Prevention of Chronic Renal Allograft Rejection by Soluble CD83

Zhu, Lan; Lian, Dameng; Liu, Weihua; Arp, Jacqueline; Charlton, Brayden; Ge, Wei; Brand, Stephen R.; Healey, Dan; Nicolette, Charles A.; García, Bertha; Wang, Hao

doi:10.1097/tp.0b013e318200005c

Cited by 39 publications

(32 citation statements)

References 67 publications

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“…100 d compared with a median survival of 35 d in untreated animals (19). To further understand the molecular basis for how sCD83 prevents allograft rejection, we tested the dependency of sCD83 activity on TLR4 signaling by using TLR4-deficient mice as kidney donors.…”

Section: Discussionmentioning

confidence: 99%

“…These observations prompted several groups to develop recombinant sCD83 proteins (15)(16)(17) to evaluate the immunosuppressive activity of sCD83 for therapeutic use in models of autoimmunity and transplantation. Preparations derived from expression of the soluble portion of CD83 lacking the transmembrane domain used in in vivo models of murine and rat kidney and heart allograft transplantation prevented organ transplant rejection (18)(19)(20). Moreover, sCD83 induced tolerance in skin allograft transplants (21).…”

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confidence: 99%

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Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Horvatinovich

Grogan

Norris

et al. 2017

The Journal of Immunology

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The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R–associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE2 in a COX-2–dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Horvatinovich

Grogan

Norris

et al. 2017

The Journal of Immunology

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“…In subsequent studies using recombinant sCD83 molecules, it could be shown that sCD83 has prominent immunosuppressive properties. We and others reported that recombinant sCD83 inhibits DC maturation (28,29) and blocks T cell stimulation (28,30). It has also been reported that CD83 is a regulator of B cell function (31,32).…”

mentioning

confidence: 99%

“…Because animals were also protected from a second EAE relapse without an additional sCD83 administration, sCD83-specific and long-term tolerogenic mechanisms should have been induced (33). In addition, it has been reported that sCD83 could modulate transplantrelated immune responses in murine models of allograft transplantation (29,34,35).…”

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confidence: 99%

Topical Application of Soluble CD83 Induces IDO-Mediated Immune Modulation, Increases Foxp3+ T Cells, and Prolongs Allogeneic Corneal Graft Survival

Bock

Rößner

Onderka

et al. 2013

The Journal of Immunology

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Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-β. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-β, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.

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“…A CD83-nak szerepe van a DC-k érésében egérben és emberben egyaránt, bizonyítottan. Egérkísérletek során igazoltan autoimmungátló hatása van, és más immunszuppresszív szerrel kombinációban alkalmazva megelőzi a szívtranszplan-tátum kilökődését [36].…”

Section: Toleranciaindukcióunclassified

Recent options in drug therapy after solid organ transplantation

2012

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A szervtranszplantáció ötvenéves történetében az immunszuppresszív terápia fejlődésének köszönhetően egyre jobb szerv-és betegtúlélési eredményekről számoltak be világszerte, azonban a bázisgyógyszereknek minősülő kalcineurin inhibitorok káros mellékhatásait, elsősorban a nephrotoxicitast mellőző vegyületek kifejlesztése csak az elmúlt két évtizedben zajlott. A gazdaszervezet számára idegennek minősülő implantált szerv a recipiensből komplex immunválaszt vált ki. A dolgozatban az immunválasz vázlatos áttekintését követően a szerzők bemutatják az új, eltérő tá-madáspontokon ható gyógyszereket. Ezek vagy már gyakorlati alkalmazásban lévő, vagy rövid időn belül esetlegesen forgalomba kerülő vegyületek, amelyek távlati lehetőségeket nyújtanak a kalcineurin inhibitorok leváltására. Kiemelt hangsúlyt kap a kostimulációs blokádon keresztül ható belatacept és az elmúlt években egyre nagyobb kutatási teret nyerő toleranciaindukció, mint jövőbeli lehetőség. Orv. Hetil., 2012Hetil., , 153, 1294Hetil., -1301. Kulcsszavak: szervátültetés, immunszuppresszió, kalcineurin inhibitor, kostimulációs blokád, toleranciaindukció Recent options in drug therapy after solid organ transplantationSolid organ transplantation has shown improvement in patient and graft survival rates due to the development of immunosuppression in the last fi fty years; however only the last two decades led to the development of new, baseline immunosuppressive drugs that avoid the unlikely side effects of calcineurin inhibitors, especially nephrotoxicity. The transplanted organ is foreign to the host and, therefore, it induces a complex immune response of the recipient. In this review, a brief outline of immune response is given, followed by the introduction of new immunosuppressive drugs acting via variant pathways. These are compounds which are already in use or becoming shortly available and are potential future alternatives for the calcineurin inhibitors. This paper highlights the role of co-stimulation blockade with belatacept and the recently even more intensively studied fi eld of tolerance induction. Orv. Hetil., 2012, 153, 1294-1301 Keywords: organ transplantation, immunosuppression, calcineurin inhibitor, co-stimulation blockade, tolerance induction (Beérkezett: 2012. február 12.; elfogadva: 2012. június 17.) Rövidítések APC = (antigen presenting cell) antigén-bemutató sejt; BKV = BK-vírus; CD = (cluster of differentiation) sejtfelszíni fehérjék jelölése; CMV = cytomegalovirus; CNI = kalcineurin inhibitor; CTLA4 = citotoxikus T-lymphocyta-antigén-4; DC = dentritikus sejt; EBV = Epstein-Barr-vírus; FDA = Food and Drug Administration; FKBP12 = (FK-binding protein 12) FK-kötő fehérje 12; FOXP3 = forkhead boksz p3, egyike a transzkripciós regulátor fehérjéknek; γ-IFN = gamma-interferon; GVH = graft versus host; HUS = hemolitikus urémiás szindróma; IDO = indolamin-2,3-dioxigenáz; IL = interleukin; IL-2R = interleukin-2-receptor; JAK3 = Janus activated kinase 3, citokinreceptorokhoz kötődő tirozinkinázok egyike; LFA-1 = limphocytafunkció-asszociált anti...

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Prevention of Chronic Renal Allograft Rejection by Soluble CD83

Cited by 39 publications

References 67 publications

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Topical Application of Soluble CD83 Induces IDO-Mediated Immune Modulation, Increases Foxp3+ T Cells, and Prolongs Allogeneic Corneal Graft Survival

Recent options in drug therapy after solid organ transplantation

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