Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance.
Treatment with nonmitogenic CD3 Ab reverses established autoimmune diabetes in nonobese diabetic mice by restoring self-tolerance, and is currently under clinical evaluation in patients presenting recent onset type I diabetes. Due to the immunosuppressive potential of this strategy, it was relevant to explore how this treatment would influence the outcome of concomitant viral infections. In this study, we used a transgenic model of virally induced autoimmune diabetes (rat insulin promoter-lymphocytic choriomeningitis virus) that allows for more precise tracking of the autoaggressive response and choice of the time point for initiation of autoimmunity. CD3 was most effective during a clearly defined prediabetic phase and prevented up to 100% of diabetes by drastically lowering activation of autoaggressive CD8 lymphocytes and their production of inflammatory cytokines. Interestingly, reversion of established disease could be achieved as well, when nonmitogenic CD3 was administered late during pathogenesis to overtly diabetic recipients. Most importantly, competence to clear viral infections was maintained. Thus, administration of nonmitogenic CD3 prevents diabetes by sufficient systemic reduction of (auto)aggressive lymphocytes, but without compromising antiviral immune competence.
von Herrath
Matthias G
MG
Department of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA. matthias@liai.org
Coon
Bryan
B
Wolfe
Tom
T
Chatenoud
Lucienne
L
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D001117:Arenaviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D001666:Binding Sites, Antibody; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000235:genetics* / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics* / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D051381:Rats; D011961:Receptors, Fc / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014764:Viral Proteins / Q000235:genetics
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007140:Immunoglobulin Fab Fragments; D007328:Insulin; C505887:Ltb protein, mouse; C505888:Ltb protein, rat; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D008934:Mitogens; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D015847:Interleukin-4