[Effects of Dasatinib on the Maturation of Monocyte-Derived Dendritic Cells Derived from Healthy Donors and Chronic Myelogenous Leukemia Patients].

OBJECTIVE: To investigate the effects of dasatinib on the maturation of monocyte-derived dendritic cells (moDCs) derived from healthy donors (HDs) and chronic myelogenous leukemia (CML) patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=10) and CML patients (n=10) who had got the remission of MR4.5 with imatinib treatment. The generation of moDCs from PBMCs was completed after 7 days of incubation in DC I culture medium, and another 3 days of incubation in DC II culture medium with or without 25 nmol/L dasatinib. On the 10th day, cells were harvested and expression of molecules of maturation related marker were assessed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as DCs in the fluorescence-activated cell storting (FACS) analyzing system, then the expression of CD83, CD40 or HLA-DR in this population was analyzed respectively. RESULTS: The proportion of CD80+CD86+ cells in total cells didn't show a statistical difference between HD group and patient group (89.46%±9.70% vs 87.39%±9.34%, P=0.690). Dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.008) and HLA-DR (P=0.028) on moDCs derived from HDs compared with the control group, while the expression of CD83 on moDCs didn't show a significant difference between dasatinib group and the control group (P=0.428). Meanwhile, dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.023), CD83 (P=0.038) and HLA-DR (P=0.001) on moDCs derived from patients compared with the control group. CONCLUSION: For CML patients, the same high proportion of moDCs as HDs can be induced in vitro, which provides a basis for the application of DC-based immunotherapy strategy. Dasatinib at the concentration of 25 nmol/L can efficiently promote the maturation of moDCs derived from HDs and CML patients in vitro. Dasatinib shows potential as a DC adjuvant to be applied in DC-based immunotherapy strategies, such as DC vaccine and DC cell-therapy.

Effects of Dasatinib on the Maturation of Monocyte-Derived Dendritic Cells Derived from Healthy Donors and Chronic Myelogenous Leukemia Patients / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of dasatinib on the maturation of monocyte-derived dendritic cells (moDCs) derived from healthy donors (HDs) and chronic myelogenous leukemia (CML) patients.@*METHODS@#Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=10) and CML patients (n=10) who had got the remission of MR4.5 with imatinib treatment. The generation of moDCs from PBMCs was completed after 7 days of incubation in DC I culture medium, and another 3 days of incubation in DC II culture medium with or without 25 nmol/L dasatinib. On the 10th day, cells were harvested and expression of molecules of maturation related marker were assessed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as DCs in the fluorescence-activated cell storting (FACS) analyzing system, then the expression of CD83, CD40 or HLA-DR in this population was analyzed respectively.@*RESULTS@#The proportion of CD80+CD86+ cells in total cells didn't show a statistical difference between HD group and patient group (89.46%±9.70% vs 87.39%±9.34%, P=0.690). Dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.008) and HLA-DR (P=0.028) on moDCs derived from HDs compared with the control group, while the expression of CD83 on moDCs didn't show a significant difference between dasatinib group and the control group (P=0.428). Meanwhile, dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.023), CD83 (P=0.038) and HLA-DR (P=0.001) on moDCs derived from patients compared with the control group.@*CONCLUSION@#For CML patients, the same high proportion of moDCs as HDs can be induced in vitro, which provides a basis for the application of DC-based immunotherapy strategy. Dasatinib at the concentration of 25 nmol/L can efficiently promote the maturation of moDCs derived from HDs and CML patients in vitro. Dasatinib shows potential as a DC adjuvant to be applied in DC-based immunotherapy strategies, such as DC vaccine and DC cell-therapy.

Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells.

