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

Leukocytes infiltrate the pancreatic islets of nonobese diabetic mice, caus ing beta -cell destruction and autoimmune Type I diabetes. Here, we complet ely blocked adoptive transfer of diabetes and reduced spontaneous disease i ncidence from 71% to 17% by simultaneously administering a combination of a ntibodies directed against alpha4, beta2, and beta7 integrins and their lig ands 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 entrapp ed in a peri-islet location as inactive exiles, no longer expressing normal levels of interferon-gamma, interleukin-4, and iNOS. Only IL-10 expression was retained, which could aid immunosuppression. Infiltrating leukocytes r etained a peri-islet location, even 215 days following suspension of antibo dy treatment, potentially forming a barrier to the entry of active, autoant igen-reactive T cells. Combination treatment was effective against spontane ous disease when administered from 7 days of age but ineffective when initi ated late in the prediabetic period (day 40 or 70). Nevertheless, anti-alph aA subunit mAb monotherapy alone was very effective, reducing insulitis to levels similar to those obtained with combinational antibody treatment, sug gesting that alpha4 integrins are major receptors contributing to leukocyte infiltration. Treatment with anti-alpha4 integrin antibody retained some t herapeutic benefit when administered from days 7, 40, or 70 of age. The res ults have implications for the treatment of diabetes and provide a unique i nsight into the fate of disease-forming leukocytes following anti-CAM thera py.