Tolerogenic Dendritic Cells on Transplantation: Immunotherapy Based on Second Signal Blockage

Dendritic cells (DCs), the most important professional antigen-presenting cells (APC), play crucial role in both immunity and tolerance. It is well known that DCs are able to mount immune responses against foreign antigens and simultaneously tolerate self-antigens. Since DCs can be modulated depending on the surrounding microenvironment, they can act as a bridge between innate and adaptive immunity. However, the mechanisms that support this dual role are not entirely clear. Recent studies have shown that DCs can be manipulatedex vivoin order to trigger their tolerogenic profile, what can be a tool to be used in clinical trials aiming the treatment of various diseases and the prevention of transplant rejection. In this sense, the blockage of costimulatory molecules on DC, in the attempt of inhibiting the second signal in the immunological synapse, can be considered as one of the main strategies under development. This review brings an update on current therapies using tolerogenic dendritic cells modulated with costimulatory blockers with the aim of reducing transplant rejection. However, although there are current clinical trials using tolerogenic DC to treat allograft rejection, the actual challenge is to modulate these cells in order to maintain a permanent tolerogenic profile.

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Between biology and medicine: perspectives on the use of dendritic cells in anticancer therapy

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0010.5808 ◽

2017 ◽

Vol 71 (0) ◽

pp. 0-0

Author(s):

Agnieszka Szczygieł ◽

Elżbieta Pajtasz-Piasecka

Keyword(s):

Dendritic Cells ◽

Ex Vivo ◽

Anticancer Therapy ◽

Point Of View ◽

Proper Function ◽

Innate And Adaptive Immunity ◽

Factors Affecting ◽

Antigen Presenting

Dendritic cells (DCs), as a link between innate and adaptive immunity, play a pivotal role in maintaining homeostasis of the immune system. The DC population is characterized by heterogeneity; it consists of many subpopulations which, despite their phenotypic and localization differences, play an essential function – they are professional antigen presenting cells. Due to their role, DCs can be utilized in a new cancer treatment strategy. Their main purpose is to generate an anticancer response leading to the elimination of cancer cells. The tumor microenvironment, abundant in immunosuppressive factors (e.g. IL-10, TGF-β, Arg1, IDO), impairs the proper function of DCs. For this reason, various strategies are necessary for ex vivo preparation of DC-based vaccines and for the support of in vivo DCs to fight against tumors. DC-based vaccines are combined with other forms of immunotherapy (e.g. blockade of immune checkpoint molecules, e.g. PD-1 or CTLA-4) or conventional types of therapies (e.g. chemotherapy). Despite the enormous progress that has been made in anticancer therapy in the past two decades, there are still many unresolved issues regarding the effectiveness of the DCs usage. In this paper we described, in both a mouse and a human subject, a series of DC subpopulations, differentiating in normal conditions or under the influence of cancer microenvironment. We listed factors affecting the quality of the in vivo and ex vivo generations of antitumoral responses, significant from a therapeutic point of view. Moreover, the most important strategies for the use of DCs in anticancer therapies, as well as further developments on this field, have been discussed.

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Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells

10.1101/334508 ◽

2018 ◽

Author(s):

Thi Thu Phuong Tran ◽

Karsten Eichholz ◽

Patrizia Amelio ◽

Crystal Moyer ◽

Glen R Nemerow ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Responses ◽

Persistent Infections ◽

Cell Immunity ◽

Tolerogenic Dendritic Cells ◽

Antigen Presenting ◽

Tolerogenic Dcs

AbstractFollowing repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised, reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus-specific T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregsare generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen-loaded tolerogenic DCs can drive naïve T cells to mature into adenovirus-specific Tregs. Our results may provide ways to improve antiviral therapy and/or pre-screening high-risk individuals undergoing immunosuppression.Author summaryWhile numerous studies have addressed the cellular and humoral response to primary virus encounters, relatively little is known about the interplay between persistent infections, neutralizing antibodies, antigen-presenting cells, and the T-cell response. Our studies suggests that if adenovirus–antibody complexes are taken up by professional antigen-presenting cells (dendritic cells), the DCs generate an environment that causes bystander dendritic cells to become tolerogenic. These tolerogenic dendritic cells favors the creation of adenovirus-specific regulatory T cells. While this pathway likely favors pathogen survival, there may be advantages for the host also.

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Dendritic Cells The Tumor Microenvironment and the Challenges for an Effective Antitumor Vaccination

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/425476 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 45

Author(s):

Fabian Benencia ◽

Leslee Sprague ◽

John McGinty ◽

Michelle Pate ◽

Maria Muccioli

Keyword(s):

Clinical Trials ◽

Dendritic Cells ◽

Tumor Microenvironment ◽

Immune Responses ◽

Immune Cells ◽

Therapeutic Potential ◽

Human Cancer ◽

Dc Vaccines ◽

Tumor Clearance ◽

Antigen Presenting

Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment.

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The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells

Blood ◽

10.1182/blood-2011-10-387613 ◽

2012 ◽

Vol 119 (21) ◽

pp. 5005-5015 ◽

Cited By ~ 5

Author(s):

Joanna Fares ◽

Richard Koller ◽

Rita Humeniuk ◽

Linda Wolff ◽

Juraj Bies

Keyword(s):

Dendritic Cells ◽

Tumor Suppressor ◽

Immune Responses ◽

Ex Vivo ◽

Positive Role ◽

Antigen Uptake ◽

Mhc Ii ◽

T Cell Stimulation ◽

Elevated Activity ◽

Antigen Presenting

Abstract The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo–generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses.

