• alloantigen-specific immune tolerance
• allogeneic hematopoietic cell
• apoptotic cell
• efferocytosis
• graft survival
• nonspecific over-immunosuppression
• transplantation
• transplanted-cell death

• Graft Rejection/prevention & control
• Transplantation Tolerance
• Immunosuppression Therapy
• Apoptosis

• chemokine
• cytokine
• decidual dendritic cells
• gp96
• pregnancy

• Alopecia areata
• Dendritic cells
• Immunology
• Langerhans cells
• Treatment

• AMG 487
• Dendritic cells
• Development inhibition
• Dysfunction

Mice immunized with recombinant Echinococcus granulosus antigens Eg10 and Eg mMDH do not show elevated resistance to E. granulosus infection but show aggravated infection instead. To gain a deeper insight in the immune tolerance mechanisms in mice immunized with Eg10 and Eg mMDH, this study simulated the immune tolerance process in vitro by culturing bone marrow-derived dendritic cells (BMDCs) in the presence of Eg10 or Eg mMDH. Scanning electron microscopy revealed that Eg10- and Eg mMDH-treated DCs exhibited immature cell morphology, while addition of LPS to the cells induced changes in cell morphology and an increase in the number of cell-surface protrusions. This observation was consistent with the increased expression of the cell-surface molecules MHCII and CD80 in Eg10- and Eg mMDH-treated DCs pretreated with LPS. DCs exposed to the two antigens had a very weak ability to induce T-cell proliferation, but could promote the formation of Treg cells. Introduction of the indoleamine 2,3-dioxygenase (IDO) inhibitor, 1-methyl tryptopha (1-MT) enhanced the ability of the antigens to induce T cells and inhibited the induction of Treg cells. Eg mMDH-treated DCs showed a strong response to 1-MT: the DCs had high mRNA levels of IDO, IL-6, and IL-10, while 1-MT decreased the expression. In contrast, DCs treated with Eg10 did not show significant changes after 1-MT treatment. Eg mMDH inhibited DC maturation and promoted IDO expression, which, on the one hand, decreased the ability of DCs to induce T-cell proliferation, resulting in T-cell anergy, and on the other hand, induced the formation of Tregs, resulting in an immunosuppressive effect. In contrast, the escape mechanisms induced by Eg10 did not primarily depend on the IDO pathway and might involve other mechanisms that need to be further explored.

Hepatitis B can cause acute or chronic liver damage due to hepatitis B virus (HBV) infection. Cirrhosis or hepatocellular carcinoma (HCC) caused by chronic HBV infection often leads to increased mortality. However, the gut and liver have the same embryonic origin; therefore, a close relationship must exist in terms of anatomy and function, and the gut microbiota plays an important role in host metabolic and immune modulation. It is believed that structural changes in the gut microbiota, bacterial translocation, and the resulting immune injury may affect the occurrence and development of liver inflammation caused by chronic HBV infection based on the in-depth cognition of the concept of the “gut-liver axis” and the progress in intestinal microecology. This review aims to summarize and discuss the immunologic role of the gut microbiota in chronic HBV infection.

Graft-versus-host disease (GVHD) is a serious and deadly complication of patients, who undergo hematopoietic stem cell transplantation (HSCT). Despite prophylactic treatment with immunosuppressive agents, 20–80% of recipients develop acute GVHD after HSCT. And the incidence rates of chronic GVHD range from 6 to 80%. Standard therapeutic strategies are still lacking, although considerable advances have been gained in knowing of the predisposing factors, pathology, and diagnosis of GVHD. Targeting immune cells, such as regulatory T cells, as well as tolerogenic dendritic cells or mesenchymal stromal cells (MSCs) display considerable benefit in the relief of GVHD through the deletion of alloactivated T cells. Monoclonal antibodies targeting cytokines or signaling molecules have been demonstrated to be beneficial for the prevention of GVHD. However, these remain to be verified in clinical therapy. It is also important and necessary to consider adopting individualized treatment based on GVHD subtypes, pathological mechanisms involved and stages. In the future, it is hoped that the identification of novel therapeutic targets and systematic research strategies may yield novel safe and effective approaches in clinic to improve outcomes of GVHD further. In this article, we reviewed the current advances in targeted immunotherapy for the prevention of GVHD.

• graft-versus-host disease
• hematopoietic stem cell transplantation
• immune cells
• immune inhibitors
• immunotherapy

A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health.

This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA).

In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction.

A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.

