Novel <scp>CD</scp>3‐specific antibody induces immunosuppression via impaired phosphorylation of <scp>LAT</scp> and <scp>PLC</scp>γ1 following <scp>T</scp>‐cell stimulation

Shiheido, Hirokazu; Aoyama, Takane; Takahashi, Hiroya; Hanaoka, Kaori; Abe, Tomoki; Nishida, Emi; Chen, Chen; Koga, Orie; Hara, Masaki; Shibagaki, Yoshio; Morita, Akimichi; Nikawa, Takeshi; Hattori, Satoshi; Watanabe, Takeshi; Shimizu, Jun

doi:10.1002/eji.201344146

Cited by 3 publications

(7 citation statements)

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“…In contrast, these cytokine levels produced by Dow2-treated mice were markedly reduced. Furthermore, we observed that Dow2 appeared to upregulate Treg suppressive activity while having no effect on Treg induction [17]. As shown in our current study, the number of CD4 + Foxp3 + T cells in Dow2-treated EAU mice was increased compared with normal or control EAU mice.…”

Section: Discussionsupporting

confidence: 69%

“…Unlike conventional anti-mouse CD3ε Abs (e.g., 145–2C11), Dow2 does not activate T cells and can induce T-cell anergy. In our previous study, we found that administration of Dow2 in vivo effectively prolonged the survival of cardiac allografts [17]. In addition, target recognition or the determinant recognized by Dow2 is close to but differs from that recognized by anti-mouse CD3ε Abs 145–2C11.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we established that the anti-mouse CD3ε Ab Dow2 functionally downregulates the expression of TCR/CD3 on murine T cells [17]. Unlike conventional anti-mouse CD3ε Abs (e.g., 145–2C11), Dow2 does not activate T cells and can induce T-cell anergy.…”

Section: Discussionmentioning

confidence: 99%

“…We recently established two novel anti-CD3 monoclonal Abs, anti-mouse Dow2 and anti-human 20-2b2, which downregulate TCR/CD3 in T cells [17, 18]. Dow2 recognizes mouse CD3ε without activating T cells [17], while 20-2b2 binds and modulates TCR on human T cells [18].…”

Section: Introductionmentioning

confidence: 99%

“…Dow2 recognizes mouse CD3ε without activating T cells [17], while 20-2b2 binds and modulates TCR on human T cells [18]. In contrast to OKT3, T cells are minimally activated following treatment with these Abs, TCR expression is downregulated in T cells, and there is neither T-cell proliferation nor a cytokine storm.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of T cell-mediated inflammation in uveitis by a novel anti-CD3 antibody

et al. 2017

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BackgroundA novel anti-mouse CD3ε antibody, Dow2, recognizes mouse CD3ε without activating T cells and suppresses T-cell activation. The purpose of this study was to determine whether Dow2 can inhibit T cells in uveitis.MethodsExperimental autoimmune uveitis (EAU) was induced in mice by immunization with retinal peptides, followed by administration of Dow2. Inflammation was evaluated by color fundus photography, optical coherence tomography, fluorescein angiography, and histology. Intraocular cells from EAU mice were used to examine the effect of Dow2 on retinal antigen-specific T cells. The effects of Dow2, conventional CD3ε antibodies, and isotype control immunoglobulin G (IgG) on splenic T cells were compared by assessing cell proliferation by the mixed lymphocyte reaction assay, inflammatory cytokine production by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, and gene expression by quantitative reverse-transcription polymerase chain reaction (RT-PCR). T-cell subpopulations were characterized by flow cytometry to evaluate the expression of CD4, CD8, CD44, CD62L, and Foxp3.ResultsDow2 significantly reduced T-cell activation and counteracted activation associated with anti-CD3ε antibodies. Unlike conventional CD3ε antibodies, Dow2 treatment did not upregulate T helper (Th)1-/Th17-associated gene expression and cytokine production in splenic T cells. Interferon (IFN)-γ production by retinal antigen-specific T cells was also significantly reduced. Ocular inflammation was significantly reduced in Dow2-treated EAU mice compared to control EAU mice, with fewer T cells infiltrating into the retinas of Dow2-treated EAU mice. In immunohistochemistry, Th1 and Th17 cells invaded the retina in control EAU mice but not Dow2-treated EAU mice. No effects on peripheral T-cell numbers were observed following systemic administration of Dow2.ConclusionThe novel anti-CD3 antibody Dow2 can inhibit T cell-mediated inflammation in uveitis models. Thus, inhibition of T-cell activation by anti-CD3 therapy with this new antibody may protect uveitis patients from severe ocular inflammation.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of T cell-mediated inflammation in uveitis by a novel anti-CD3 antibody

et al. 2017

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Modulation of the Human T Cell Response by a Novel Non-Mitogenic Anti-CD3 Antibody

et al. 2014

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The agonistic anti-human CD3ε antibody (Ab), OKT3, has been used to control acute transplant rejection. The in vivo administration of OKT3 was previously shown to induce the partial depletion of T cells and unresponsiveness (anergy) in the remaining CD4+ T cells. However, this therapy is also associated with the systemic release of several cytokines, which leads to a series of adverse side effects. We established a novel anti-human CD3ε Ab, 20-2b2, which recognized a close, but different determinant on the CD3ε molecule from that recognized by OKT3. 20-2b2 was non-mitogenic for human CD4+ T cells, could inhibit the activation of T cells in vitro, and induced T cell anergy in in vivo experiments using humanized mice. Cytokine release in humanized mice induced by the administration of 20-2b2 was significantly less than that induced by OKT3. Our results indicated that the CD3ε molecule is still an attractive, effective, and useful target for the modulation of T cell responses. The establishment of other Abs that recognize CD3ε, even though the determinant recognized by those Abs may be close to or different from that recognized by OKT3, may represent a novel approach for the development of safer Ab therapies using anti-CD3 Abs, in addition to the modification of OKT3 in terms of the induction of cytokine production.

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Management of immunosuppressant agents following liver transplantation: Less is more

Ascha

Hanouneh

2016

WJH

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Immunosuppression in organ transplantation was revolutionary for its time, but technological and population changes cast new light on its use. First, metabolic syndrome (MS) is increasing as a public health issue, concomitantly increasing as an issue for post-orthotopic liver transplantation patients; yet the medications regularly used for immunosuppression contribute to dysfunctional metabolism. Current mainstay immunosuppression involves the use of calcineurin inhibitors; these are potent, but nonspecifically disrupt intracellular signaling in such a way as to exacerbate the impact of MS on the liver. Second, the impacts of acute cellular rejection and malignancy are reviewed in terms of their severity and possible interactions with immunosuppressive medications. Finally, immunosuppressive agents must be considered in terms of new developments in hepatitis C virus treatment, which undercut what used to be inevitable viral recurrence. Overall, while traditional immunosuppressive agents remain the most used, the specific side-effect profiles of all immunosuppressants must be weighed in light of the individual patient.

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Novel CD3‐specific antibody induces immunosuppression via impaired phosphorylation of LAT and PLCγ1 following T‐cell stimulation

Abstract: The activation of T cells is known to be accompanied by the temporary downmodula-

Cited by 3 publications

References 43 publications

Inhibition of T cell-mediated inflammation in uveitis by a novel anti-CD3 antibody

Inhibition of T cell-mediated inflammation in uveitis by a novel anti-CD3 antibody

Modulation of the Human T Cell Response by a Novel Non-Mitogenic Anti-CD3 Antibody

Management of immunosuppressant agents following liver transplantation: Less is more

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