The Innate Immune System Favors Emergency Monopoiesis at the Expense of DC Differentiation to Control Bacterial Infections

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2722-2722
Author(s):  
Kristin Bieber ◽  
Karina A. Pasquevich ◽  
Manina Günter ◽  
Matthias Grauer ◽  
Oliver Pötz ◽  
...  
Keyword(s):  
Immune System ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Conflicts Of Interest ◽  
Bacterial Load ◽  
Innate Immune ◽  
General Response ◽  
The Impact ◽  
Myeloid Progenitors

Abstract Dendritic cells (DCs) are critical in host defense against infection, bridging the innate and adaptive immune system. Patients with sepsis display reduced circulating and splenic DCs and impaired DC function that may contribute to prolonged immune suppression and exacerbation of infection. However, the mechanisms of pathogen-induced DC depletion remain poorly understood. Here, a mouse model of systemic bacterial infection was employed to analyze the impact of different bacterial pathogens on DC development in vivo. We found that the numbers of bone marrow (BM) hematopoietic progenitors committed to the DC lineages were reduced following systemic infection with different Gram-positive and Gram-negative bacteria. In parallel, a TLR4-dependent increase of committed monocyte progenitors in the BM as well as mature monocytes in the spleen was observed. In line, adoptively transferred FLT3+ myeloid progenitors (MPs) developed preferentially to monocytes at the expense of DCs in infected animals. Analyses performed on mixed BM chimeras suggested that both the reduction of DC progenitors and the induction of monopoiesis following infection were dependent on extrinsic TLR4 signaling driving the secretion of IFN-g regulated chemokines. Consistently, these effects were completely abrogated by suppression of IFN-g signaling. Elevated monocyte numbers in the spleen triggered by infection were due to a CCR2-dependent egress from the BM. In CCR2-deficient mice, in which monocytosis reportedly is abrogated, we observed a significantly increased bacterial load in the spleen and a reduced survival rate, highlighting the importance of monocytes for bacterial clearance. Together, our data provide evidence for a general response of myeloid progenitors upon bacterial infection to enhance monocyte production, thereby increasing the availability of innate immune cells as a first line of defense against invading pathogens. Concomitantly the development of DCs is impaired, which may be responsible for transient immunosuppression in e.g. bacterial sepsis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Real-Time In Vivo Detection and Monitoring of Bacterial Infection Based on NIR-II Imaging

2021 ◽  
Vol 9 ◽  
Author(s):  
Sijia Feng ◽  
Huizhu Li ◽  
Chang Liu ◽  
Mo Chen ◽  
Huaixuan Sheng ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Real Time ◽  
Bacterial Infections ◽  
Near Infrared ◽  
Imaging System ◽  
Bacterial Load ◽  
Dynamic Imaging ◽  
In Vivo Detection

Treatment according to the dynamic changes of bacterial load in vivo is critical for preventing progression of bacterial infections. Here, we present a lead sulfide quantum dots (PbS QDs) based second near-infrared (NIR-II) fluorescence imaging strategy for bacteria detection and real-time in vivo monitoring. Four strains of bacteria were labeled with synthesized PbS QDs which showed high bacteria labeling efficiency in vitro. Then bacteria at different concentrations were injected subcutaneously on the back of male nude mice for in vivo imaging. A series of NIR-II images taken at a predetermined time manner demonstrated changing patterns of photoluminescence (PL) intensity of infected sites, dynamically imaging a changing bacterial load in real-time. A detection limit around 102–104 CFU/ml was also achieved in vivo. Furthermore, analysis of pathology of infected sites were performed, which showed high biocompatibility of PbS QDs. Therefore, under the guidance of our developed NIR-II imaging system, real-time detection and spatiotemporal monitoring of bacterial infection in vivo can be achieved, thus facilitating anti-infection treatment under the guidance of the dynamic imaging of bacterial load in future.

scholarly journals Phage Therapy of Pneumonia Is Not Associated with an Overstimulation of the Inflammatory Response Compared to Antibiotic Treatment in Mice