• Dendritic cells (DCs)
• Gut homeostasis
• Immune responses
• Intestinal microbiota
• Metabolic disorder
• Regulatory T cells (Tregs)

While emerging evidence indicates that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides prospect as disease-modifying therapy. Our observations reveal that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) treatment of monocyte-derived DC results in a semimature phenotype and anti-inflammatory cytokine profile as compared to conventional DC, in both healthy controls and MS patients. Importantly, 1,25(OH)₂D₃-treated DC induce T cell hyporesponsiveness, as demonstrated in an allogeneic mixed leukocyte reaction. Next, following a freeze-thaw cycle, 1,25(OH)₂D₃-treated immature DC could be recovered with a 78% yield and 75% viability. Cryopreservation did not affect the expression of membrane markers by 1,25(OH)₂D₃-treated DC nor their capacity to induce T cell hyporesponsiveness. In addition, the T cell hyporesponsiveness induced by 1,25(OH)₂D₃-treated DC is antigen-specific and robust since T cells retain their capacity to respond to an unrelated antigen and do not reactivate upon rechallenge with fully mature conventional DC, respectively. These observations underline the clinical potential of tolerogenic DC (tolDC) to correct the immunological imbalance in MS. Furthermore, the feasibility to cryopreserve highly potent tolDC will, ultimately, contribute to the large-scale production and the widely applicable use of tolDC.

Objective. To dissect the efficacy of Tol-DC therapy with or without IS in multiple animal models of transplantation. Methods and Results. PubMed, Medline, Embase, and the Cochrane Library were searched for reviews published up to April 2015. Six systematic reviews and a total of 61 articles were finally included. Data were grouped by organ transplantation models and applied to meta-analysis. Our meta-analysis shows that Tol-DC therapy successfully prolonged allograft survival to varying extents in all except the islet transplantation models and with IS drugs further prolonged the survival of heart, skin, and islet allografts in mice, but not of heart allografts in rats. Compared with IS drugs alone, Tol-DC therapy with IS extended islet allograft survival in rats but failed to influence the survival of skin, small intestine, and heart allografts in rats or of heart and skin allografts in mice. Conclusion. Tol-DC therapy significantly prolonged multiple allograft survival and further prolonged survival with IS. However, standardized protocols for modification of Tol-DC should be established before its application in clinic.

• Dendritic cells
• TLR4
• TLR7
• innate immunity
• multiple sclerosis

• Adult
• Belgium
• Cells, Cultured
• Dendritic Cells/immunology
• Female
• Gene Expression Regulation
• Humans
• Interferon Regulatory Factor-1/genetics
• Interferon Regulatory Factor-1/metabolism
• Interferon Regulatory Factor-7/genetics
• Interferon Regulatory Factor-7/metabolism
• Interferon-alpha/metabolism
• Interleukin-12/metabolism
• Male
• Middle Aged
• Multiple Sclerosis, Relapsing-Remitting/immunology
• Receptors, Interferon/genetics
• Receptors, Interferon/metabolism
• Signal Transduction
• Toll-Like Receptor 4/metabolism
• Toll-Like Receptor 7/metabolism
• Interferon gamma Receptor

• Dendritic Cells/metabolism
• Exercise/physiology
• Female
• Humans
• Inflammation/blood
• Inflammation/metabolism
• Interleukin-10/metabolism
• Male
• Matrix Metalloproteinase 8/metabolism
• Middle Aged
• Multiple Sclerosis/blood
• Multiple Sclerosis/metabolism
• Multiple Sclerosis/therapy
• Resistance Training
• Tumor Necrosis Factor-alpha/metabolism

• Clinical grade
• Dendritic cells
• Electroporation
• RNA
• WT1
• Wilms’ tumor 1

• Cancer Vaccines
• Cells, Cultured
• Cryopreservation
• Dendritic Cells
• Electroporation
• Humans
• RNA, Messenger
• Vaccination
• WT1 Proteins/genetics
• Wilms Tumor/therapy

In healthy individuals, one exercise bout induces a substantial increase in the number of circulating leukocytes, while their function is transiently suppressed. The effect of one exercise bout in multiple sclerosis (MS) is less studied. Since recent evidence suggests a role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of one combined endurance/resistance exercise bout on the number and function of DC in MS patients and healthy controls. Our results show a rapid increase in the number of DC in response to physical exercise in both MS patients and controls. Further investigation revealed that in particular DC expressing the migratory molecules CCR5 and CD62L were increased upon acute physical activity. This may be mediated by Flt3L- and MMP-9-dependent mobilization of DC, as demonstrated by increased circulating levels of Flt3L and MMP-9 following one exercise bout. Circulating DC display reduced TLR responsiveness after acute exercise, as evidenced by a less pronounced upregulation of activation markers, HLA-DR and CD86, on plasmacytoid DC and conventional DC, respectively. Our results indicate mobilization of DC, which may be less prone to drive inflammatory processes, following exercise. This may present a negative feedback mechanism for exercise-induced tissue damage and inflammation.

