Expression of Intercellular Adhesion Molecule 1 on Pancreatic β-Cells Accelerates β-Cell Destruction by Cytotoxic T-Cells in Murine Autoimmune Diabetes

Abstract

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by being involved in the extravasation of lymphocytes from the circulation into the inflamed pancreas. However, the mechanism of beta-cell destruction by which expression of ICAM-1 on beta-cells may facilitate adhesion of effector cells still remains to be elucidated. Several lines of evidence suggest that this adhesion molecule is involved in the destruction of pancreatic beta-cells by killer lymphocytes in the NOD mouse, which shows an autoimmune diabetic syndrome similar to that of human IDDM. Immunohistochemical study under light microscopy demonstrated that all of the mononuclear cells infiltrating the islets strongly expressed ICAM-1 and leukocyte function-associated antigen 1 (LFA-1), a counterreceptor of ICAM-1, whereas ICAM-1 expression on islet cells was not apparent. However, immunohistochemical staining under electron microscopy revealed that islet beta-cells adjacent to infiltrating lymphocytes were clearly stained by an anti-ICAM-1 monoclonal antibody (mAb). Flow cytometric analysis showed that the ICAM-1 expression on NOD islet cells and NOD-derived insulinoma cells (MIN6N8a) was inducible by interferon (IFN)-gamma or tumor necrosis factor-alpha. These cytokines had an additive effect on the ICAM-1 induction. Susceptibility of MIN6N8a cells to lysis by a NOD islet-derived CD8+ cytotoxic T-cell clone was greatly enhanced by IFN-gamma pretreatment, and this enhancement was abolished by anti-ICAM-1 and anti-LFA-1 mAbs. When both mAbs were administered into NOD mice with spontaneous or adoptively transferred diabetes, the development of diabetes was significantly prevented.(ABSTRACT TRUNCATED AT 250 WORDS)

CD8 cytotoxic T-cell clone rapidly transfers autoimmune diabetes in very young NOD and MHC class I-compatible scid mice

“…However, this clone did not respond to NOD spleen cells, C57BL/6 islets, and B6-derived insulinoma MIN6. As previously reported [14] gradually diabetic during 6 weeks after transfer. However, only 1 of 6 NOD mice became diabetic when 1 × 10 6 YNK1.3 cells were administered at 7-daysold.…”

“…Recent reports demonstrate that lymphocytic inflammation is mediated largely by LFA-1/ICAM-1 and very late antigen-4 (VLA-4; a 4/b1-integrin)/ VCAM-1 interactions [16,17]. Significant contribution of these two pairs of adhesion molecules to autoimmune inflammation of pancreatic islets in NOD mice was also reported [14,[18][19][20][21][22]. YNK1.3 cells expressed the activation marker CD25 and the adhesion molecule LFA-1, ICAM-1, but not CD28, CD69 and a 4-integrin.…”

“…Seven-day-old NOD mice were injected intraperitoneally with 500 m g of either R1-2; anti-a4-integrin and M/K2; anti-vascular cell adhesion molecule-1 (VCAM-1) mAbs [13] or KAT-1; anti-intercellular adhesion molecule-1 (ICAM-1) and KBA; anti-leukocyte function-associated antigen-1 (LFA-1) mAbs [14] ) were preincubated with 10 m g/ml relevant mAbs for 30 min at 4°C before injection into corresponding mAbspretreated NOD recipients. Diabetic incidence was monitored up to 7 days after transfer and pancreatic insulitis of four mice in each group was evaluated at 3 days after transfer.…”

“…Diabetic incidence was monitored up to 7 days after transfer and pancreatic insulitis of four mice in each group was evaluated at 3 days after transfer. The severity of insulitis was assessed by using the scoring system as follows [13,14]: 0) normal islets; 1) mononuclear cell infiltration in less than 25 % of the islets; 2) 25-50 % of the islet infiltrated; 3) over 50 % infiltrated; 4) small retracted islets with few mononuclear cells.…”

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

“…Miyagaki, Osaka University, Osaka, Japan) (26), were grown in DMEM containing 15% FBS, 2 mM glutamine, and penicillin-streptomycin (Life Technologies, Gaithersburg, MD). Recombinant rat IFN-␥ was generously provided by P. H. van der Meide (Utrecht University, Utrecht, The Netherlands).…”