Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3325-3333 ◽  
Author(s):  
Cécile Guillot ◽  
Séverine Ménoret ◽  
Carole Guillonneau ◽  
Cécile Braudeau ◽  
Maria G. Castro ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Combined Treatment ◽  
Interleukin 10 ◽  
No Production ◽  
Allograft Survival

Abstract Costimulatory blockade using cytotoxic T lymphocyte–associated antigen 4 immunoglobulin (CTLA4Ig) efficiently down-regulates immune responses in animal models and is currently used in autoimmune and transplantation clinical trials, but the precise cellular and molecular mechanisms involved remain unclear. Rats that received allogeneic heart transplants and were treated with adenoviruses coding for CTLA4Ig show long-term allograft survival. The immune mechanisms regulating induction of long-term allograft acceptance were analyzed in splenocytes using mixed leukocyte reactions (MLRs). MLRs of splenocytes but not purified T cells from CTLA4Ig-treated rats showed higher than 75% inhibition compared with controls. Splenocytes from CTLA4Ig-treated rats inhibited proliferation of naive and allogeneically primed splenocytes or T cells. MLR suppression was dependent on soluble secreted product(s). Production of soluble inhibitory product(s) was triggered by a donor antigen-specific stimulation and inhibited proliferation in an antigen-nonspecific manner. CTLA4Ig levels in the culture supernatant were undetectable and neither interleukin-10 (IL-10), transforming growth factor β1 (TGFβ1), IL-4, nor IL-13 were responsible for suppression of MLRs. Inhibition of nitrous oxide (NO) production or addition of IL-2 could not restore proliferation independently, but the combined treatment synergistically induced proliferation comparable with controls. Stimulation of APCs using tumor necrosis factor (TNF)–related activation-induced cytokine (TRANCE) or CD40L and addition of IL-2 normalized MLRs of CTLA4Ig-treated splenocytes. Finally, dendritic cells (DCs), but not T cells, from CTLA4Ig-treated rats inhibited naive MLRs. Altogether, these results provide evidence that after in vivo CTLA4Ig treatment, splenocytes, and in particular DCs, can inhibit alloantigen-induced proliferative responses through secretion of inhibitory products, thus promoting alloantigen-specific tolerance in vivo.

Indoleamine 2,3-dioxgenase-transfected mesenchymal stem cells suppress heart allograft rejection by increasing the production and activity of dendritic cells and regulatory T cells

2019 ◽  
Vol 68 (3) ◽  
pp. 728-737 ◽  
Author(s):  
Ji-Gang He ◽  
Bei-Bei Li ◽  
Liang Zhou ◽  
Dan Yan ◽  
Qiao-Li Xie ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Dendritic Cells ◽  
Transforming Growth Factor Beta ◽  
Allograft Rejection ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Heart Allograft

Expression of indoleamine 2,3-dioxygenase (IDO) in mesenchymal stem cells (MSC) is thought to contribute to MSC-mediated immunosuppression. A lentiviral-based transgenic system was used to generate bone marrow stem cells (BMSC) which stably expressed IDO (IDO-BMSCs). Coculture of IDO-BMSCs with dendritic cells (DC) or T cells was used to evaluate the immunomodulatory effect of IDO-BMSCs. A heterotopic heart transplant model in rats was used to evaluate allograft rejection after IDO-BMSC treatment. Mechanisms of IDO-BMSC-mediated immunosuppression were investigated by evaluating levels of proinflammatory and anti-inflammatory cytokines, and production of Tregs. A significant decrease in DC marker-positive cells and a significant increase in Tregs were observed in IDO-BMSC cocultured. Treatment of transplanted rats with IDO-BMSCs was associated with significantly prolonged graft survival. Compared with the control groups, transplanted animals treated with IDO-BMSCs had a (1) significantly higher ejection fraction and fractional shortening, (2) significantly lower expression of CD86, CD80, and MHCII, and significantly higher expression in CD274, and Tregs, and (3) significantly higher levels of interleukin-10 (IL-10), transforming growth factor beta-1 (TGF-β1), TGF-β2, and TGF-β3, and significantly lower levels of IL-2 and interferon gamma. Our results expand our understanding of the molecular mechanisms underlying suppression of heart allograft rejection via IDO-expressing BMSCs.

scholarly journals Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2694-2705 ◽  
Author(s):  
Sherrie J. Divito ◽  
Zhiliang Wang ◽  
William J. Shufesky ◽  
Quan Liu ◽  
Olga A. Tkacheva ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Indirect Pathway ◽  
Allograft Survival ◽  
Complex Molecules ◽  
Cell Responses ◽  
Histocompatibility Complex