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Nicolas Dufour ◽  
Raphaëlle Delattre ◽  
Anne Chevallereau ◽  
Jean-Damien Ricard ◽  
Laurent Debarbieux
Keyword(s):  
Inflammatory Response ◽  
Antibiotic Treatment ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Bacterial Load ◽  
The United States ◽  
Experimental Models ◽  
Interleukin 12 ◽  
The Impact

ABSTRACT Supported by years of clinical use in some countries and more recently by literature on experimental models, as well as its compassionate use in Europe and in the United States, bacteriophage (phage) therapy is providing a solution for difficult-to-treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce. Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) was treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (ceftriaxone, cefoxitin, or imipenem-cilastatin; intraperitoneal). Healthy mice also received phages alone. The severity of pulmonary edema, acute inflammatory cytokine concentration (blood and lung homogenates), complete blood counts, and bacterial and bacteriophage counts were determined at early (≤12 h) and late (≥20 h) time points. The efficacy of bacteriophage to decrease bacterial load was faster than with antibiotics, but the two displayed similar endpoints. Bacteriophage treatment was not associated with overinflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities than did antibiotics. In the absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of antiviral cytokines (gamma interferon [IFN-γ] and interleukin-12 [IL-12]) and chemokines in the lungs but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals. The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to that with antibiotic treatment.

scholarly journals AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathaniel B. Bone ◽  
Eugene J. Becker ◽  
Maroof Husain ◽  
Shaoning Jiang ◽  
Anna A. Zmijewska ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Abdominal Sepsis ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Lung Infections ◽  
Sepsis Survivors ◽  
The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

scholarly journals Differential Effects of HIV Protease Inhibitors on Release and Activation of Platelet-Derived TGF-β1: Potential Association with HIV-Linked CVD

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2341-2341
Author(s):  
Kouzbari Karim ◽  
Gostynska Sandra ◽  
Sonia Elhadad ◽  
Dube Pratibha ◽  
Jeffrey Laurence ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Low Dose ◽  
Cardiac Fibrosis ◽  
Conflicts Of Interest ◽  
Platelet Rich Plasma ◽  
Minor Effect ◽  
The Impact ◽  
Tgf Β1 ◽  
In Vivo Assessment

