TY - JOUR
T1 - Oral administration of OKT3 monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells
AU - Ilan, Yaron
AU - Zigmond, Ehud
AU - Lalazar, Gadi
AU - Dembinsky, Adi
AU - Ben Ya'Acov, Ami
AU - Hemed, Nila
AU - Kasis, Ibrahim
AU - Axelrod, Elizabeth
AU - Zolotarov, Lidya
AU - Klein, Athalia
AU - El Haj, Madi
AU - Gandhi, Roopali
AU - Baecher-Allan, Claire
AU - Wu, Henry
AU - Murugaiyan, Gopal
AU - Kivisakk, Pia
AU - Farez, Mauricio F.
AU - Quintana, Francisco J.
AU - Khoury, Samia J.
AU - Weiner, Howard L.
PY - 2010/1
Y1 - 2010/1
N2 - Introduction: Parenteral OKT3 is used to treat transplant rejection and a humanized anti-CD3 Mab has shown positive clinical effects in new onset diabetes. Oral administration of anti-CD3 has not been tested in humans, but suppresses autoimmunity in animal models. Beta-glucosylceramide enhances NKT cell and regulatory T cell activity and enhances the effects of oral anti-CD3 in animals. Materials and methods: Fifteen healthy volunteers (three per group) received orally administered OKT3 over a dose range of 0.2 to 5.0 mg daily with or without beta-glucosylceramide 7.5 mg for 5 days. Safety and immune parameters were measured on days 5, 10, and 30. Results and discussion: Oral OKT3 enhanced T cell proliferation, suppressed Th1 and Th17 responses by 43% and 41%, respectively, increased TGF-β/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells, and affected the IgG repertoire as measured by antigen arrays. Co-administration of oral beta-glucosylceramide induced similar effects. No side effects were observed and no subjects developed human anti-mouse antibodies. Conclusion: These findings demonstrate that oral anti-CD3 monoclonal antibody is safe and biologically active in humans and presents a new avenue for the treatment of autoimmune diseases.
AB - Introduction: Parenteral OKT3 is used to treat transplant rejection and a humanized anti-CD3 Mab has shown positive clinical effects in new onset diabetes. Oral administration of anti-CD3 has not been tested in humans, but suppresses autoimmunity in animal models. Beta-glucosylceramide enhances NKT cell and regulatory T cell activity and enhances the effects of oral anti-CD3 in animals. Materials and methods: Fifteen healthy volunteers (three per group) received orally administered OKT3 over a dose range of 0.2 to 5.0 mg daily with or without beta-glucosylceramide 7.5 mg for 5 days. Safety and immune parameters were measured on days 5, 10, and 30. Results and discussion: Oral OKT3 enhanced T cell proliferation, suppressed Th1 and Th17 responses by 43% and 41%, respectively, increased TGF-β/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells, and affected the IgG repertoire as measured by antigen arrays. Co-administration of oral beta-glucosylceramide induced similar effects. No side effects were observed and no subjects developed human anti-mouse antibodies. Conclusion: These findings demonstrate that oral anti-CD3 monoclonal antibody is safe and biologically active in humans and presents a new avenue for the treatment of autoimmune diseases.
KW - Anti-CD3
KW - Dendritic cells
KW - IL-17
KW - Immunotherapy
KW - Mucosal tolerance
KW - TGF-beta
UR - http://www.scopus.com/inward/record.url?scp=77249178418&partnerID=8YFLogxK
U2 - 10.1007/s10875-009-9323-7
DO - 10.1007/s10875-009-9323-7
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C2 - 19756989
AN - SCOPUS:77249178418
SN - 0271-9142
VL - 30
SP - 167
EP - 177
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
IS - 1
ER -