INHIBITION OF SUBMANDIBULAR AND LACRIMAL GLAND INFILTRATION IN NONOBESE DIABETIC MICE BY TRANSGENIC EXPRESSION OF SOLUBLE TNF-RECEPTOR P55

Besides a prominent mononuclear cell infiltration of the islets of Lan gerhans, nonobese diabetic (NOD) mice also show massive cellular infil trates of the submandibular and lacrimal glands concomitant with histo logical signs of tissue damage, To obtain insights into the mechanisms operative during the initiation and progression of tissue damage, we followed by in situ hybridization the appearance of cells containing m RNA of the gene encoding the proinflammatory cytokine TNF-alpha in the cellular infiltrates, Cells expressing TNF-alpha are mainly located i n infiltrates, are absent in nonaffected glands, and are preferentiall y found among CD4(+) T cells, Secretion of TNF-alpha by gland-infiltra ting cells was confirmed by an ELISPOT procedure, Direct evidence for an instrumental role of TNF-alpha in initiation and progression of sub mandibular and lacrimal gland infiltration is provided by the observed significant reduction in the extent of infiltration in nonobese diabe tic mice transgenic for a soluble TNF receptor p55 fused to the Fc par t of human IgG3, This protection from infiltration is paralleled by de creased expression of the adhesion molecules ICAM-1 and VCAM-1 in subm andibular and lacrimal glands, These data suggest a central role of TN F-alpha in the initiation and progression of autoimmune tissue destruc tion of salivary glands and indicate beneficial effects of soluble TNF receptors in the treatment of organ-specific autoimmune diseases.