Combination antiretroviral therapies (cART) have markedly reduced mortality in HIV infection. However, cardiovascular disease (CVD), including heart failure linked to fibrosis, remains a major cause of morbidity and mortality in HIV/cART patients. The magnitude of this risk increases with use of certain protease inhibitors (PI), but the underlying mechanism remains unclear. We showed that the PI ritonavir leads to increased plasma levels of the pro-fibrotic cytokine TGF-β1, cardiac dysfunction, and pathologic cardiac fibrosis in wild-type (wt) C57BL/6 mice. Mice with targeted depletion of platelet TGF-β1 had reduced cardiac fibrosis and partially preserved cardiac function following ritonavir exposure (Laurence, et al. PLoS One 2017;12:e0187185). Several groups have examined the effects of a variety of cART agents on agonist-induced platelet aggregation, but correlations with clinical CVD are weak. Since platelets are a rich source of TGF-β1, we hypothesized that ritonavir and other PIs linked clinically to an increased CVD risk directly activate platelets to release TGF-β1 and activate latent (L)TGF-β1 to initiate signaling for organ fibrosis. We examined the impact of clinically relevant doses of ritonavir, alone and in combination with two other contemporary PIs, atazanavir and darunavir, which are currently used along with low dose ritonavir in so-called PI-boosted cART regimens. We incubated human platelet-rich plasma and washed platelets with PIs alone or in combinations at various doses for 10 min at 37°C in a platelet aggregometer (BioData. Corp). Total and active TGF-β1 levels were measured by ELISA. For in vivo assessment, we treated wt mice with a low dose of ritonavir, as used in PI-boosted cART, and measured the levels of plasma TGF-β1 by ELISA, and TGF-β1 signaling in tissues by immunofluorescence imaging for pSmad2. We found that ritonavir dose-dependently increased total TGF-β1 release from freshly-isolated platelet-rich plasma and washed human platelets. This release was blocked by ceefurin-1 and MK517, potent inhibitors of the ATP binding cassette transporter ABCC4. Darunavir alone did not cause release of TGF-β1, and did not alter significantly ritonavir-induced TGF-β1 release (Figure-1A). Atazanavir alone did induce release of TGF-β1 from platelets and did not affect the extent of such release induced by ritonavir (Figure-1A). Since total TGF-β1 released from platelets must be activated in order to signal, we tested whether these PIs could activate LTGF-β1. Ritonavir alone, in low dose, activated TGF-β1 by 4-5-fold (Fig-1B). Darunavir alone did not activate LTGF-β1, and had only a minor effect on ritonavir-induced TGF-β1 activation (Fig-1B). In marked contrast, while atazanavir also did not activate LTGF-β1, it significantly inhibited ritonavir-induced LTGF-β1 activation (Fig-1B). For in vivo assessment, wt mice were injected daily for 8 weeks with ritonavir, which dose-dependently increased plasma TGF-β1 levels (mean levels with vehicle 2.1 ng/ml; 6.4 ng/ml with 5 mg/kg ritonavir; 8.5 ng/ml with 10 mg/kg ritonavir). Increased TGF-β1 levels correlated with development of pathologic fibrosis and increased phosphorylated Smad signaling in hearts of ritonavir-treated vs. vehicle-treated mice. Clinical correlations with these in vitro and in vivo mouse studies are important. The fact that ritonavir effected both release and activation of platelet TGF-β1 is consistent with its ability to induce cardiac fibrosis and dysfunction in mice, and its association with accelerated CVD in HIV-infected individuals. Our findings that low dose ritonavir in combination with darunavir induced release and activation of platelet TGF-β1, whereas atazanavir blocked TGF-β1 activation, are consistent with the strong association of ritonavir-boosted darunavir, but not ritonavir-boosted atazanavir, with CVD in the setting of HIV (Ryom, et al. Lancet-HIV 2018;5:e291-e300). Future work will examine the effects of other contemporary cART agents, including cobicistat, which is currently replacing ritonavir in many PI-boosted therapies and some integrase-boosted regimens, on TGF-β1 release and activation, for which correlations with clinical CVD are not yet available. Identification of the mechanism of pathologic fibrosis in the heart, and potentially other organs affected by certain cART regimens, such as the kidney, may suggest specific therapeutic interventions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Platelet Count on Bleeding in the Setting of Anti-Platelet Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18
Author(s):  
Robert Hugh Lee ◽  
Wolfgang Bergmeier
Keyword(s):  
Real Time ◽  
Conflicts Of Interest ◽  
Thrombotic Event ◽  
Platelet Inhibition ◽  
Intravital Imaging ◽  
Severe Thrombocytopenia ◽  
Platelet Counts ◽  
Anti Platelet Therapy ◽  
The Impact

Anti-platelet therapy (APT) is used for secondary prevention of thrombosis. The most commonly prescribed anti-platelet drugs are aspirin and P2Y12 inhibitors, including clopidogrel, prasugrel and ticagrelor. Dual anti-platelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is often used in the first 1-12 months after an initial thrombotic event and has a greater anti-thrombotic effect than single agents, but is also associated with a higher risk of bleeding. Due to this risk of hemorrhage, the appropriate use of DAPT in patients requiring percutaneous coronary intervention (PCI) with baseline or periprocedural thrombocytopenia remains unclear. To study the impact of thrombocytopenia on bleeding with APT, we used intravital imaging in a murine hemostasis model and adoptive platelet transfer to generate mice with specific platelet counts with or without platelet inhibition. To generate experimental mice, we used transgenic mice in which platelets express a chimeric GPIb receptor with the extracellular domain replaced with a domain of the human IL-4R (hIL-4R/GPIb-Tg). Endogenous platelets were depleted by injection of anti-hIL-4R antibody, and the recipient mice were then transfused with wild-type (WT) platelets from donor mice treated, or not, with single or dual APT (aspirin 20 mg/kg; clopidogrel 25 mg/kg) to achieve specific platelet counts ranging from 50,000 to 400,000 platelets/μL. We also compared these mice with WT mice (with normal platelet counts, ~1,200,000 platelets/μL) treated with APT. Platelet inhibition was confirmed prior to performing in vivo experiments. Hemostasis was determined by intravital imaging in our saphenous vein laser injury model, in which a 50 μm injury was induced by laser ablation. Real-time top-down epifluorescence imaging was used to determine time to initial hemostasis, rebleeding events, and platelet and fibrin accumulation. In each mouse, 3-5 injuries were induced at different sites and each injury was visualized for 10 minutes. Following real-time imaging, spinning disk confocal Z-stacks of platelet plugs were obtained for 3D reconstruction to compare platelet plug volume. In untreated WT mice, hemostasis was achieved in ~20 seconds. In WT mice treated with DAPT, initial hemostasis was often rapidly achieved but this was followed by significant rebleeding events. Paradoxically, platelet accumulation was increased in WT + DAPT mice due to extravascular accumulation of platelets which occurred during bleeding. However, in plugs that stabilized, plug volume was reduced in WT + DAPT mice. In hIL-4R/GPIb-Tg mice with reduced platelet counts, untreated platelets were able to form a stable hemostatic plug even at 50,000/μL, although time to hemostasis was slightly prolonged. However, as platelet counts decreased in mice with DAPT-treated platelets, initial hemostasis became more prolonged and many injuries never achieved initial hemostasis. These results suggest that DAPT may not be safe in the setting of severe thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans

