Administration of dendritic cells transduced with antisense oligodeoxyribonucleotides targeting CD80 or CD86 prolongs allograft survival

Liang, Xiaoyan; Lü, Lina; Chen, Zongyou; Vickers, Timothy A.; Zhang, Hong; Fung, John J.; Shen, Qian

doi:10.1097/01.tp.0000076470.35404.49

Cited by 43 publications

(25 citation statements)

References 25 publications

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“…[48][49][50] Another report recently showed that NF-kB pathway suppression by RelB siRNA succeeded in inhibiting DC maturation with CD80 and CD86 repression, resulting in the prevention of allograft rejection. 51 In the present study, we demonstrated the significant effects of PU.1 siRNA treatment in a murine CHS model.…”

Section: Role Of Pu1 In the Expression Of Cd80 And Cd86 2219mentioning

confidence: 99%

“…52,53 Conversely, their other crucial role is to block the development of several autoimmune diseases or to induce donor-specific tolerance to allografts by abrogation of CD28/B7 signals. [47][48][49][50] Through these apparently opposing roles of CD80 and CD86, PU.1 can be targeted for clinical treatment due to its inducible and inhibitory effects.…”

Section: Role Of Pu1 In the Expression Of Cd80 And Cd86 2219mentioning

confidence: 99%

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Critical role of transcription factor PU.1 in the expression of CD80 and CD86 on dendritic cells

Kanada

Nishiyama

Nakano

et al. 2011

Blood

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In this study, we investigated the role of a transcription factor, PU.1, in the regulation of CD80 and CD86 expression in dendritic cells (DCs). A chromatin immunoprecipitation assay revealed that PU.1 is constitutively bound to the CD80 and CD86 promoters in bone marrow-derived DCs. In addition, co-expression of PU.1 resulted in the transactivation of the CD80 and CD86 promoters in a reporter assay. The binding of PU.1 to cis-enhancing regions was confirmed by electromobility gel-shift assay. As expected, inhibition of PU.1 expression by short interfering RNA (siRNA) in bone marrow-derived DCs resulted in marked down-regulation of CD80 and CD86 expression. Moreover, overexpression of PU.1 in murine bone marrow-derived lineage-negative cells induced the expression of CD80 and CD86 in the absence of monocyte/ DC-related growth factors and/or cytokines. Based on these results, we conclude that PU.1 is a critical factor for the expression of CD80 and CD86. We also found that subcutaneous injection of PU.1 siRNA or topical application of a cream-emulsified PU.1 siRNA efficiently inhibited murine contact hypersensitivity. Our results suggest that PU.1 is a potential target for the treatment of immune-related diseases. (Blood. 2011; 117(7):2211-2222) IntroductionT-cell initiation requires 2 signals from antigen-presenting cells (APCs). The first signal comes from ligation of the T-cell receptor and the major histocompatibility complex (MHC)/antigen presented on the surface of APCs, and the second signal is via additional costimulatory molecules, including the interaction between the CD28 family on T cells and B7, eg, CD80 (B7-1) and CD86 (B7-2), expressed on the APC. 1-3 CD80 and CD86 are members of the immunoglobulin supergene family encoded by separate genes, and are expressed on dendritic cells (DCs) or up-regulated on activated macrophages/monocytes, B cells, and activated T cells. 1-6 CD80 or CD86 can provide costimulatory signals by engaging CD28 or CTLA4 (cytotoxic T-lymphocyte antigen 4; CD152) on T cells. The engagement of CD28 with CD80 or CD86 leads to multiple effects on the immune response, including T-cell activation and differentiation and tissue migration. [7][8][9] In contrast to CD28, the outcome of CTLA4 engagement on T cells is to suppress proliferation by transmitting an inhibitory signal. 10 In addition, a subset of T cells with potent immunoregulatory properties, CD4 ϩ CD25 ϩ regulatory T cells, constitutively expresses CTLA4. 11,12 Thus, interactions between CTLA4 and CD80 or CD86 provides an immunosuppressive function in modulating T-cell proliferation and plays a role in immune tolerance. Based on these observations, the regulated expression of costimulatory molecules is critical for immune function. Therefore, revealing the molecular mechanisms of gene expression of costimulatory molecules is essential for an understanding of the regulation of T cell-mediated immune responses.Despite the importance of CD80 and CD86, the critical transcription factor for gene expression of CD80 or CD86 is sti...

