title: Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (rituximab) therapy in type 1 diabetes.
abstract: Type 1 diabetes mellitus is believed to be due to the autoimmune destruction of β-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte Ab, can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease-associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease-associated target Ags, and C-peptide levels of participants who did (responders) or did not (nonresponders) show signs of β-cell preservation 1 y after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after four weekly doses of mAb. T cell proliferative responses to diabetes-associated Ags were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 mo (58%), the proliferative responses to diabetes-associated total (p = 0.032), islet-specific (p = 0.048), and neuronal autoantigens (p = 0.005) increased over the 12-mo observation period. This relationship was not seen in placebo-treated patients. We conclude that in patients with type 1 diabetes mellitus, anti-B cell mAb causes increased proliferative responses to diabetes Ags and attenuated β-cell loss. The way in which these responses affect the disease course remains unknown.
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT 06511, USA. kevan.herold@yale.edu
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pescovitz
authors.forename: Paula
authors.initials: P
authors.lastname: McGee
authors.forename: Heidi
authors.initials: H
authors.lastname: Krause-Steinrauf
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Spain
authors.forename: Kasia
authors.initials: K
authors.lastname: Bourcier
authors.forename: Adam
authors.initials: A
authors.lastname: Asare
authors.forename: Zhugong
authors.initials: Z
authors.lastname: Liu
authors.forename: John M
authors.initials: JM
authors.lastname: Lachin
authors.forename: H Michael
authors.initials: HM
authors.lastname: Dosch
mesh_terms: D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D002096:C-Peptide / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D008297:Male; D000069283:Rituximab; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001324:Autoantigens; D002096:C-Peptide; D007155:Immunologic Factors; D000069283:Rituximab