Understanding and eliciting protective immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an urgent priority. To facilitate these objectives, we profile the repertoire of human leukocyte antigen class II (HLA-II)-bound peptides presented by HLA-DR diverse monocyte-derived dendritic cells pulsed with SARS-CoV-2 spike (S) protein. We identify 209 unique HLA-II-bound peptide sequences, many forming nested sets, which map to sites throughout S including glycosylated regions. Comparison of the glycosylation profile of the S protein to that of the HLA-II-bound S peptides reveals substantial trimming of glycan residues on the latter, likely induced during antigen processing. Our data also highlight the receptor-binding motif in S1 as a HLA-DR-binding peptide-rich region and identify S2-derived peptides with potential for targeting by cross-protective vaccine-elicited responses. Results from this study will aid analysis of CD4+ T cell responses in infected individuals and vaccine recipients and have application in next-generation vaccine design.

IFN-γ regulates the transformation of microglia into dendritic-like cells via the ERK/c-myc signaling pathway during cerebral ischemia/reperfusion in mice.

Cerebral ischemia-reperfusion injury induces a secondary immune inflammatory reaction that exacerbates brain injury and clinical prognosis. Dendritic cells (DCs) and microglia are both important regulators of neuroinflammation. Studies have confirmed that a large number of cells express the DC surface marker CD11c in the ischemic area, and some of these cells also express microglial markers. However, the specific mechanism of transformation between microglia and DCs and their roles in the process of cerebral ischemia-reperfusion injury are still not clear. In this study, we established a mouse model and flow cytometry was used to detect the expression of mature DC surface molecules in activated microglia. IFN-γ knockout mice were used to determine the regulatory effect of IFN-γ on microglial transformation. We found that CD11c+ cells were derived from microglia after ischemia-reperfusion injury, and this group of cells highly expressed MHC-II molecules and other costimulatory molecules, such as CD80 and CD86, which were regulated by IFN-γ and its downstream signaling molecules ERK/c-myc. In summary, our results showed in cerebral ischemia-reperfusion injury, IFN-γ regulates the transformation of microglia to DC-like cells. Microglial-derived DC-like cells possess the ability to present antigens and activate naïve T cells which is regulated by the ERK/c-myc signaling pathway.

Expressions of Foxp3+ regulatory T cells and myeloid dentritic cells in human colorectal cancer and tumor draining lymph node tissues and their significances / 吉林大学学报(医学版)

Objective: To explore the expressions of Foxp3 ' Tregs and CDllc mDCs in the colorectal cancer (CRC) tissue and their infiltrations in the tumor draining lymph node (TDLN) tissue, and to explore the clinical significances. Methods: Fifty-two samples of surgical resection of the CRC patients were collected The expressions of Foxp3 + Tregs and CDllc mDCs in the specimens of the CRC patients and TDLN tissue were detected by immunohistochemistry, and the relationship between the expression frequencies of Foxp3 + Tregs and CD11c+ mDCs and the clinicopathological characteristics of the patients were discussed Results: The positive expression frequency of Foxp3 + Tregs in cancer tissue of the CRC patients was higher than that in adjacent normal mucosa tissue (P0. 05). Conclusion: The occurrence and development of CRC are related to the changes of Foxp3 Tregs and CDllc mDCs expression frequencies in the local microenvironment of cancer tissue. Foxp3+ Tregs and CD11c+ mDCs play a role in inhibiting the cellular immunity in tumor microenvironment.

A novel MtHSP70-FPR1 fusion protein enhances cytotoxic T lymphocyte responses to cervical cancer cells by activating human monocyte-derived dendritic cells via the p38 MAPK signaling pathway.

