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(Journal of Leukocyte Biology. 2001;70:510-517.)
© 2001 by Society for Leukocyte Biology

Leukocytes infiltrating the pancreatic islets of nonobese diabetic mice are transformed into inactive exiles by combinational anti-cell adhesion therapy

Sharada Kommajosyula^*, Shiva Reddy, Kristina Nitschke, Jagat R. Kanwar^*, Muralidhar Karanam and Geoffrey W. Krissansen^*

Departments of
^* Molecular Medicine and
Pediatrics, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand

Correspondence: Geoffrey W. Krissansen, Associate Professor, Department of Molecular Medicine, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand. E-mail: gw.krissansen{at}auckland.ac.nz Received October 6, 2000; revised March 6, 2001; revised May 25, 2001; accepted May 29, 2001.

Leukocytes infiltrate the pancreatic islets of nonobese diabetic mice, causing ß-cell destruction and autoimmune Type I diabetes. Here, we completely blocked adoptive transfer of diabetes and reduced spontaneous disease incidence from 71% to 17% by simultaneously administering a combination of antibodies directed against 4, ß2, and ß7 integrins and their ligands VCAM-1, MAdCAM-1, and ICAM-1 for 52 and 28 days, respectively. CD4 and CD8 T cells and macrophages were excluded from islets and remained entrapped in a peri-islet location as inactive exiles, no longer expressing normal levels of interferon-, interleukin-4, and iNOS. Only IL-10 expression was retained, which could aid immunosuppression. Infiltrating leukocytes retained a peri-islet location, even 215 days following suspension of antibody treatment, potentially forming a barrier to the entry of active, autoantigen-reactive T cells. Combination treatment was effective against spontaneous disease when administered from 7 days of age but ineffective when initiated late in the prediabetic period (day 40 or 70). Nevertheless, anti-4 subunit mAb monotherapy alone was very effective, reducing insulitis to levels similar to those obtained with combinational antibody treatment, suggesting that 4 integrins are major receptors contributing to leukocyte infiltration. Treatment with anti-4 integrin antibody retained some therapeutic benefit when administered from days 7, 40, or 70 of age. The results have implications for the treatment of diabetes and provide a unique insight into the fate of disease-forming leukocytes following anti-CAM therapy.

Key Words: integrins • MAdCAM-1 • VCAM-1 • ICAM-1 • diabetes • insulitis

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