Protection against adoptive transfer of autoimmune diabetes mediated through very late antigen-4 integrin.
The very late antigen-4 (VLA-4) integrin expressed on the surface of lymphocytes and macrophages can regulate their migration to inflammatory sites as well as control cellular activation. The role of VLA-4 in the establishment of autoimmune diabetes is not easily predicted given the multiplicity of adhesion pathways and their differential use by various cell types. The contribution of VLA-4 to insulin-dependent diabetes mellitus was investigated by administration of VLA-4-specific monoclonal antibodies (MoAb) in an adoptive transfer model of disease in NOD mice. This study shows that VLA-4-specific MoAbs profoundly inhibit the development of diabetes with protection sustained by repeated MoAb exposure. Insulitis was completely inhibited during treatment and progressed to a severe degree once MoAb treatment was suspended, yet approximately 40% of treated recipients failed to become diabetic during 1-2 months post-treatment. Although we cannot rule out depletion of a relatively minor subpopulation of cells by prolonged anti-VLA-4 MoAb exposure, this inhibition of diabetes onset by treatment with MoAbs to VLA-4 supports a dependence on VLA-4 for cellular functions leading to diabetes and demonstrates that a significant disease modifying effect can be mediated by targeting the VLA-4 integrin.
Burkly
L C
LC
Department of Immunology, Biogen, Cambridge, Massachusetts 02142.
Jakubowski
A
A
Hattori
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D016219:Immunotherapy, Adoptive; D007328:Insulin / Q000032:analysis / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D010182:Pancreatic Diseases / Q000276:immunology / Q000473:pathology; D016029:Receptors, Very Late Antigen / Q000276:immunology / Q000502:physiology*; D013154:Spleen / Q000276:immunology
D000911:Antibodies, Monoclonal; D007328:Insulin; D016029:Receptors, Very Late Antigen