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Section: Role Of Pu1 In the Expression Of Cd80 And Cd86 2219mentioning

confidence: 99%

Section: Role Of Pu1 In the Expression Of Cd80 And Cd86 2219mentioning

confidence: 99%

Critical role of transcription factor PU.1 in the expression of CD80 and CD86 on dendritic cells

Kanada

Nishiyama

Nakano

et al. 2011

Blood

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“…Таргетирование связанных с мембраной молекул на ДК путём интерференции РНК (RNAi) или антисмысловым олигодезоксирибонуклеотидом (ODN) также было использовано для успешного создания толерогенных ДК. Например, сайленсинг экспрессии CD40, CD80 или CD86 у ДК превращает их в иммуносупрессивные клетки благодаря индуцированию антиген-специфичной Т-клеточной гипореактивности или апоптозу [106][107][108]. Более того, эти молчащие ДК также перспективны для терапии, так как их введение значительно пролонгирует выживание трансплантатов у аллогенных моделей трансплантации [106,107] и препятствует развитию диабета у NOD мышей [109].…”

Section: дендритные клетки (дк) (Dc)unclassified

“…Например, сайленсинг экспрессии CD40, CD80 или CD86 у ДК превращает их в иммуносупрессивные клетки благодаря индуцированию антиген-специфичной Т-клеточной гипореактивности или апоптозу [106][107][108]. Более того, эти молчащие ДК также перспективны для терапии, так как их введение значительно пролонгирует выживание трансплантатов у аллогенных моделей трансплантации [106,107] и препятствует развитию диабета у NOD мышей [109]. Другая основная мишень для генерации толерогенных ДК генным сайленсингом -ядерный фактор каппа В (NF-kB), фактор транскрипции, который играет центральную роль в созревании ДК.…”

Section: дендритные клетки (дк) (Dc)unclassified

Role of innate immunity in tolerance induction

2015

BIOMED KHIM

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“…In another study, Tol-DC was generated through the treatment of antisense ODN to inhibit the expression of CD80 or CD86 . Allograft survival was prolonged by administration of modified DCs, which could induce T-cell hyporesponsiveness and apoptosis of T-cells [89]. In addition, silencing of CD80 or CD86 with siRNA inhibited T cell responses in mixed lymphocyte reaction (MLR), generated T regulatory cells [90], and improved cardiac allograft survival [91].…”

Section: Potential Targets For Gene Silencingmentioning

confidence: 99%

RNA interference for improving the outcome of islet transplantation

Mahato

2011

Advanced Drug Delivery Reviews

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Islet transplantation has the potential to cure type 1 diabetes. Despite recent therapeutic success, it is still not common because a large number of transpanted islets get damaged by multiple challenges including instant blood mediated inflammatory reaction, hypoxia/reperfusion injury, inflammatory cytokines, and immune rejection. RNA interference (RNAi) is an novel strategy to selectively degrade target mRNA. The use of RNAi technologies to downregulate the expression of harmful genes has the potential to improve the outcome of islet transplantation. The aim of this review is to gain a thorough understanding of biological obstacles to islet transplantation and discuss how to overcome these barriers using different RNAi technologies. This eventually will help improve islet survival and function post transplantaion. Chemically synthesized small interferring RNA (siRNA), vector based short haripin RNA (shRNA), and their critical design elements (such as sequences, promoters, backbone) are discussed. The application of combinatorial RNAi in islet transplantation is also discussed. Last but not the least, several delivery strategies for enhanced gene silencing are discussed, including chemical modification of siRNA, complex formation, bioconjugation, and viral vectors.

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Administration of dendritic cells transduced with antisense oligodeoxyribonucleotides targeting CD80 or CD86 prolongs allograft survival

Abstract: Transduction with antisense ODN targeting CD80 or CD86mRNA is a feasible and effective approach to modify DCs that renders them tolerogenic by inducing T-cell hyporesponsiveness and apoptosis. This may lead to the development of new therapeutic strategies in transplantation.

Cited by 43 publications

References 25 publications

Critical role of transcription factor PU.1 in the expression of CD80 and CD86 on dendritic cells

Critical role of transcription factor PU.1 in the expression of CD80 and CD86 on dendritic cells

Role of innate immunity in tolerance induction

RNA interference for improving the outcome of islet transplantation

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