Suppression of murine thyroiditis via blockade of the CD40-CD40L interaction.
The CD40 ligand (gp39) is transiently expressed on activated CD4+ T cells and mediates cognate helper function by interacting with CD40 on B cells. Increasing evidence suggests, however, critical involvement of gp39 not only in antibody-mediated responses but also in the development of effector T cells. Here, we have investigated the effect of in vivo gp39 blockade on the induction of murine experimental autoimmune thyroiditis (EAT), a T-cell-mediated disease. Over a 5-week period, EAT was induced in SJL mice with thyroglobulin (Tg) and adjuvant. Concomitantly, mice received intraperitoneal (i.p.) injections of MR1, a gp39-specific hamster monoclonal antibody (mAb), at 4-day intervals. Control mice were challenged with Tg but received equivalent doses of hamster immunoglobulin (HIg). It was observed that the control mice developed severe thyroiditis whereas the MR1-treated mice exhibited very low levels of infiltration that were mostly focal in nature. Blockade of gp39 was effective since the Tg-specific IgG titres were low or undetectable in all MR1-treated animals compared with the controls. In addition, upon restimulation with Tg in vitro, lymph node cells (LNC) from Tg-primed, MR1-treated mice proliferated less strongly and secreted significantly lower amounts of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) than LNC from untreated or HIg-treated controls. These results strongly suggest that in vivo blockade of gp39 suppresses EAT by inhibiting the priming of inflammatory Tg-specific T-helper type 1 cells.
Carayanniotis
G
G
Faculty of Medicine, Memorial University of Newfoundland, St John's, Canada.
Masters
S R
SR
Noelle
R J
RJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand; D005260:Female; D007116:Immunization, Passive; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D018417:Th1 Cells / Q000276:immunology; D013954:Thyroglobulin / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000276:immunology* / Q000517:prevention & control
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D013954:Thyroglobulin