OBJECTIVE: To evaluate the potential effects of recombinant mycobacterium tuberculosis heat shock protein 70-formyl peptide receptor 1 (MtHSP70-FPR1) fusion protein on human monocyte-derived dendritic cell (moDC) maturation; cytotoxic T lymphocyte (CTL) responses to cervical cancer (CC) cells; and the roles of the p38 MAPK, ERK, and JNK pathways in its transition. METHODS: Monocytes were positively selected with a MACS column with antiCD14 antibody-conjugated microbeads from umbilical cord blood. MoDCs were stimulated with MtHSP70-FPR1, MtHSP70, a mix of MtHSP70 and FPR1, FPR1, or phosphate buffer solution (PBS) as control. Flow cytometry was used to analyze the surface molecule expression of moDCs and IFN-γ-producing CD8+ T cells. T cell proliferation was assessed using [3][H]-thymidine assays. The cytotoxicity of moDC-activated T cells against CC cells was evaluated by MTT assays. Cytokine production was determined by enzyme-linked immunosorbent assay. Western blotting was used to investigate protein expression. RESULTS: Compared with MtHSP70, MtHSP70 + FPR1, FPR1, or PBS-mediated moDCs, MtHSP70-FPR1-pulsed moDCs expressed higher levels of CD80, CD86, CD83, HLA-DR, and CCR7; secreted more IL-12p70, TNF-ɑ and IL-1ß; and elicited stronger CTL priming and proliferation, resulting in an effective, HLA-I-dependent killing effect on CC cells. The p38 MAPK, ERK, and JNK pathways were all activated in MtHSP70-FPR1-mediated moDC maturation, but the p38 MAPK pathway played a vital role. CONCLUSIONS: The excellent capability of MtHSP70-FPR1 fusion protein to induce phenotypical and functional maturation of moDCs and CC-specific CTL responses partly illustrates the potential clinical benefits of DC-based immunotherapy for CC.

Inate immunity in rosacea. Langerhans cells, plasmacytoid dentritic cells, Toll-like receptors and inducible oxide nitric synthase (iNOS) expression in skin specimens: case-control study.

Rosacea is a chronic inflammatory condition with predominant facial involvement. Because of that, many patients sense that rosacea affects quality of life. The etiology of rosacea remains unknown. Recent studies have suggested that aberrant innate immunity is central to this disease. The aim of this study was to examine the presence of Langerhans cells, plasmacytoid dentritic cells (PDC), the expression of Toll-like receptors (TLR) and inducible oxide nitric synthase (iNOS) in skin of patients with rosacea, to highlight the participation of innate immunity in its pathogenesis. 28 biopsy specimens were taken from patients with clinical and histopathological findings of rosacea. Immunohistochemical demonstration of Langerhans cells (anti-CD1a antibody), PDC (anti-CD 123 antibody), TLR2, TLR4 and iNOS was performed in skin samples and compared with normal skin controls. The expression of Langerhans cells was lower in rosacea group than in control group. PDC were found in skin samples of rosacea as isolated cells and forming small clusters. Expression of TLR2, TLR4 and iNOS was higher in rosacea samples than in normal skin controls. This research demonstrates early and late stage components of innate immunity in specimens of rosacea ratifying the existence of an altered innate immunity in its pathogenesis.

Neoplasia blástica de células dendríticas plasmocitoides: casos clínicos / Blastic plasmacytoid dendritic cell neoplasm: report of three cases

Blastic plasmacytoid dendritic cell neoplasm is a rare hematological malignancy derived from immature plasmacytoid dendritic cells. The tumor cells have an immature blastic appearance, and diagnosis is based on the expression of CD4, CD56 y CD123 in the absence of other lymphoid, natural killer, or myeloid antigens. The majority of affected individuals are older people with a mean age of 66 years. Male to female ratio is approximately 3:1. Common presentation includes cutaneous lesions followed by tumor dissemination. Treatment with conventional chemotherapy is ineffective and allogeneic hematopoietic stem cell transplantation is required to achieve remission. We report three male patients, aged 23, 27 and 51 years with the disease. All had multiple, infiltrated pink plaques and nodules on the skin of their face, neck and thorax, measuring 1 to 12 cm in diameter. All tumors were histologically characterized by a monotonous proliferation of medium size cells with blastic features. Tumor cells were positive for CD123, CD56, CD4 and CD7 in all cases. After a mean of follow-up of 14.6 months, one patient died of the disease, one patient is alive and the disease relapsed after 17 months of remission and one patient is alive with no evidence of the disease.