2018 ◽  
Vol 104 (4) ◽  
pp. 1187-1199 ◽  
Author(s):  
Ahmed Iqbal ◽  
Lynne R Prince ◽  
Peter Novodvorsky ◽  
Alan Bernjak ◽  
Mark R Thomas ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Immune System ◽  
Innate Immune System ◽  
Low Dose ◽  
Inflammatory Responses ◽  
Platelet Reactivity ◽  
Innate Immune ◽  
Endotoxin Challenge ◽  
Intermediate Monocytes

Abstract Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P < 0.01; vs sham-saline 26.20 ± 3.86/μL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P < 0.001; vs sham-saline 19.05 ± 3.81/μL, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P < 0.05; vs sham-saline 3.81± 1.42/μL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P < 0.01; vs sham-saline 3.08 ± 1.01/μL, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.

scholarly journals The innate immune system and neurogenesis as modulating mechanisms of electroconvulsive therapy in pre-clinical studies

2020 ◽  
Vol 34 (10) ◽  
pp. 1086-1097
Author(s):  
Juliette Giacobbe ◽  
Carmine M Pariante ◽  
Alessandra Borsini
Keyword(s):  
Cell Proliferation ◽  
Immune System ◽  
Electroconvulsive Therapy ◽  
Clinical Studies ◽  
Innate Immune System ◽  
Innate Immune ◽  
System Response ◽  
Treatment Resistant ◽  
The Impact ◽  
Over Time

Background: Electroconvulsive therapy (ECT) is a powerful and fast-acting anti-depressant strategy, often used in treatment-resistant patients. In turn, patients with treatment-resistant depression often present an increased inflammatory response. The impact of ECT on several pathophysiological mechanisms of depression has been investigated, with a focus which has largely been on cellular and synaptic plasticity. Although changes in the immune system are known to influence neurogenesis, these processes have principally been explored independently from each other in the context of ECT. Objective: The aim of this review was to compare the time-dependent consequences of acute and chronic ECT on concomitant innate immune system and neurogenesis-related outcomes measured in the central nervous system in pre-clinical studies. Results: During the few hours following acute electroconvulsive shock (ECS), the expression of the astrocytic reactivity marker glial fibrillary acidic protein (GFAP) and inflammatory genes, such as cyclooxygenase-2 (COX2), were significantly increased together with the neurogenic brain-derived neurotrophic factor (BDNF) and cell proliferation. Similarly, chronic ECS caused an initial upregulation of the same astrocytic marker, immune genes, and neurogenic factors. Interestingly, over time, inflammation appeared to be dampened, while glial activation and neurogenesis were maintained, after either acute or chronic ECS. Conclusion: Regardless of treatment duration ECS would seemingly trigger a rapid increase in inflammatory molecules, dampened over time, as well as a long-lasting activation of astrocytes and production of growth and neurotrophic factors, leading to cell proliferation. This suggests that both innate immune system response and neurogenesis might contribute to the efficacy of ECT.

