The role of the ICOS/B7RP‐1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitis

Abstract

ICOS/B7RP-1 is a new member of the CD28/B7 family of costimulatory molecules and plays differential roles in autoimmune diseases. In this study, we examined the role of ICOS/B7RP-1 pathway in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU), an animal model of human autoimmune uveitis. ICOS expression was found on infiltrating CD4 + T cells in the region of the retina in EAU-induced mice. The anti-B7RP-1 monoclonal antibody (mAb)-treated or ICOS-deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP-1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Moreover, administration of anti-B7RP-1 mAb effectively ameliorated the disease induced by adoptive transfer of pathogenic T cells. The anti-B7RP-1 mAb treatment inhibited the expansion and/or effector function of pathogenic T cells, given that proliferative response and IFN-c production by lymph node cells were reduced upon restimulation with the antigen peptide in vitro. These results suggest that the ICOS/B7RP-1 interaction plays a critical role in the pathogenesis of uveitis. We also indicated that ICOS-mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Th1 disease induced in the same manner as EAU.

Down-regulation of inducible co-stimulator (ICOS) by intravitreal injection of small interfering RNA (siRNA) plasmid suppresses ongoing experimental autoimmune uveoretinitis in rats

“…These results strongly suggested that the ICOS/B7RP-1 co-stimulatory pathway plays a critical role in EAU. Notably, our observations differ somewhat from Yoshihiko Usui's report that blockade of ICOS/B7RP-1 by anti-B7RP-1 mAb during the induction phase of EAU in mice exhibited no effect, and that the disease was reduced by blocking the ICOS/B7RP-1 interaction during the effector phase [29]. Such differences may result from alternate negative regulation of the ICOS/B7RP-1 pathways and species-specific differences.…”

“…Prior research on the ICOS pathway was performed via gene knockout and systematic antibody blockage [24,29]. However, all the treatments of systemic administration have the mutual disadvantage of hypoimmunity that may limit clinical application.…”

T Helper Cell-specific Regulation of Inducible Costimulator Expression via Distinct Mechanisms Mediated by T-bet and GATA-3

“…Nevertheless, ICOS signaling is also implicated in autoimmune disorders and graft versus host disease. For instance, ICOS blockade by treatment with anti-B7RP-1 monoclonal Ab or genetic inactivation substantially reduced clinical progression of murine experimental autoimmune uveoretinitis (45), whereas targeting of ICOS expressed on alloreactive donor T cells inhibited graft versus host disease and promoted bone marrow engraftment in recipient mice (46).…”

OX40, OX40L and Autoimmunity: a Comprehensive Review

“…Two studies have however shown the reverse: in mice given sheep anti-glomerular basement membrane antibodies, the resultant nephritis is exacerbated by blocking OX40L antibody with increased IFNγ+T cell infiltration [129]. A second study reported in abstract form only reports exacerbation of EAU with OX40L blockade, although this is in contrast to other EAU and EAE studies [130][131][132][133].…”