Macrophage and lymphocyte homing in experimental diabetes

Diabetes mellitus was induced in C57BL/6 mice by multiple low doses of streptozotozin (STZ). By transferring lymphocytes from these diabetic animals to healthy recipient mice insulitis can be induced in healthy recipient mice. On day 21 after the start of STZ-treatment splenic lymphocytes were separated in vitro and stained with the fluorochrom acridine red for adoptive transfer. The recipient mouse had been pretreated with a subdiabetogenic dose of STZ (5 mg/kg) i.p. 24 h prior to the lymphocyte transfer. With in vivo microscopy we measured the lymphocyte adherence to the endothelium of islets of the recipient mouse. After the administration of mAbs directed against LFA-1, ICAM-1, murine VCAM-1, VLA-4, MadCAM or alpha4,beta7-integrin prior to the cell transfer we could demonstrate a significant decrease of donor lymphocyte adherence in islets (P<0.01). The pretreatment of the recipient mice with STZ 24 h before the transfer of lymphocytes might attract macrophages to the islets. Therefore we pretreated the recipients with antibodies to cytokines or silica. mAb IFN-gamma, pAb TNF-alpha, pAb IL-1alpha or silica reduced lymphocyte adherence to islet endothelium significantly (P<0.01). The presented results support the following interpretation: The pretreatment of the recipient mice with the islet specific toxin STZ in subdiabetogenic doses attracts macrophages to the islets. The macrophages release cytokines leading to an increased expression of adhesion molecules on the endothelium of the islets. The consequence is lymphocyte homing selectively to the islets. The cascade of lymphocyte homing is complex and various pairs of adhesion molecules are involved. The discussion on the importance of the single pairs of adhesion molecules is irrelevant, since the cascade of lymphocyte homing can be disturbed by the application of a mAb to any one adhesion molecule involved in the cascade of lymphocyte homing.