Neoplasia de células dendríticas plasmocitoides blásticas con respuesta inicial a quimioterapia y recaída en sistema nervioso central: caso clínico / Blastic plasmacytoid dendritic cell neoplasm with complete clinical remission with chemotherapy and central nervous system relapse: report of one case

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematologic malignancy that most commonly manifests as cutaneous lesions with or without bone marrow involvement and leukemic dissemination. The demonstration of tumor cells with the characteristic immunophenotype with expression of CD56, generally CD4 and dendritic cell antigens (CD123, cyTCL-1, HLA-DR), in the absence of myeloid or lymphoid lineage markers is required for the diagnosis. Responses to chemotherapy are initially satisfactory, with frequent systemic and central nervous system relapses. We report a 24 year-old male with BPDCN, initially diagnosed and treated as non-Hodgkin CD4+ T-cell lymphoma, with initial complete remission who evolved with early central nervous system relapse. A second attempt of chemotherapy failed and the patient died two months later.

Dectin-1-activated dendritic cells: A potent Th9 cell inducer for tumor immunotherapy.

Dendritic cell (DC)-based immunotherapy has great promise for cancer treatment. We have recently demonstrated that dectin-1-activated DCs trigger potent antitumor Th9 cells in vivo. Dectin-1-activated DC-induced antitumor responses rely on the induced Th9/IL-9. These findings offer new strategies for the development of more effective DC vaccines in tumor immunotherapy.

Interferon-targeted therapy in systemic lupus erythematosus: Is this an alternative to targeting B and T cells?

Clinical trials of investigational agents in systemic lupus erythematosus (SLE) have focused on targeting dysregulated B and T cells; however, recent translational research findings of the importance of the dysregulation of the innate immune system in SLE have led to clinical trials that target interferon. Three biologics that target type I interferons have been tested for their efficacy and safety in active SLE patients; these phase II trials have tested the hypothesis that down-regulation of interferon-regulated gene expression (the interferon signature) lessen the clinical burden of SLE. Rontalizumab, an anti-interferon-α monoclonal antibody, was studied in patients who had discontinued immunosuppressants. This study failed to show efficacy as assessed by both two outcome assessments; however, in low interferon signature patients, response was higher and corticosteroid usage was less in rontalizumab-treated patients. Sifalimumab, another anti-interferon-α monoclonal antibody, was studied in patients who remained on standard of care therapy. This study showed significantly better efficacy in patients treated with two sifalimumab dosages; significant differences were seen in the high interferon signature group. In a similar design and in a similar population as the sifalimumab study, anifrolumab, a monoclonal antibody that binds to a type I interferon receptor, was studied in patients who remained on standard of care therapy. In this study, one dosage group demonstrated efficacy and statistically significant effects were achieved in both tested dosage groups with secondary end points. Oral corticosteroid reduction to ≤7.5 mg daily was achieved in one of the tested dosage groups and organ-specific outcomes were significantly improved in that same group. For all studies, no significant differences in serious adverse effects were seen; although, herpes zoster infections were increased in sifalimumab- and anifrolumab-treated patients and influenza rates were increased in anifrolumab-treated patients. Anifrolumab is currently in pivotal phase III studies. Data appear to support the concept that targeting type I interferon in SLE patients associates with clinical efficacy and safety. Further data are forthcoming from ongoing phase III clinical trials of anifrolumab. Other drug development efforts should be considered that target plasmacytoid dendritic cells and toll like receptors given the effects these components have on interferon production.

Human plasmacytoid dentritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway.

