HVEM knock-out mice have been shown to exhibit increased morbidity in a model of concanavalin A-mediated T cell-dependent autoimmune hepatitis, as well as increased susceptibility to myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalitis [10,11]. Interestingly, the BTLA knock-out mice have a somewhat similar

phenotype to the HVEM knock-out mice in that T cells from the mice exhibited enhanced proliferative responses to in vitro anti-CD3ε stimulation, but not to concanavalin A [1,12]. The BTLA knock-out mice also exhibited increased specific antibody responses and increased susceptibility to MOG peptide-induced experimental autoimmune encephalitis [1]. Several in vivo studies have been performed with click here HVEM-Ig that demonstrate its beneficial effect in mouse models of transplantation rejection and uveitis ABC294640 mouse [13–16]. However, these studies all predate the identification of the HVEM : BTLA axis,

and it is not clear whether these in vivo effects are due to the neutralization of signalling through HVEM by LIGHT and lymphotoxin- or the actions of the soluble HVEM-Ig through BTLA. No in vivo disease models or mechanism-based studies with a uniquely BTLA specific reagent have been described in the literature. Interestingly, Cheung et al. identified the UL144 (Unique Long 144) protein from the human cytomegalovirus (HuCMV) as being capable of binding hBTLA, but not LIGHT, and inhibiting in vitro lymphocyte proliferation [17–19]. HuCMV infection is Oxymatrine a serious disease in immunosuppressed patients and the UL144 is one of many open reading frames present in clinical isolates but not in commonly used laboratory strains [20–25]. UL144 is homologous to the N terminal, putative BTLA binding region of hHVEM. There is no known murine equivalent. This suggests that that the virus may have evolved the ability to target the BTLA pathway in an effort to induce immunosuppression in its human host. This raises the intriguing possibility that targeting BTLA may be an attractive pharmacological approach for the treatment of human inflammatory diseases. This hypothesis

is supported further by associations of BTLA polymorphisms with clinical rheumatoid arthritis and inflammatory bowel disease and the demonstrated crucial role for BTLA in models of inflammatory bowel disease (IBD) [26–28]. In this study, we set out to determine the exact requirements for BTLA specific reagents to inhibit T and B lymphocyte proliferation in vitro and to test their ability to ameliorate inflammation in a mechanistically relevant in vivo model. We found that HVEM and a panel of different monoclonal antibodies bound murine BTLA specifically on both B and T cells and that some antibodies inhibited anti-CD3ε-induced T cell proliferation in vitro, but only when constrained appropriately with a putatively cross-linking reagent.