CD40/CD40L and CD28/B7 costimulatory pathways markedly ameliorates acute rejection of lung allografts in wild type but not Bcl-2 transgenic recipients.

AB - Lung allografts are considered to be more immunogenic than other solid organs. Little is known about the effectiveness of immunosuppressive regimens after lung transplantation. Herein, we describe a novel model of murine vascularized orthotopic lung transplantation we used to study the effects of costimulatory blockade on lung rejection. Transplants were performed in the Balb → B6 strain combination. Recipients were either not immunosuppressed or received perioperative CD40/CD40L and CD28/B7 costimulatory blockade. Nonimmunosupressed Balb/c → B6 lung transplants had severe acute rejection 7 days after transplantation and CD8 + T cells outnumbered CD4 + T cells within the allografts. Alternatively, B6 recipients that received perioperative costimulatory blockade had minimal inflammation and there were nearly equal numbers of CD8 + and CD4 + T cells in these grafts. Approximately one third of graft-infiltrating CD4 + T cells expressed Foxp3. CD4 + T cells isolated from these grafts induced apoptosis of alloreactive CD8 + T cells that were stimulated with donor splenocytes in vitro. In contrast with wild-type B6 recipient mice, we observed severe rejection of Balb/c lungs 7 days after transplantation into Bcl-2 transgenic B6 recipients that had received costimulatory blockade. CD8 + T cells outnumbered CD4 + T cells in these immunosuppressed Bcl-2 transgenic recipients and, compared with immunosuppressed wild-type B6 recipients, a lower percentage of graft-infiltrating CD4 + T cells expressed Foxp3, and a higher percentage of graft-infiltrating CD8 + T cells expressed intereferon-γ. Thus, our results show that perioperative blockade of the CD40/CD40L and CD28/B7 costimulatory pathways markedly ameliorates acute rejection of lung allografts in wild type but not Bcl-2 transgenic recipients.

UR - http://www.scopus.com/inward/record.url?scp=60949093099&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60949093099&partnerID=8YFLogxK

U2 - 10.1016/j.transproceed.2008.10.068

DO - 10.1016/j.transproceed.2008.10.068

M3 - Article

C2 - 19249562

AN - SCOPUS:60949093099

VL - 41

SP - 385

EP - 387

JO - Transplantation Proceedings

JF - Transplantation Proceedings

SN - 0041-1345

IS - 1

ER -