Plasmacytoid dendritic cells (pDCs) are a major source of type I interferon (IFN) and are important for host defense by sensing microbial DNA via TLR9. pDCs also play a critical role in the pathogenesis of IFN-driven autoimmune diseases. Yet, this autoimmune reaction is caused by the recognition of self-DNA and has been linked to TLR9-independent pathways. Increasing evidence suggests that the cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) is a critical component in the detection of pathogens and contributes to autoimmune diseases. It has been shown that binding of DNA to cGAS results in the synthesis of cGAMP and the subsequent activation of the stimulator of interferon genes (STING) adaptor to induce IFNs. Our results show that the cGAS-STING pathway is expressed and activated in human pDCs by cytosolic DNA leading to a robust type I IFN response. Direct activation of STING by cyclic dinucleotides including cGAMP also activated pDCs and knockdown of STING abolished this IFN response. These results suggest that pDCs sense cytosolic DNA and cyclic dinucleotides via the cGAS-STING pathway and that targeting this pathway could be of therapeutic interest.

Dendritic cell interactions with Histoplasma and Paracoccidioides.

Fungi are among the most common microbes encountered by humans. More than 100, 000 fungal species have been described in the environment to date, however only a few species cause disease in humans. Fungal infections are of particular importance to immunocompromised hosts in whom disease is often more severe, especially in those with impaired cell-mediated immunity such as individuals with HIV infection, hematologic malignancies, or those receiving TNF-α inhibitors. Nevertheless, environmental disturbances through natural processes or as a consequence of deforestation or construction can expose immunologically competent people to a large number of fungal spores resulting in asymptomatic acquisition to life-threatening disease. In recent decades, the significance of the innate immune system and more importantly the role of dendritic cells (DC) have been found to play a fundamental role in the resolution of fungal infections, such as in dimorphic fungi like Histoplasma and Paracoccidioides. In this review article the general role of DCs will be illustrated as the bridge between the innate and adaptive immune systems, as well as their specific interactions with these 2 dimorphic fungi.

Expression of CD11c+HLA-DR+dendritic cells and related cytokines in the follicular fluid might be related to pathogenesis of ovarian hyperstimulation syndrome.

OBJECTIVE: To explore the expressions of CD11c+HLA-DR+dentritic cells in the follicular fluid of patients with OHSS and their significances. SUBJECTS: 100 individuals. TREATMENT: embryos were observed. The distribution of dentritic cells in follicular fluid and the levels of IL-10, IL-12, IL-18 and IL-23 in follicular fluid were detected. METHODS: There were ovarian hyperstimulation syndrome (OHSS) group and control group in this study. The OHSS group consisted of 50 patients with OHSS and the control group consisted of 50 patients who underwent in vitro fertilization-embryo transfer (IVF-ET) only due to male factors. The statuses of embryos were compared between the two groups. The distribution of dentritic cells in follicular fluid was determined with flow cytometry, and the levels of IL-10, IL-12, IL-18 and IL-23 in follicular fluid were detected with enzyme-linked immunosorbent assay (ELISA) in all patients. RESULTS: The two-pronuclear (2PN) fertility rate, high-quality embryo rate and available embryo rate were all significantly lower in OHSS group than in control group (all P<0.05). The number of CD11c+HLA-DR+dentritic cells (P<0.05) and the levels of IL-10, IL-12, IL-18 and IL-23 were all significantly higher in OHSS group than in control group (all P<0.01). CONCLUSION: The follicular fluid of the patients with OHSS is in an inflammatory status, the inflammatory status may be involved in OHSS and the microenvironment of follicular fluid may affects oocyte quality and embryo development.

Mesenchymal stem cell-induced CD8α+Jagged2high CD11bhigh regulatory dendritic cells prevent and treat mouse aGVHD / 中国病理生理杂志

