The pathogenesis of adoptive murine autoimmune diabetes requires an interaction between alpha 4-integrins and vascular cell adhesion molecule-1.
An adoptive transfer model of insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic mouse was used to examine the roles of alpha 4-integrin, vascular cell adhesion molecule 1 (VCAM-1); and intercellular adhesion molecule 1 (ICAM-1) in the pathogenesis of autoimmune diabetes. Antibodies specific for both alpha 4-integrin and one of its ligands, VCAM-1, were able to delay onset of diabetes and decrease the incidence of the disease in adoptive transfer studies. This blocking of disease was accompanied by a marked decrease in lymphocytic infiltration of the islets of Langerhans. Furthermore, these antibodies preferentially block entrance of CD4 T cells into the tissue. Antibodies specific for ICAM-1 had little effect on the onset or incidence of IDDM. Thus, we conclude that an alpha 4-integrin-VCAM-1 interaction is important in T cell entry into the islets of Langerhans and in the pathogenesis of IDDM. In addition, the cascade of events leading to T cell transit across endothelium may be different for CD4 and CD8 cells, and may differ depending on the endothelium involved. Our results support the more general conclusion that an alpha 4-integrin-VCAM-1 interaction may be crucial in allowing activated effector CD4T cells to leave the blood and enter tissue to clear infection.
Baron
J L
JL
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510.
Reich
E P
EP
Visintin
I
I
Janeway
C A
CA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016516:CD4-CD8 Ratio; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D016219:Immunotherapy, Adoptive; D016023:Integrins / Q000032:analysis / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016029:Receptors, Very Late Antigen / Q000502:physiology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D016023:Integrins; D016029:Receptors, Very Late Antigen; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1