CTLA4-Ig-modified dendritic cells inhibit lymphocyte-mediated alloimmune responses and prolong the islet graft survival in mice

Yang, Di; Qiu, Wenhong; Zhu, Hong-Jian; Lei, Ping; Wen, Xue; Dai, Hong; Zhou, Wei; Shen, Guanxin

doi:10.1016/j.trim.2008.05.005

Cited by 26 publications

(15 citation statements)

References 27 publications

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“…IL-12p35, CD40, or CD86) (reviewed in [2,9]). These genetically-induced DCreg have been shown, in some instances, to induce T cell hyporesponsiveness and to prolong allograft survival in mice [42], to induce Treg differentiation [43], and to suppress autoimmune diabetes or delayed-type hypersensitivity in mice [44]. …”

Section: Strategies For Generating Dcregmentioning

confidence: 99%

Regulatory dendritic cell therapy: From rodents to clinical application

2014

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Dendritic cells (DC) are highly-specialized, bone marrow-derived antigen-presenting cells that induce or regulate innate and adaptive immunity. Regulatory or “tolerogenic” DC play a crucial role in maintaining self tolerance in the healthy steady-state. These regulatory innate immune cells subvert naïve or memory T cell responses by various mechanisms. Regulatory DC (DCreg) also exhibit the ability to induce or restore T cell tolerance in many animal models of autoimmune disease or transplant rejection. There is also evidence that adoptive transfer of DCreg can regulate T cell responses in non-human primates and humans. Important insights gained from in vitro studies and animal models have led recently to the development of clinical grade human DCreg, with potential to treat autoimmune disease or enhance transplant survival while reducing patient dependency on immunosuppressive drugs. Phase I trials have been conducted in type-1 diabetes and rheumatoid arthritis, with results that emphasize the feasibility and safety of DCreg therapy. This mini-review will outline how observations made using animal models have been translated into human use, and discuss the challenges faced in further developing this form of regulatory immune cell therapy in the fields of autoimmunity and transplantation.

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Section: Strategies For Generating Dcregmentioning

confidence: 99%

Regulatory dendritic cell therapy: From rodents to clinical application

2014

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“…To our knowledge, there has not been a systematic review of the literature using similar criteria. We selected 13 studies according to the above inclusion criteria, which included adoptive mouse (9 articles) and rat (4 articles) islet transplantation models [10], [13], [14], [15], [16], [19], [20], [21], [22], [11], [12], [17], [18]. The detection rate in PubMed and Embase was 23.8% (10 articles) and 12.4% (13 articles), respectively (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Adoptive Infusion of Tolerogenic Dendritic Cells Prolongs the Survival of Pancreatic Islet Allografts: A Systematic Review of 13 Mouse and Rat Studies

Sun

Shan

et al. 2012

PLoS ONE

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ObjectiveThe first Phase I study of autologous tolerogenic dendritic cells (Tol-DCs) in Type 1 diabetes (T1D) patients was recently completed. Pancreatic islet transplantation is an effective therapy for T1D, and infusion of Tol-DCs can control diabetes development while promoting graft survival. In this study, we aim to systematically review islet allograft survival following infusion of Tol-DCs induced by different methods, to better understand the mechanisms that mediate this process.MethodsWe searched PubMed and Embase (from inception to February 29th, 2012) for relevant publications. Data were extracted and quality was assessed by two independent reviewers. We semiquantitatively analyzed the effects of Tol-DCs on islet allograft survival using mixed leukocyte reaction, Th1/Th2 differentiation, Treg induction, and cytotoxic T lymphocyte activity as mechanisms related-outcomes. We discussed the results with respect to possible mechanisms that promote survival.ResultsThirteen articles were included. The effects of Tol-DCs induced by five methods on allograft survival were different. Survival by each method was prolonged as follows: allopeptide-pulsed Tol-DCs (42.14±44 days), drug intervention (39 days), mesenchymal stem cell induction (23 days), genetic modification (8.99±4.75 days), and other derivation (2.61±6.98 days). The results indicate that Tol-DC dose and injection influenced graft survival. Single-dose injections of 104 Tol-DCs were the most effective for allograft survival, and multiple injections were not superior. Tol-DCs were also synergistic with immunosuppressive drugs or costimulation inhibitors. Possible mechanisms include donor specific T cell hyporesponsiveness, Th2 differentiation, Treg induction, cytotoxicity against allograft reduction, and chimerism induction.ConclusionsTol-DCs induced by five methods prolong MHC mismatched islet allograft survival to different degrees, but allopeptide-pulsed host DCs perform the best. Immunosuppressive or costimulatory blockade are synergistic with Tol-DC on graft survival. Multiple injections are not superior to single injection. Yet more rigorously designed studies with larger sample sizes are still needed in future.

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“…Exogenous CTLA4-Ig gene transfer has been demonstrated to induce immune tolerance in vivo [38]–[39], with multiple factors contributing to the overall function of CTLA4 in transplant immune modulation [40]. First, it was demonstrated that CTLA-4 reduces the contact between T cells and APCs and leads to a decrease in pro-inflammatory cytokine production and proliferation [41].…”

Section: Discussionmentioning

confidence: 99%

Alternative Immunomodulatory Strategies for Xenotransplantation: CD80/CD86-CTLA4 Pathway-Modified Immature Dendritic Cells Promote Xenograft Survival

Tian

Zhai

et al. 2013

PLoS ONE

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BackgroundXenotransplantation is a promising approach to circumventing the current organ shortage. However, T-cell-dependent anti-xenoresponses are a major challenge to successful xenografts. Given the advantages of the use of CTLA4-Ig in the survival of allografts, the purpose of the study was to investigate the therapeutic potential of CTLA4-IgG4 modified immature dendritic cells (imDCs) in the prevention of islets xenograft rejection.MethodsCTLA4-IgG4 was constructed by the fusion of the extracellular regions of porcine CTLA4 to human the hIgG4 Fc region. The imDCs were induced and cultured from porcine peripheral blood mononuclear cells (PBMC). The CTLA4-IgG4 modified imDCs were delivered via the portal vein to the liver of diabetic mice (insulin-dependent diabetes mellitus) before islet xenografting, and mCTLA4-Ig was administered intravenously after xenotransplantation.ResultsThe xenograft survival of mice receiving unmodified imDCs was approximately 30 days. However, following administration of CTLA4-IgG4 modified imDCs before grafting and mCTLA4-Ig after grafting, xenografts survived for more than 100 days. Flow cytometric analysis showed that the CD4+CD25+Foxp3+ Treg population was increased in spleens. The efficacy of donor CTLA4-IgG4 modified imDCs correlated partially with the amplification of Tregs.ConclusionsThese results confirm that selective inhibition of the direct and indirect pathways of T-cell activation by donor CTLA4-IgG4 modified imDCs and receptor CTLA4-Ig is a highly effective strategy to promote survival of xenografts.

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CTLA4-Ig-modified dendritic cells inhibit lymphocyte-mediated alloimmune responses and prolong the islet graft survival in mice

Cited by 26 publications

References 27 publications

Regulatory dendritic cell therapy: From rodents to clinical application

Regulatory dendritic cell therapy: From rodents to clinical application

Adoptive Infusion of Tolerogenic Dendritic Cells Prolongs the Survival of Pancreatic Islet Allografts: A Systematic Review of 13 Mouse and Rat Studies

Alternative Immunomodulatory Strategies for Xenotransplantation: CD80/CD86-CTLA4 Pathway-Modified Immature Dendritic Cells Promote Xenograft Survival

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