• T cell activation
• dendritic cells
• immunotherapy
• multiple sclerosis

Lanthanide doped CaF₂ nanoparticles are useful for in vivo optical and MR imaging and as nanothermometer probes, which do not induce pro-inflammatory cytokine secretion.

• APCs, antigen-presenting cell
• BCG, Bacille Calmette-Guerin
• BCR, B-cell receptor
• CDCA1, cell division cycle associated 1
• CRC, colorectal cancer
• CT, Cancer-testis
• CTL, cytotoxic T-lympocites
• DCs, dendritic cells
• EGT, electro-gene-transfer
• FDA, Food & drug administration
• GB, glioblastoma
• GM-CSF, granulocyte macrophage-colony stimulating factor
• HER2, human epidermal growth factor receptor 2
• HLA, human leukocyte antigen
• HPV, human papillomavirus
• HSPs, stress/heat shock proteins
• IFNg, interferon gamma
• Ig Id, immunoglobulin idiotype
• LPs, long peptides
• MAGE-A1, Melanoma-associated antigen 1
• MHC, major histocompatibility complex
• MS, mass spectrometry
• MVA, modified vaccinia strain Ankara
• NSCLC, non-small-cell lung carcinoma
• PAP, prostatic acid phosphatase
• PRRs, Pattern Recognition Receptors
• PSA, Prostate-specific antigen
• RCR, renal cell cancer
• SSX-2, Synovial sarcoma X breakpoint 2
• TAAs, tumor-associated antigens
• TACAs, Tumor-associated carbohydrate antigens
• TARP, T-cell receptor gamma alternate reading frame protein
• TLRs, Toll-Like Receptors
• TPA, transporter associated with antigen processing
• WES, whole exome sequencing
• WGS, whole genome sequencing
• cancer vaccine
• clinical trials
• epitopes
• hTERT, human Telomerase reverse transcriptase
• immunotherapeutics
• mCRPC, metastatic castrate-resistant prostate cancer
• tumor-associated antigens

• Adjuvants, Immunologic/therapeutic use
• Antigens, Neoplasm/immunology
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Humans
• Neoplasms/immunology
• Neoplasms/therapy
• Precision Medicine
• Tumor Escape/immunology

• Dendritic cells
• MS-associated genetic risk factors
• costimulatory molecules
• migration
• multiple sclerosis

In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigen-presenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases.

Earlier investigations have revealed a surprising complexity and variety in the range of interaction between cells of the innate and adaptive immune system. Our understanding of the specialized roles of dendritic cell (DC) subsets in innate and adaptive immune responses has been significantly advanced over the years. Because of their immunoregulatory capacities and because very small numbers of activated DC are highly efficient at generating immune responses against antigens, DCs have been vigorously used in clinical trials in order to elicit or amplify immune responses against cancer and chronic infectious diseases. A better insight in DC immunobiology and function has stimulated many new ideas regarding the potential ways forward to improve DC therapy in a more fundamental way. Here, we discuss the continuous search for optimal in vitro conditions in order to generate clinical-grade DC with a potent immunogenic potential. For this, we explore the molecular and cellular mechanisms underlying adequate immune responses and focus on most favourable DC culture regimens and activation stimuli in humans. We envisage that by combining each of the features outlined in the current paper into a unified strategy, DC-based vaccines may advance to a higher level of effectiveness.

A variety of immune-based therapies has been developed in order to boost or induce protective CD8⁺ T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2 gag mRNA enhances their capacity to induce HIV gag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2 gag-expressing DCs to expand functional HIV-specific CD8⁺ T cells. However, although most of the patients had detectable gag-specific CD8⁺ T cell responses, no significant differences in the level of expansion of functional CD8⁺ T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.

• Animals
• Autoimmunity
• Cell Communication/immunology
• Cellular Microenvironment/immunology
• Humans
• Immune Tolerance
• Immunity, Cellular
• Immunotherapy
• Infections/immunology
• Infections/therapy
• Inflammation
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplasms/therapy
• Receptor Cross-Talk/immunology

• ZIA CL002118 Intramural NIH HHS
• ZIA CL002118-03 Intramural NIH HHS