Abstract The prevailing idea regarding the mechanism(s) by which therapeutic immunosuppressive dendritic cells (DCs) restrain alloimmunity is based on the concept that they interact directly with antidonor T cells, inducing anergy, deletion, and/or regulation. However, this idea has not been tested in vivo. Using prototypic in vitro–generated maturation-resistant (MR) DCs, we demonstrate that once MR-DCs carrying donor antigen (Ag) are administered intravenously, they decrease the direct and indirect pathway T-cell responses and prolong heart allograft survival but fail to directly regulate T cells in vivo. Rather, injected MR-DCs are short-lived and reprocessed by recipient DCs for presentation to indirect pathway CD4+ T cells, resulting in abortive activation and deletion without detrimental effect on the number of indirect CD4+ FoxP3+ T cells, thus increasing the regulatory to effector T cell relative percentage. The effect on the antidonor response was independent of the method used to generate therapeutic DCs or their viability; and in accordance with the idea that recipient Ag-presenting cells mediate the effects of therapeutic DCs in transplantation, prolongation of allograft survival was achieved using donor apoptotic MR-DCs or those lacking surface major histocompatibility complex molecules. We therefore conclude that therapeutic DCs function as Ag-transporting cells rather than Ag-presenting cells to prolong allograft survival.

scholarly journals Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10–producing suppressive CD4+ T cells

2012 ◽  
Vol 209 (1) ◽  
pp. 109-121 ◽  
Author(s):  
Dapeng Li ◽  
Gabrielle Romain ◽  
Anne-Laure Flamar ◽  
Dorothée Duluc ◽  
Melissa Dullaers ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Oxidized Ldl ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Interleukin 10 ◽  
Protein Antigens ◽  
Host Immune Responses

Dendritic cells (DCs) can initiate and shape host immune responses toward either immunity or tolerance by their effects on antigen-specific CD4+ T cells. DC-asialoglycoprotein receptor (DC-ASGPR), a lectinlike receptor, is a known scavenger receptor. Here, we report that targeting antigens to human DCs via DC-ASGPR, but not lectin-like oxidized-LDL receptor, Dectin-1, or DC-specific ICAM-3–grabbing nonintegrin favors the generation of antigen-specific suppressive CD4+ T cells that produce interleukin 10 (IL-10). These findings apply to both self- and foreign antigens, as well as memory and naive CD4+ T cells. The generation of such IL-10–producing CD4+ T cells requires p38/extracellular signal-regulated kinase phosphorylation and IL-10 induction in DCs. We further demonstrate that immunization of nonhuman primates with antigens fused to anti–DC-ASGPR monoclonal antibody generates antigen-specific CD4+ T cells that produce IL-10 in vivo. This study provides a new strategy for the establishment of antigen-specific IL-10–producing suppressive T cells in vivo by targeting whole protein antigens to DCs via DC-ASGPR.

scholarly journals Interleukin-10-Treated Dendritic Cells Modulate Immune Responses of Naive and Sensitized T Cells In Vivo

2002 ◽  
Vol 119 (4) ◽  
pp. 836-841 ◽  
Author(s):  
Gabriele Müller ◽  
Anke Müller ◽  
Thomas Tüting ◽  
Kerstin Steinbrink ◽  
Joachim Saloga ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Interleukin 10

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

Immunomodulatory Drugs (IMiDs), Lenalidomide and Pomalidomide, Suppress Th1-Inducing Capacity of Dendritic Cells but Enhance Th2-Mediated Allergic Response

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2520-2520
Author(s):  
Tomoki Ito ◽  
Phan Thi Xuan Vien ◽  
Muneo Inaba ◽  
Hideaki Yoshimura ◽  
Masaaki Hotta ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Allergic Response ◽  
High Rate ◽  
Th2 Cells ◽  
Immunomodulatory Drugs ◽  
Th2 Response

