Involvement of beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the development of diabetes in obese diabetic mice.
Nonobese diabetic (NOD) mice develop autoimmune-mediated lymphocytic inflammation of pancreatic islets (insulitis) that leads to beta-cell destruction and development of diabetes. Inflamed islets show expression of lymphocyte alpha 4 beta 7 integrin and endothelial mucosal addressin cell adhesion molecule-1 (MAdCAM-1), adhesion molecules involved in tissue-selective migration of lymphocytes to mucosal lymphoid tissues. To elucidate the roles of the mucosal lymphocyte/endothelial adhesion system in the development of diabetes, we treated NOD mice with monoclonal antibody against beta 7 integrin or MAdCAM-1. Treatment of mice from age 7 to 28 days or 8 to 12 weeks with either antibody led to significant and long-standing protection against the spontaneous development of diabetes and insulitis. In contrast, neither treatment prevented the development of salivary gland inflammation (sialadenitis), indicating that the effect was tissue-selective. Monoclonal antibody treatment had no demonstrable effect on numbers or phenotypes of peripheral lymphocytes or on the immune response to pancreatic islet or exogenous antigens. These data indicate that lymphocyte and endothelial adhesion molecules involved in the migration of lymphocytes into mucosal lymphoid tissues play a role in the development of diabetes in NOD mice. Moreover, the results suggest that treatment of humans with antibodies against tissue-selective lymphocyte or endothelial adhesion molecules may selectively inhibit the development of autoimmune diseases such as diabetes.
Yang
X D
XD
Department of Microbiology and Immunology, Stanford University School of Medicine, California, USA.
Sytwu
H K
HK
McDevitt
H O
HO
Michie
S A
SA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001324:Autoantigens / Q000276:immunology; D015815:Cell Adhesion Molecules; D003920:Diabetes Mellitus / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D007136:Immunoglobulins / Q000494:pharmacology / Q000502:physiology*; D007167:Immunotherapy; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009088:Mucoproteins / Q000494:pharmacology / Q000502:physiology*; D010195:Pancreatitis / Q000517:prevention & control; D012793:Sialadenitis / Q000517:prevention & control; D013154:Spleen / Q000473:pathology
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C071777:integrin alpha4beta7