α4 integrin in islet allograft rejection1

Mark D Stegall, Patrick G. Dean, Dora Ninova, Ari J. Cohen, Guy M. Shepard, Carol Gup, Ronald G. Gill

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background. Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between α4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival. Methods. Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against α4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of α4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis. Results. Treatment with anti-α4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-α4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, α4 integrin+, cytotoxic T cells. Conclusions. These data show that α4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualita tively affecting either T cell activation or migration to the graft. Conversely, anti-α4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between α4 integrin and its ligands may provide novel forms of immunosuppression.

Original languageEnglish (US)
Pages (from-to)1549-1555
Number of pages7
JournalTransplantation
Volume71
Issue number11
StatePublished - Jun 15 2001

Fingerprint

Integrins
Allografts
Vascular Cell Adhesion Molecule-1
Transplants
Peptides
Antibodies
T-Lymphocytes
Ligands
Streptozocin
Fibronectins
Hyperglycemia
Immunosuppression
Blood Glucose
Tail
Anti-Idiotypic Antibodies
Veins
Transplantation
Binding Sites
Kidney

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Stegall, M. D., Dean, P. G., Ninova, D., Cohen, A. J., Shepard, G. M., Gup, C., & Gill, R. G. (2001). α4 integrin in islet allograft rejection1 Transplantation, 71(11), 1549-1555.

α4 integrin in islet allograft rejection1 . / Stegall, Mark D; Dean, Patrick G.; Ninova, Dora; Cohen, Ari J.; Shepard, Guy M.; Gup, Carol; Gill, Ronald G.

In: Transplantation, Vol. 71, No. 11, 15.06.2001, p. 1549-1555.

Research output: Contribution to journalArticle

Stegall, MD, Dean, PG, Ninova, D, Cohen, AJ, Shepard, GM, Gup, C & Gill, RG 2001, 'α4 integrin in islet allograft rejection1 ', Transplantation, vol. 71, no. 11, pp. 1549-1555.
Stegall MD, Dean PG, Ninova D, Cohen AJ, Shepard GM, Gup C et al. α4 integrin in islet allograft rejection1 Transplantation. 2001 Jun 15;71(11):1549-1555.
Stegall, Mark D ; Dean, Patrick G. ; Ninova, Dora ; Cohen, Ari J. ; Shepard, Guy M. ; Gup, Carol ; Gill, Ronald G. / α4 integrin in islet allograft rejection1 In: Transplantation. 2001 ; Vol. 71, No. 11. pp. 1549-1555.
@article{5c16c412a10846f3a83ef7cef2543f39,
title = "α4 integrin in islet allograft rejection1",
abstract = "Background. Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between α4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival. Methods. Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against α4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of α4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis. Results. Treatment with anti-α4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-α4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, α4 integrin+, cytotoxic T cells. Conclusions. These data show that α4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualita tively affecting either T cell activation or migration to the graft. Conversely, anti-α4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between α4 integrin and its ligands may provide novel forms of immunosuppression.",
author = "Stegall, {Mark D} and Dean, {Patrick G.} and Dora Ninova and Cohen, {Ari J.} and Shepard, {Guy M.} and Carol Gup and Gill, {Ronald G.}",
year = "2001",
month = "6",
day = "15",
language = "English (US)",
volume = "71",
pages = "1549--1555",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - α4 integrin in islet allograft rejection1

AU - Stegall, Mark D

AU - Dean, Patrick G.

AU - Ninova, Dora

AU - Cohen, Ari J.

AU - Shepard, Guy M.

AU - Gup, Carol

AU - Gill, Ronald G.

PY - 2001/6/15

Y1 - 2001/6/15

N2 - Background. Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between α4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival. Methods. Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against α4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of α4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis. Results. Treatment with anti-α4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-α4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, α4 integrin+, cytotoxic T cells. Conclusions. These data show that α4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualita tively affecting either T cell activation or migration to the graft. Conversely, anti-α4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between α4 integrin and its ligands may provide novel forms of immunosuppression.

AB - Background. Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between α4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival. Methods. Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against α4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of α4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis. Results. Treatment with anti-α4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-α4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, α4 integrin+, cytotoxic T cells. Conclusions. These data show that α4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualita tively affecting either T cell activation or migration to the graft. Conversely, anti-α4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between α4 integrin and its ligands may provide novel forms of immunosuppression.

UR - http://www.scopus.com/inward/record.url?scp=0035874624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035874624&partnerID=8YFLogxK

M3 - Article

VL - 71

SP - 1549

EP - 1555

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 11

ER -