Autoimmune

thyroiditis, or Graves’ disease, is due to increased infiltration of lymphocytes into the thyroid where they recognize the thyroid stimulating hormone receptor; this leads to autoantibody production, tissue necrosis and loss of thyroid function. The importance of CD40 signalling in Graves’ disease was recognized after the discovery that CD40 is present on thyroid epithelial find more cells [54], where it interacts with CD40L (CD154)-expressing autoreactive T cells. In agreement with this observation, blockade of the CD40–CD40L interaction with anti-CD40L antibodies has been shown to prevent experimental thyroiditis [55]. Type 1 diabetes, or insulin-dependent diabetes, is caused by autoreactive T cells that recognize antigens such as insulin and glutamic acid decarboxylase Tamoxifen clinical trial on B cells

in the islets of Langerhans. B cells also play important roles in disease pathogenesis, as revealed by B cell-deficient NOD mice [56] and treatment of NOD mice with CD40L antibodies [57]. As the CD40 signal is critical for antibody production and Ig class-switching, depletion of CD40+ B cells, or deletion of endogenous B cells, lowers autoantibody production in these mice and decreases disease severity. In addition to CD40+ B, CD40+ T cells are important in the induction of diabetes in NOD mice [58]. The importance of CD40–CD40L has also been underscored in collagen-induced arthritis (CIA). Treatment of mice with collagen type II and anti-CD40L antibodies blocked joint inflammation, serum antibody titres to collagen, synovial infiltrates and erosion of cartilage and bone [59]. Also, when treated with anti-CD40L antibodies, lupus-prone mice showed reduced glomerulonephritis [60]. Similarly, in an open-label study in SLE patients treated with anti-CD40L, humanized mAb exhibited

disease alleviation, including reduced anti-ds-DNA titres [61,62]. Blockade of CD40–CD40L interaction by anti-CD40L antibodies reduced the incidence and severity of T helper type 1 (Th1)-mediated experimental autoimmune uveoretinitis (EAU) in susceptible B10.RIII mice immunized with autoantigen interphotoreceptor retinoid binding protein (IRBP) in complete Freund’s adjuvant (CFA) [63]. Further analysis revealed that in anti-CD40L Axenfeld syndrome antibody-treated mice innate responses to autoantigen IRBP were reduced significantly, but no Th2 dominance was observed [63]. The alleviation of EAE and MS by anti-CD40L therapy [64] further signifies the importance of CD40–CD40L axis in autoimmune diseases (Table 1, Fig. 1c). CD134 (OX40), an inducible T cell co-stimulatory molecule, is one of the most extensively studied members of the TNF superfamily. OX40 expression is activation-induced and, once expressed, OX40 binds OX40L (CD134L) present on a variety of cells [65–67]. OX40 signalling promotes T cell activation, induction of cell survival genes and production of cytokines [68]. OX40 signals play crucial roles in autoimmune and viral diseases, cancer and transplantation [68].