title: An oral CD3-specific antibody suppresses T-cell-induced colitis and alters cytokine responses to T-cell activation in mice.
abstract: OBJECTIVE
  New therapeutic approaches are needed for inflammatory bowel diseases. A monoclonal antibody against CD3 (anti-CD3) suppresses T-cell-mediated autoimmune diseases such as experimental allergic encephalomyelitis. We explored the effects of anti-CD3 in mice with colitis.
  
  
  METHODS
  Severe combined immunodeficient mice were given injections of CD4(+)CD45RB(high) T cells to induce colitis. Four weeks later, the mice were given 2 or 5 μg/day of anti-CD3 or hamster immunoglobulin (Ig)G (control), via gavage, for 5 or 10 days. The effect of oral anti-CD3 on cytokine responses was studied by activating T cells using intraperitoneal injections of anti-CD3 monoclonal antibody 2 days after oral administration of the antibody. We collected intestine samples for histology analysis and cells were analyzed by flow cytometry. Cytokines in sera were analyzed by cytometric bead array.
  
  
  RESULTS
  Oral administration of anti-CD3 protected the mice from wasting disease and intestinal inflammation. Analyses of spleen and mesenteric lymph node cells showed no differences in total cell counts, or percentages of CD4(+) and forkhead box P3(+) regulatory T cells, between mice given anti-CD3 or the control immunoglobulin. Colitis therefore was not suppressed by induction of forkhead box P3(+) regulatory T cells, or depletion or limited expansion of T cells. Oral administration of anti-CD3 ameliorated the enteropathy induced by intraperitoneal injection of the antibody. In mice with enteropathy, oral anti-CD3 reduced levels of inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin (IL)-6; it also increased levels of the anti-inflammatory cytokines IL-10 and transforming growth factor-β. The effects of oral anti-CD3 required IL-10.
  
  
  CONCLUSIONS
  Oral administration of anti-CD3 to mice induces changes in the mucosal immune response that prevent colitis, independent of specific antigen, and reduce T-cell activation in an IL-10-dependent manner. Oral anti-CD3 therefore might be developed for the treatment of patients with inflammatory bowel disease.
authors: Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Katharina
authors: K
authors: Forster
authors: Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Ashleigh
authors: A
authors: Goethel
authors: Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Catherine Wing-Tak
authors: CW
authors: Chan
authors: Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Galliano
authors: G
authors: Zanello
authors: Surgical Pathology, Department of Pathology and Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada.
authors: Catherine
authors: C
authors: Streutker
authors: Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Zane Cohen Center for Digestive Research, Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address: KCroitoru@mtsinai.on.ca.
authors: Kenneth
authors: K
authors: Croitoru
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood*; D051858:Forkhead Transcription Factors; D007155:Immunologic Factors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007413:Intestinal Mucosa / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory; D016212:Transforming Growth Factor beta / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019282:Wasting Syndrome / Q000517:prevention & control
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007155:Immunologic Factors; D020381:Interleukin-17; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma