In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 70, No. 4 ( 2001-10-01), p. 510-517
Abstract:
Leukocytes infiltrate the pancreatic islets of nonobese diabetic mice, causing β-cell destruction and autoimmune Type I diabetes. Here, wecompletely blocked adoptive transfer of diabetes and reducedspontaneous disease incidence from 71% to 17% by simultaneouslyadministering a combination of antibodies directed against α4, β2,and β7 integrins and their ligands VCAM-1, MAdCAM-1, and ICAM-1 for52 and 28 days, respectively. CD4 and CD8 T cells and macrophages wereexcluded from islets and remained entrapped in a peri-islet location asinactive exiles, no longer expressing normal levels of interferon-γ,interleukin-4, and iNOS. Only IL-10 expression was retained, whichcould aid immunosuppression. Infiltrating leukocytes retained aperi-islet location, even 215 days following suspension of antibodytreatment, potentially forming a barrier to the entry of active, autoantigen-reactive T cells. Combination treatment was effectiveagainst spontaneous disease when administered from 7 days of age butineffective when initiated late in the prediabetic period (day 40 or70). Nevertheless, anti-α4 subunit mAb monotherapy alone was veryeffective, reducing insulitis to levels similar to those obtained withcombinational antibody treatment, suggesting that α4 integrins aremajor receptors contributing to leukocyte infiltration. Treatment withanti-α4 integrin antibody retained some therapeutic benefit whenadministered from days 7, 40, or 70 of age. The results haveimplications for the treatment of diabetes and provide a unique insightinto the fate of disease-forming leukocytes following anti-CAMtherapy.
Type of Medium:
Online Resource
ISSN:
0741-5400
,
1938-3673
DOI:
10.1189/jlb.70.4.510
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2001
detail.hit.zdb_id:
2026833-6
SSG:
12
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