Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant.
Mucosal (nasal or oral) administration of anti-CD3 mAb is effective in ameliorating animal models of autoimmunity (experimental autoimmune encephalomyelitis, diabetes, and lupus) by inducing LAP(+) regulatory T cells. We tested this approach in an arthritis model using type II collagen. We found that nasal anti-CD3 was more effective than oral anti-CD3 in attenuating the development of arthritis. Nasal anti-CD3 induced a LAP(+) regulatory T cell that secreted high levels of IL-10 and suppressed collagen-specific T cell proliferation and anti-collagen Ab production. However, neither nasal nor oral anti-CD3 attenuated disease when given to animals with ongoing arthritis, and this was associated with a lack of induction of LAP(+) regulatory T cells. We found, however, that coadministration of a novel emulsome adjuvant, which enhances Th2 responses, resulted in the induction of LAP(+) regulatory T cells and suppression of ongoing arthritis by both nasal and oral anti-CD3. Suppression of arthritis by mucosal anti-CD3 was associated with less joint damage, a decrease of TNF-alpha and IFN-gamma mRNA expression in joints, and a reduction in anti-collagen Abs. These results demonstrate that mucosal anti-CD3 therapy may serve as a therapeutic approach in arthritis and that the biologic effect is enhanced by an emulsome-based adjuvant.
Wu
Henry Yim
HY
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Maron
Ruth
R
Tukpah
Ann-Marcia
AM
Weiner
Howard L
HL
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000502:physiology; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017252:CD3 Complex / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D024043:Collagen Type II / Q000633:toxicity*; D004655:Emulsions; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009061:Mouth Mucosa / Q000276:immunology / Q000378:metabolism; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000502:physiology; D011498:Protein Precursors / Q000096:biosynthesis* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D024043:Collagen Type II; D004655:Emulsions; D010455:Peptides; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; C472416:latency-associated propeptide, TGF-beta