title: Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.
abstract: BACKGROUND
  Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease.
  
  
  METHODS
  We studied the effects of a nonactivating humanized monoclonal antibody against CD3--hOKT3gamma1(Ala-Ala)--on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease.
  
  
  RESULTS
  Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment.
  
  
  CONCLUSIONS
  Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.
authors.affiliation: Naomi Berrie Diabetes Center and the Department of Medicine, Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York 10032, USA. kh318@columbia.edu
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: William
authors.initials: W
authors.lastname: Hagopian
authors.forename: Julie A
authors.initials: JA
authors.lastname: Auger
authors.forename: Ena
authors.initials: E
authors.lastname: Poumian-Ruiz
authors.forename: Lesley
authors.initials: L
authors.lastname: Taylor
authors.forename: David
authors.initials: D
authors.lastname: Donaldson
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: David M
authors.initials: DM
authors.lastname: Harlan
authors.forename: Danlin
authors.initials: D
authors.lastname: Xu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Zivin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D002096:C-Peptide / Q000097:blood; D017252:CD3 Complex / Q000276:immunology*; D016516:CD4-CD8 Ratio; D002648:Child; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D018655:Lymphocyte Count; D008297:Male
chemical_list: D000911:Antibodies, Monoclonal; D002096:C-Peptide; D017252:CD3 Complex; D016207:Cytokines; D006442:Glycated Hemoglobin