Long-term reversal of established autoimmunity upon transient blockade of the LFA-1/intercellular adhesion molecule-1 pathway.
Transgenic models and administration of mAbs directed against the LFA-1/intercellular adhesion molecule 1 (ICAM-1) pathway have shown that these costimulatory molecules play a key role in generating effector cells mediating inflammatory responses. In this report, durable remission of recent diabetes in nonobese diabetic (NOD) mice was induced by transient expression of an immunoadhesin gene encoding the soluble form of ICAM-1 (sICAM-1/Ig). A single i.v. injection of an adenovirus vector encoding the immunoadhesin gene led to 70% diabetes remission as opposed to 0% in mice injected with a control adenovirus vector. Despite the rapid decline of sICAM-1/Ig serum levels, diabetes remission remained stable in 50% of NOD mice for >6 mo. sICAM-1/Ig expression also led to long-term protection against diabetes in prediabetic NOD mice. sICAM-1/Ig in vitro induced an agonistic effect of T cell activation in a TCR-transgenic model, increasing T cell proliferation and IL-2 secretion. Importantly, protected mice were not immunosuppressed because they rejected skin allografts normally and developed immunity against the adenovirus vector. Rather, sICAM-1/Ig induced active tolerance, as assessed by the persistence of diabetogenic T cells in protected mice and the reversal of protection by immunosuppression with cyclophosphamide.
Bertry-Coussot
Lydia
L
Institut National de la Santé et de la Recherche Médicale, Unité 25, Equipe 0016, Université René Descartes, Paris, France.
Lucas
Bruno
B
Danel
Claire
C
Halbwachs-Mecarelli
Lise
L
Bach
Jean-François
JF
Chatenoud
Lucienne
L
Lemarchand
Patricia
P
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D007275:Injections, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013997:Time Factors
D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1