AIM:To investigate the role of mesenchymal stem cell-induced regulatory dendritic cells ( MSC-DCregs) in mouse acute graft-versus-host disease( aGVHD) model.METHODS: Bone marrow cells from BALB/c ( H-2 d ) mice were isolated and were induced to differentiate into DCs.The DCs were selected by flow cytometry, and after 10 d co-culture with MSCs, they were induced to be MSC-DCregs.Male 8-week-old C57BL/6 (H-2b) mice were used as do-nor mice.The female 8-week-old BALB/c (H-2d) mice, who had received 100 cm source-skin distance, 30 cm ×30 cm radiation field, 700 cGy total body irradiation (TBI) pretreatment were used as recipient mice.The recipients were divided into 5 groups:control group, TBI group ( injected with medium only) , bone marrow transplantation group ( injected with 1 ×107 bone marrow cells), aGVHD group (injected with 1 ×107 bone marrow cells and 1 ×107 spleen cells), and MSC-DCregs group (injected with 1 ×107 bone marrow cells, 1 ×107 spleen cells and 1 ×106 MSC-DCregs).The white blood cell count, recipients’ chimerism, clinical evaluation of aGVHD, survival analysis and pathological changes were deter-mined.RESULTS:Hematopoieic recovery was seen at 10 d after transplantation.The recipients’ chimerism was parallel to the donors’ at 30 d.The median survival time of the mice in aGVHD group and MSC-DCregs group was 27 d and 33 d, and the survival rates at 30 d were 20% and 100% (P<0.01), respectively.The clinical scores of the mice in MSC-DCregs group were lower than those in aGVHD group ( P<0.01) .Moreover, the pathological changes in the skin and liver of the mice in MSC-DCregs group were less serious than those in aGVHD group.CONCLUSION: The MSC-DCregs in-duce an aGVHD tolerance in vivo, and further research of its mechanism is still in great necessary.

Simultaneous changes in serum HMGB1 and IFN-α levels and in LAIR-1 expression on plasmatoid dendritic cells of patients with juvenile SLE. New therapeutic options?

We investigated the simultaneous changes in serum levels of HMGB1 and IFN-α as well as in LAIR-1 expression on plasmatoid dendritic cells (pDCs) of juvenile systemic lupus erythematosus (jSLE) patients in order to explore their involvement in the disease pathogenesis and their correlation with disease activity and other characteristics. In total, 62 blood samples were studied from 26 jSLE patients (18 girls), aged 8-16 years. Twenty healthy subjects (16 girls) of comparable age were included as healthy controls (HCs). Concentrations of serum HMGB1 and IFN-α were assessed by ELISA and LAIR-1 expression on pDCs by five-color flow cytometry. The disease activity index was assessed by SLEDAI and ECLAM scores. It was found that mean serum levels both of HMGB1 and IFN-α were significantly increased in jSLE patients compared to HCs and in jSLE patients with active disease with or without active nephritis compared to those with inactive disease. Mean serum levels of HMGB1 were positively correlated with levels of IFN-α and both were positively correlated with the SLEDAI and ECLAM scores. The expression of LAIR -1 on pDCs of jSLE patients was significantly lower than that of HCs. In conclusion, our findings indicate that serum HMGB1 not only represents a potential marker of disease activity but together with the lack of LAIR-1 inhibitory function may contribute to the sustained inflammatory action of IFN-α in jSLE. In this regard, blocking the action of HMGB1 and its receptors or enhancing the expression/inhibitory function of LAIR-1 on pDCs should be included in future immune interventions for controlling jSLE.

Potential role of plasmacytoid dendritic cells for FOXP3+ regulatory T cell development in human colorectal cancer and tumor draining lymph node.

