Atsuo Tanimoto

JTA–009, a fully human antibody against human AILIM/ICOS, ameliorates graft–vs–host reaction in SCID mice grafted with human PBMCs

OBJECTIVE Activation-inducible lymphocyte immunomediatory molecule (AILIM; also referred to as inducible costimulator [ICOS]) is the third molecule identified in the CD28 family participating in T-cell activation. AILIM/ICOS has been implicated in both effector and pathogenic T-cell functions, as evidenced by the beneficial effects of AILIM/ICOS blockade in several murine disease models. In the present study, the role of human AILIM/ICOS in T-cell function was investigated using a fully human monoclonal antibody specific to human AILIM/ICOS (JTA-009). MATERIALS AND METHODS The effect of JTA-009 on allogenic T-cell proliferation was examined using human mixed lymphocyte reaction (MLR). To investigate the efficacy of AILIM/ICOS blockade in vivo, a graft-vs-host disease (GVHD) model, in which severe combined immunodeficient (SCID) mice were grafted with human peripheral blood mononuclear cells (PBMCs), was used. RESULTS In MLR, suppressive effect of JTA-009 on allogenic T-cell proliferation was detected with comparable potency to CD28 blockade by cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig at an intermediate culture phase. JTA-009 acts as a blocking antibody in vivo and inhibited binding of human AILIM/ICOS to mouse AILIM/ICOS ligand (B7h). Treatment with JTA-009 significantly prolonged survival of mice, with reductions of human interferon-gamma levels in blood and number of human cells in spleens. CONCLUSION These results demonstrate that human AILIM/ICOS plays a role in the GVHD pathogenesis mediated by human T cells, and its blockade is attractive for abrogating undesired T-cell responses as is well-documented in mice.

Inhibition of tumor necrosis factor-α production by SK&F 98625, a CoA-independent transacylase inhibitor, in cultured rat peritoneal macrophages

Abstract When rat peritoneal macrophages were incubated in medium containing thapsigargin, tumor necrosis factor-α (TNF-α) production was increased time-dependently. In the presence of SK&F 98625, a CoA-independent transacylase inhibitor, the thapsigargin-induced TNF-α production was inhibited dose-dependently. Platelet-activating factor (PAF) and prostaglandin E2 (PGE2) production were also inhibited by SK&F 98625. The SK&F 98625-induced inhibition of TNF-α production was not prevented by addition of PGE2. PAF antagonists such as E6123, L-652,731 and CV-6209 partially inhibited the thapsigargin-induced TNF-α production, suggesting that concurrently produced PAF in thapsigargin-stimulated macrophages up-regulates TNF-α production. The inhibition by SK&F 98625 of thapsigargin-induced TNF-α production might be partly due to the inhibition of PAF production.

A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents

Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE‐052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE‐052 inhibited the Th1‐, Th2‐ and Th17‐type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE‐052 inhibited skin inflammation in hapten‐induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)‐4 production in skin, and enhanced IgE production in serum. Oral administration of JTE‐052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL‐23. The maximal efficacy of JTE‐052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE‐052 ointment ameliorated hapten‐induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE‐052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE‐052 is a promising candidate as an anti‐inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application.

JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation

BACKGROUND Using JAK inhibitors to inhibit cytokine signaling is presumed to be a possible means of treating skin inflammatory disorders such as contact dermatitis. OBJECTIVE To clarify the action site of JAK inhibitors in skin inflammatory disorders. METHODS We analyzed the mechanism of action of the JAK inhibitor JTE-052 using murine skin inflammation models, including contact hypersensitivity (CHS) and irritant contact dermatitis. Cells isolated from ear tissue or lymph node (LN) were analyzed by flow cytometry. The amounts of cytokines in the culture medium were measured by ELISA or bead array system. Proliferation of LN cells was evaluated by measurement of tritiated thymidine incorporation. RESULTS Oral administration of JTE-052 during both sensitization and elicitation phase attenuated CHS, but did not affect croton oil-induced irritant contact dermatitis. JTE-052 potently inhibited T cell proliferation and activation by antigen presentation in vitro, and attenuated skin inflammation in a sensitized-lymphocyte transfer model without suppressing T cell migration. JTE-052 did not affect hapten-induced cutaneous dendritic cell migration into draining lymph nodes or their costimulatory molecule expressions. CONCLUSION The JAK inhibitor JTE-052 exerts an inhibitory effect on antigen-specific T cell activation and subsequent inflammation in acquired skin immunity, such as CHS.