Mucosal addressin is required for the development of diabetes in nonobese diabetic mice.
Immune responses are best initiated in the environment of lymphoid tissues wherein circulating lymphocytes enter by interacting with endothelial adhesion molecules. In type 1 diabetes, immune responses against pancreatic islets develop, but the environment in which this occurs remains unidentified. To determine whether lymphocyte homing to lymphoid organs is involved in the pathogenesis of diabetes in nonobese diabetic (NOD) mice, we blocked the function of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is a vascular addressin-mediating lymphocyte homing into mucosal lymphoid tissues, in these mice. While ineffective if started later, a blockade started at 3 wk of age reduced the incidence of diabetes from 50% to 9% (p < 0.01). This finding is associated with Peyer's patch atrophy, a marked decrease of naive (CD44(low) CD45RB(high)) T lymphocytes, and a reduction in the relative numbers of memory (CD44(high)) T lymphocytes in the spleen. The potential of these spleen cells to cause diabetes was diminished. Anti-MAdCAM-1 treatment also inhibited both lymphocyte entry into the pancreas and diabetes development in NOD/SCID recipients after the transfer of lymphocytes derived from the mesenteric lymph nodes of young, but not of diabetic, NOD donors. Therefore, MAdCAM-1 may be required during two distinct steps in an early phase of diabetes development: for the entry of naive lymphocytes into the lymphoid tissues in which diabetes-causing lymphocytes are originally primed, and for the subsequent homing of these lymphocytes into the pancreas. The role of MAdCAM-1 as a mucosal vascular addressin suggests that mucosal lymphoid tissues are involved in the initiation of pathologic immune responses in NOD mice.
Hänninen
A
A
MediCity Research Laboratory, University of Turku, Finland.
Jaakkola
I
I
Jalkanen
S
S
D019264:Adoptive Transfer; D000818:Animals; D015815:Cell Adhesion Molecules; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D005260:Female; D018960:Hyaluronan Receptors / Q000032:analysis; D007136:Immunoglobulins / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D016688:Mice, Inbred NOD; D009088:Mucoproteins / Q000502:physiology*; D010179:Pancreas / Q000276:immunology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D013154:Spleen / Q000276:immunology
D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D007136:Immunoglobulins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1