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Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22105386 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5386

Author(s):

Maria Namwanje ◽

Bijay Bisunke ◽

Thomas V. Rousselle ◽

Gene G. Lamanilao ◽

Venkatadri S. Sunder ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Therapeutic Potential ◽

Ex Vivo ◽

Mitochondrial Dynamics ◽

Graft Loss ◽

Kidney Injury ◽

Adaptive Immune ◽

Consumption Rates ◽

Regulatory Phenotype

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

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Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity

Biochemical Society Transactions ◽

10.1042/bst0320629 ◽

2004 ◽

Vol 32 (4) ◽

pp. 629-632 ◽

Cited By ~ 65

Author(s):

T. Lehner ◽

Y. Wang ◽

T. Whittall ◽

E. McGowan ◽

C.G. Kelly ◽

...

Keyword(s):

Amino Acids ◽

Dendritic Cells ◽

Immune Responses ◽

Cd40 Ligand ◽

Interleukin 12 ◽

Cytokines And Chemokines ◽

Cc Chemokines ◽

Factor Α ◽

Antigen Presenting ◽

Necrosis Factor

Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1–358), followed by an 18 kDa peptide-binding domain (amino acids 359–494) and a C-terminal 10 kDa fragment (amino acids 495–609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359–610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFα(tumour necrosis factor α), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70–CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.

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Regulation of the Migration of Distinct Dendritic Cell Subsets

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.635221 ◽

2021 ◽

Vol 9 ◽

Author(s):

Meng Feng ◽

Shuping Zhou ◽

Yong Yu ◽

Qinghong Su ◽

Xiaofan Li ◽

...

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Immune Responses ◽

The Body ◽

Inflammatory Factors ◽

Pathogenic Microorganisms ◽

Migration Patterns ◽

Dendritic Cell Subsets ◽

And Migration ◽

Antigen Presenting

Dendritic cells (DCs), a class of antigen-presenting cells, are widely present in tissues and apparatuses of the body, and their ability to migrate is key for the initiation of immune activation and tolerogenic immune responses. The importance of DCs migration for their differentiation, phenotypic states, and immunologic functions has attracted widespread attention. In this review, we discussed and compared the chemokines, membrane molecules, and migration patterns of conventional DCs, plasmocytoid DCs, and recently proposed DC subgroups. We also review the promoters and inhibitors that affect DCs migration, including the hypoxia microenvironment, tumor microenvironment, inflammatory factors, and pathogenic microorganisms. Further understanding of the migration mechanisms and regulatory factors of DC subgroups provides new insights for the treatment of diseases, such as infection, tumors, and vaccine preparation.

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Evaluation of Feline Monocyte-Derived Dendritic Cells Loaded with Internally Inactivated Virus as a Vaccine against Feline Immunodeficiency Virus

Clinical and Vaccine Immunology ◽

10.1128/cvi.00421-07 ◽

2008 ◽

Vol 15 (3) ◽

pp. 452-459 ◽

Cited By ~ 4

Author(s):

Giulia Freer ◽

Donatella Matteucci ◽

Paola Mazzetti ◽

Francesca Tarabella ◽

Valentina Catalucci ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Immune Functions ◽

Peripheral Blood Mononuclear ◽

Challenge Virus ◽

Homologous Virus ◽

Antibody Titers ◽

Cellular Immune ◽

Antigen Presenting

ABSTRACT Dendritic cells are the only antigen-presenting cells that can present exogenous antigens to both helper and cytolytic T cells and prime Th1-type or Th2-type cellular immune responses. Given their unique immune functions, dendritic cells are considered attractive “live adjuvants” for vaccination and immunotherapy against cancer and infectious diseases. The present study was carried out to assess whether the reinjection of autologous monocyte-derived dendritic cells loaded with an aldithriol-2-inactivated primary isolate of feline immune deficiency virus (FIV) was able to elicit protective immune responses against the homologous virus in naive cats. Vaccine efficacy was assessed by monitoring immune responses and, finally, by challenge with the homologous virus of vaccinated, mock-vaccinated, and healthy cats. The outcome of challenge was followed by measuring cellular and antibody responses and viral and proviral loads and quantitating FIV by isolation and a count of CD4+/CD8+ T cells in blood. Vaccinated animals exhibited clearly evident FIV-specific peripheral blood mononuclear cell proliferation and antibody titers in response to immunization; however, they became infected with the challenge virus at rates comparable to those of control animals.

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Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus

Cells ◽

10.3390/cells8101291 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1291 ◽

Cited By ~ 2

Author(s):

Ritprajak ◽

Kaewraemruaen ◽

Hirankarn

Keyword(s):

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Ex Vivo ◽

Immunosuppressive Drugs ◽

Clinical Implications ◽

Systemic Lupus ◽

Tolerogenic Dendritic Cells

Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs. Therefore, DC-targeted therapies to either suppress DC immunogenicity or to promote DC tolerogenicity are of high interest. This review describes details of the typical characteristics of in vivo and ex vivo tolDC, which will help to select a protocol that can generate tolDC with high functional quality for clinical treatment of autoimmune disease in individual patients. In addition, we discuss the recent studies uncovering metabolic pathways and their interrelation intertwined with DC tolerogenicity. This review also highlights the clinical implications of tolDC-based therapy for SLE treatment, examines the current clinical therapeutics in patients with SLE, which can generate tolDC in vivo, and further discusses on possibility and limitation on each strategy. This synthesis provides new perspectives on development of novel therapeutic approaches for SLE and other autoimmune diseases.

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