Abstract Background: Analogs of thalidomide, lenalidomide (LEN) and pomalidomide (POM), are novel anti-multiple myeloma (MM) drugs (so-called Immunomodulatory Drugs; IMiDs). LEN has been reported to enhance function of effector immune cells such as T cells and NK cells and to induce selective reduction of regulatory T cells. Meanwhile, LEN and POM treatments lead to relatively high rate onset of itchy skin with rash like allergic reaction. However, cellular and molecular mechanisms underlying their immunomodulatory effects still remain largely unclear. Although there is evidence indicating the immunomodulatory actions of LEN on mouse conventional dendritic cells (DCs), there are few reports showing their effects on human DC subsets. DCs are pivotal in orchestrating both innate and acquire immunity as the center of the immune regulatory system, and series of analyses have clarified a functional plasticity of DCs to induce Th1 or Th2 response. Therefore, we focused on the effects of LEN and POM on the function of human myeloid DCs (mDCs), which are the major regulators to induce Th1 or Th2 responses and play a pathogenic role in allergy by their dysregulated Th2-inducing function (Ito T. J Exp Med 2005; 202: 1213). Methods: Using cell sorting, flow cytometry, real-time PCR, and ELISA methods, function and signaling were analyzed in blood human CD11+ mDCs from healthy adult volunteers. Sera were obtained from 24 MM patients with before and after LEN therapy. Written informed consent was obtained for all patients. This study was approved by the Institutional Review Board of Kansai Medical University. Results: We found that both agents at clinical in vivo plasma concentration of 0.1 µM to 1 µM did not affect the mDC survival and their CD86 and OX40-ligand expression in response to toll-like receptor (TLR)-ligands (LPS, poly IC, or R848) and Th2-inducing cytokine, thymic stromal lymphopoietin (TSLP) for 24 h culture. Either LEN or POM inhibited dose-dependently mDC-derived Th1-associated cytokines, IL-12 in response to R848 (1 µM LEN; 5.2 % of cont. and 0.3 µM POM; 12 % of cont.), IFN-λ in response to poly IC (1 µM LEN; 5.4 % of cont. and 0.3 µM POM; 10 % of cont.), and TNFα in response to R848 (1 µM LEN; 36 % of cont. and 0.3 µM POM; 17 % of cont.), but enhanced IL-10 production in response to R848 (1 µM LEN; 4.8-fold increase and 0.3 µM POM; 7.5-fold increase). When mDCs were stimulated with TSLP, both agents significantly enhanced the production of Th2-recruiting chemokine CCL17/TARC (1 µM LEN; 2.4 fold increase and 0.3 µM POM; 3.9 fold increase), which functions as chemoattractant for memory Th2 cells and contribute to aggravation of allergic inflammation. These capacities of POM were stronger than those of LEN. In addition, we revealed that, in response to LPS or R848, both LEN and POM downregulated not only IRF4 mRNA in human mDCs as in LEN-treated myeloma cells, but also STAT4 mRNA, which is important for DC-mediated Th1 response and IL-12 production. In mDCs treated with TSLP, both agents were found to upregulate STAT6 mRNA, which is responsible for TSLP-mediated CCL17 secretion (Arima K. Sci Signal2010;3:ra4). Clinically, serum CCL17/TARC levels are associated with the disease activity of atopic dermatitis and sensitively reflect short-term changes in skin conditions. We also found, in MM patients, serum CCL17 levels at the onset of LEN-associated rash during 4 weeks (n=9; 1271 ± 376 pg/ml) were significantly higher (p <0.001) compared to those without rash in LEN treatment (n=15; 476 ± 236 pg/ml) and those before treatment (296 ± 172 pg/ml). Conclusion: Our data suggest that the IMiDs, while suppress the Th1-inducing capacity of DCs, rather lead to enhance allergic response at DC phase through modulation of signaling pathways in this stream of action. Thus, IMiDs could have the potential to shift DC-mediated response from Th1 to Th2, and our findings provide a plausible explanation for pathogenesis of IMiD-associated rash in the treatment for MM. Disclosures Ito: Celgene corporation: Honoraria; GSK: Patents & Royalties.

scholarly journals Interleukin 10 Gene-Modified Bone Marrow-Derived Dendritic Cells Attenuate Liver Fibrosis in Mice by Inducing Regulatory T Cells and Inhibiting the TGF-β/Smad Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Yejin Xu ◽  
Xinyue Tang ◽  
Min Yang ◽  
Shengguo Zhang ◽  
Shanshan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Liver Fibrosis ◽  
Regulatory T Cells ◽  
Interleukin 10 ◽  
Smad Signaling Pathway ◽  
Culture Supernatants

Aim. To explore the therapeutic effects and mechanisms of interleukin 10 gene-modified bone marrow-derived dendritic cells (DC-IL10) on liver fibrosis. Methods. In vitro, BMDCs were transfected with lentiviral-interleukin 10-GFP (LV-IL10-GFP) at the MOI of 1 : 40. Then, the phenotype (MHCII, CD80, and CD86) and allo-stimulatory ability of DC-IL10 were identified by flow cytometry, and the levels of IL-10 and IL-12 (p70) secreted into the culture supernatants were quantified by ELISA. In vivo, DC-IL10 was injected into mice with CCl4-induced liver fibrosis through the tail vein. Lymphocytes were isolated to investigate the differentiation of T cells, and serum and liver tissue were collected for biochemical, cytokine, histopathologic, immune-histochemical, and Western blot analyzes. Results. In vitro, the expressions of MHCII, CD80, and CD86 in DC-IL10 were significantly suppressed, allogeneic CD4+T cells incubated with DC-IL10 showed a lower proliferative response, and the levels of IL-10 and IL-12 (p70) secreted into the DC-IL10 culture supernatants were significantly increased and decreased, respectively. In vivo, regulatory T cells (Tregs) were significantly increased, while ALT, AST, and inflammatory cytokines were significantly reduced in the DC-IL10 treatment group, and the degree of hepatic fibrosis was obviously reversed. The TGF-β/smad pathway was inhibited following DC-IL10 treatment compared to the liver fibrosis group. Conclusion. IL-10 genetic modification of BMDCs may maintain DC in the state of tolerance and allow DC to induce T cell hyporesponsiveness or tolerance. DC-IL10 suppressed liver fibrosis by inducing Treg production and inhibiting the TGF-β/smad signaling pathway.

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