Application study on adoptive transfusion of tolerogenic dendritic cells in promoting immune tolerance of liver transplantation in rat models / 器官移植

Objective To investigate the role of tolerogenic dendritic cell (tolDC) in inducing immune tolerance in liver transplantation. Methods Liver transplantation rat models of spontaneous tolerance [Brown Norway (BN)→Lewis, tolerance group, n=6] and acute rejection (AR) (Lewis→BN) were established. In AR rat models, tolDC transfusion was performed in the study group (tolDC group, n=6) and no intervention was given in the control group (AR group, n=6). The survival time of rats in each group was observed. The transplant liver tissues of rats were prepared for pathological examination in each group. The expression of myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) in rat peripheral blood, transplant liver, spleen and lymph nodes in each group was detected by flow cytometry. The expression levels of serum interleukin (IL)-10 and interferon (IFN)-γ in each group were measured by enzyme-linked immune absorbent assay. Results Pathological manifestations of rats in the AR group mainly included inflammatory cell infiltration and tissue structural disorder in transplant liver, and the survival time was 7-14 d. In the tolDC and tolerance groups, the transplant liver tissues were almost normal, and the longest survival time exceeded 100 d. Compared with the AR group, the expression levels of CD11+mDC in peripheral blood, transplant liver, spleen and lymph nodes of rats were significantly down-regulated in the tolerance and tolDC groups (all P < 0.05), and those of CD86 and major histocompatibility complex (MHC)Ⅱon the surface of CD11+mDC were also significantly down-regulated (all P < 0.05). Compared with the AR group, the expression levels of pDC in peripheral blood, transplant liver, spleen and lymph nodes of rats were significantly up-regulated in the tolerance and tolDC groups (all P < 0.05), whereas those of MHCⅡon the surface of pDC were all significantly down-regulated (all P < 0.05). Compared with the AR group, the expression levels of serum IL-10 were significantly up-regulated, and IFN-γ were significantly down-regulated in the tolerance and tolDC groups (all P < 0.05). Conclusions As tolDC subsets, mDC and pDC play a positive role in regulating the incidence of graft immune tolerance in rats after liver transplantation.

Dendritic Cell-based Immunotherapy for Rheumatoid Arthritis: from Bench to Bedside

Dendritic cells (DCs) are professional antigen presenting cells, and play an important role in the induction of antigen-specific adaptive immunity. However, some DC populations are involved in immune regulation and immune tolerance. These DC populations are believed to take part in the control of immune exaggeration and immune disorder, and maintain immune homeostasis in the body. Tolerogenic DCs (tolDCs) can be generated in vitro by genetic or pharmacological modification or by controlling the maturation stages of cytokine-derived DCs. These tolDCs have been investigated for the treatment of rheumatoid arthritis (RA) in experimental animal models. In the last decade, several in vitro and in vivo approaches have been translated into clinical trials. As of 2015, three tolDC trials for RA are on the list of ClinicalTrial.gov (www.clinicaltrials.gov). Other trials for RA are in progress and will be listed soon. In this review, we discuss the evolution of tolDC-based immunotherapy for RA and its limitations and future prospects.

Generation of Tolerogenic Dendritic Cells and Their Therapeutic Applications

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that bridge innate and adaptive immune responses, thereby leading to immune activation. DCs have been known to recognize pathogen-associated molecular patterns such as lipopolysaccharides (LPS) and nucleic acids via their pattern recognition receptors, which trigger signaling of their maturation and effector functions. Furthermore, DCs take up and process antigens as a form of peptide loaded on the major histocompatibility complex (MHC) and present them to T cells, which are responsible for the adaptive immune response. Conversely, DCs can also play a role in inducing immune suppression under specific circumstances. From this perspective, the role of DCs is related to tolerance rather than immunity. Immunologists refer to these special DCs as tolerogenic DCs (tolDCs). However, the definition of tolDCs is controversial, and there is limited information on their development and characteristics. In this review, we discuss the current concept of tolDCs, cutting-edge methods for generating tolDCs in vitro, and future applications of tolDCs, including clinical use.

Effects of exposure to cigarette smoke on the counts and functions of tDC and Treg cells in a mouse ;model of asthma / 中华微生物学和免疫学杂志

Objective To investigate the effects of exposure to cigarette smoke on the counts and functions of tolerogenic dendritic cells(tDC) and regulatory T cells(Treg) in a mouse model of asthma. Methods Forty female BALB/c mice at age 20 days were randomly allocated into four groups including the normal saline ( NS)/air treatment group, the NS/cigarette smoke ( CS) treatment group, the ovalbumin (OVA)/air treatment group and the OVA/CS treatment group (n=10).A mouse model of asthma was es-tablished by intraperitoneally injecting OVA in an interval of two weeks to cigarette smoke for three weeks. The percentages of Treg cells in PBMCs and the changes of CD80 and CD86 expression on the surface of DCs of the mice in each group were analyzed by flow cytometry analysis.The transcriptional levels of forkhead box P3 ( Foxp3) in lung tissues were measured by real-time quantitative PCR.The levels of IFN-γ, IL-4, IL-6, IL-10, IL-12p40, IL-17A and TGF-β1 in bronchoalveolar lavage fluid ( BALF) samples were measured by ELISA.Results Exposing young mice to cigarette smoke significantly increased the percentages of Treg cells in PBMCs and the expression of Foxp3 at mRNA level in lung tissues of mice with asthma.High levels of TGF-β1 and IL-10 were detected in BALF samples of the heathy mice and those with asthma exposed to CS at a young age.The mice with asthma exposed to CS at an early age showed decreased expression of CD80 and CD86 on the surface of DCs.Lower levels of IL-12p40 and IL-6 and higher levels of IFN-γ, IL-4 and IL-17A in BALF samples were observed in mice from the OVA/CS treatment group.Conclusion Expo-sing to cigarette smoke at an early age was involved in the dysfunction of T cell-mediated immune responses in mice with asthma.This study might provide new ideas for the prevention and treatment of asthma.