FOXP3(+) regulatory T cells (Tregs) play an important role in the maintenance of tumor immunity tolerance. Compared with conventional myeloid dentritic cells (mDCs), plasmacytoid dendritic cells (pDCs) exhibit poor immunostimulatory ability, and their interaction with T cells often promotes the development of Tregs. The aim of this study was to determine FOXP3(+) Tregs and CD123(+)pDCs infiltration in colorectal cancer and tumor draining lymph node (TDLN), and to evaluate the clinical significance and relationship between pDCs infiltration and Tregs development in the CRC tolerogenic milieu. An immunohistochemical assay was conducted to assess FOXP3(+)Tregs and CD123(+)pDCs infiltration in tumor tissue and in metastatic-free TDLN (mfTDLN) and metastatic TDLN (mTDLN). The results showed that FOXP3(+) Tregs infiltration was more frequent in tumor tissue than in adjacent normal mucosa (P<0.001). FOXP3(+)Tregs infiltration was associated with advanced TNM stage and lymph node metastasis (P<0.01 and P<0.01 for TNM stage and lymph node metastasis, respectively). Different from FOXP3(+)Tregs, CD123(+)pDCs frequencies were lower in most CRC tumor tissues, whereas the positive rate of CD123 expression in CRC was significantly higher than in adjacent normal mucosa tissue (P<0.01). Compared to mfTDLN, mTDLN was significantly enriched in FOXP3(+) Tregs (P<0.01) and increased in pDC/mDC ratio (P<0.01). The statistical analysis demonstrated a significant correlation in both Tregs and pDC/mDC ratio in mTDLN. These results suggest that there are more FOXP3(+) Tregs with a stronger prognostic significance which might promote tumor tolerance, and that CD123(+)pDCs might contribute to Tregs development in the CRC tolerogenic milieu.

The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity.

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

The biological effect of exogenetic GM-CSF to dentritic cells in spesis / 中华急诊医学杂志

Objective To investigate the biological effect of GM-CSF on splenic dentritic cells (DCs)when used to treat severe sepsis and the influence on the prognosis.Methods All 160 male Kunming mice were randomly(random number)divided into four groups:control group(n =50),the mice didnt receive special treatment; CLP group(n =42),the mice underwent cecal ligation and puncture;conventional treatment group(n =34),the mice received intraperitoneal injection of 5 mg/kg ceftriaxone at 12,24,36,48,60,72 and 84 h after surgery; GM-CSF treatment group(n =34),the mice received hypodermic injection of 20 μg/kg GM-CSF besides ceftriaxone at 12,36,60,and 84 h after surgery.The mice were sacrificed at 0,12,24,48 and 72 h after CLP by cervical dislocation.The amount of splenic DCs and apoptosis rate were measured by flow cytometry,and the serum concentrations of IL-12 were detected by ELISA in each group.Meanwhile the survival prognosis was observed at 96 h.Results At every time point,the apoptosis of splenic DCs increased and the amount markedly reduced in severe sepsis(P ＜0.05),the serum concentration of IL-12 increased on an one-way curve type(P ＜0.05).The treatment of cephalosporin exacerbated the loss of DCs(P ＜ 0.05),while hadnt any effect on IL-12(P ＞ 0.05).GMCSF treatment increased the amount of DCs(P ＜ 0.05),and decreased IL-12 concentrations(P ＜ 0.05).The OR of GM-CSF was 0.079 computed by Logist regression analysis.Conclusions GM-CSF treatment severe sepsis can increase the amount of splenic DCs,decrease serum levels of IL-12,and improve prognosis.

Immunization route dictates cross-priming efficiency and impacts the optimal timing of adjuvant delivery.

Delivery of cell-associated antigen represents an important strategy for vaccination. While many experimental models have been developed in order to define the critical parameters for efficient cross-priming, few have utilized quantitative methods that permit the study of the endogenous repertoire. Comparing different strategies of immunization, we report that local delivery of cell-associated antigen results in delayed T cell cross-priming due to the increased time required for antigen capture and presentation. In comparison, delivery of disseminated antigen resulted in rapid T cell priming. Surprisingly, local injection of cell-associated antigen, while slower, resulted in the differentiation of a more robust, polyfunctional, effector response. We also evaluated the combination of cell-associated antigen with poly I:C delivery and observed an immunization route-specific effect regarding the optimal timing of innate immune stimulation. These studies highlight the importance of considering the timing and persistence of antigen presentation, and suggest that intradermal injection with delayed adjuvant delivery is the optimal strategy for achieving CD8⁺ T cell cross-priming.