Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.2.42 (DTA)
 1,693 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Invariant natural killer T (iNKT) cells are a special subset of alphabeta T cells with invariant TCR, which recognize alpha-galactosylceramide (alpha-GalCer) presented by CD1d. In addition to signals through the invariant TCR upon stimulation with alpha-GalCer, costimulatory signals, such as signals through CD28 and OX40, are indispensable for full activation of iNKT cells. In this study, we investigated the functions of a well-known costimulatory molecule, glucocorticoid-induced TNF receptor (GITR), on Ag-induced iNKT cell activation. Unexpectedly, engagement of GITR by agonistic mAb DTA-1 suppressed proliferation and cytokine production of iNKT cells upon alpha-GalCer stimulation. In addition, GITR signals in iNKT cells during only the Ag-priming phase was sufficient to inhibit the iNKT cell activation. Consistent with these results, the GITR-deficient iNKT cells showed enhanced proliferation and increased cytokine production upon alpha-GalCer stimulation both in vitro and in vivo. Furthermore, the in vivo administration of alpha-GalCer suppressed tumor metastasis more efficiently in GITR-deficient mice than in wild-type mice. Collectively, GITR plays a co-inhibitory role in Ag-induced iNKT cell activation.
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PMID:Co-inhibitory roles for glucocorticoid-induced TNF receptor in CD1d-dependent natural killer T cells. 1862 95

An agonistic antibody DTA-1, to glucocorticoid-induced TNFR-related protein (GITR), induces T-cell activation and antitumor immunity. CD4(+) effector T cells are essential in initiating GITR-induced immune activation, and the sequentially activated cytolytic CD8(+) T cells are sufficient to induce tumor rejection. Administration of DTA-1 to a tumor-bearing mouse also induces B-cell activation illustrated by CD69 expression. Substantial evidence suggests that resting B cells are tumor promoting, which has prompted the idea of B-cell depletion by Rituximab, to be combined with other agents in the clinic to augment antitumor response. In this study, we have found that mature B cells are needed for the mechanism of anti-GITR agonist to kill tumors. The treatment of GITR agonist induces profound B-cell activation, differentiation, and antibody production. In a mature B-cell-deficient mouse (JHD), DTA-1 fails to induce tumor regression with a reduced early activation of CD4(+) and CD8(+) T cells. B-cell deficiency disables the capability of the DTA-1 in generating cytolytic CD8(+) T cells and significantly reduces the cytokine production in tumor bearing mice. The tumor-killing activities of DTA-1 are still present albeit reduced in the CD40(-/-) mice, in which IgG production is impaired. We have also shown that the dependence on B cells to kill tumors differentiates GITR costimulation from CTLA4 blockade and OX40 agonism in tumor immunotherapy. The findings underscore the reciprocal T-cell-B-cell interaction to enhance antitumor immunity upon GITR costimulation. The results provide the insight that attenuating B-cell functions may not be beneficial in cancer immunotherapy based on GITR agonism.
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PMID:Mature B cells are critical to T-cell-mediated tumor immunity induced by an agonist anti-GITR monoclonal antibody. 2084 58

Immunotherapy for cancer using antibodies to enhance T-cell function has been successful in recent clinical trials. Many molecules that improve activation and effector function of T cells have been investigated as potential new targets for immunomodulatory antibodies, including the tumor necrosis factor receptor superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4(+) T cells, B cells, and interleukin-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1-specific immunoglobulin G1 (IgG1), can induce anaphylaxis in naive mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet-activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues the mice from DTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies.
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PMID:Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice. 2455 2