Donor Inflammatory Gene Polymorphisms Are Associated with Early Bacterial Infection After Unrelated Allogeneic Haematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1159-1159
Author(s):  
Haowen Xiao ◽  
Xiaoyu Lai ◽  
Gongqiang Wu ◽  
Yi Luo ◽  
Jimin Shi ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Gene Polymorphisms ◽  
Bacterial Infections ◽  
Conflicts Of Interest ◽  
T Cell Response ◽  
Early Infection ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Platelet Recovery ◽  
Significant Difference

Abstract Abstract 1159 Poster Board I-181 Background In allogeneic SCT, genetic factors such as donor and recipient gene polymorphisms of pro- and anti-inflammatory cytokines have been associated with the incidence and severity of GVHD. However, the influence of such donor and recipient gene polymorphisms on other outcomes, such as early infection after SCT, has seldom been described. TNFαa, TNF receptorII (TNFRII), IL-10 and TGF gene contain multiple single nucleotide polymorphisms (SNPs) in the promoter and codon region. We thus studied the association of this panel of candidate gene polymorphisms with the incidence of the first episodes of early bacterial infections within 100 days after allo-HSCT. Methods A total of 138 unrelated donor/recipient pairs, who had undergone HLA-matched allo-HSCT from January 2001 to March 2009 at the First Affiliated Hospital of Zhejiang University School of Medicine, were tested for TNFαa(TNFαa-857 C>T, TNFαa-863 C>A, TNFαa-1031 T>C), TNFRII (codon196 T>G), IL-10 (IL10-1082 A>G, IL10-819 T>C, IL10-592 A>C), TGF (TGF-509 T>C, TGF+869 C>T) polymorphism allele frequencies and genotype. SNPs were analysed by Multiplex SnaPshot. We considered the first episodes of early bacterial infections within 100 days after allo-HSCT have developed when sepsis, pneumonia, or septic shock was diagnosed according to previously published criteria. Results (1) 133 patients achieved complete donor chimerism in the peripheral blood and 5 patients had graft failure. All patients achieved an absolute neutrophil count (ANC) greater than 0.5×109/L at day 13 (7∼22) and platelet recovery at day 15 (7∼64). The cumulative incidence of at least one bacterial infection was 47.8% (pneumonia and intestinal infection are the most popular) within 100 days after allo-HSCT. There is no significant difference in the time to neutrophil recovery in patients who experienced early bacterial infections with those who did not (13.6 vs 12.8,P=0.115). (2) The TNFαa-857 C/C genotype and TNFRII 196 T/T genotype of the donor were significantly associated with a higher risk of early bacterial infection ( for TNFαa-857 C/C genotype: 53.3% vs 29.0%, P=0.024 ; TNFRII 196 T/T genotype: 53.5% vs 33.3%, P=0.038); (3) The TGF-509 T/T genotype of the donor was significantly associated with a higher risk of early bacterial infection (62.5% vs 41.8, P=0.038); (4) Transplantation from donors with IL10-819 C/C genotype or IL10-592 C/C genotype were significantly associated with a higher risk of early bacterial infection (for IL10-819 C/C genotype: 71.4.1% vs 45.3%, P=0.034; IL10-592 C/C genotype: 70.0.1% vs 45.8%, P=0.055); (5) The genotypes of TNFαa-863, TNFαa-1031, IL10-1082 and TGF+869 were not found to be associated with the risk of early bacterial infection. Conclusions Recent studies have shown that the generation potential of IL-10 is influenced by the polymorphism of the IL-10 gene. The IL10-819*C allele and IL10-592 *C allele are associated with higher secretion of IL-10 than IL10-819*T allele and IL10-592*A allele. In our data, a higher risk of early bacterial infection with IL10-819 C/C and IL10-592 C/C genotype was postulated to be associated with a higher IL-10 production, which suppressed reactive T-cell response. These results, which is the first report of TNFαa, TNFRII, IL-10and TGF polymorphic features of Chinese population with the risk of early bacterial infection after HLA-matched unrelated allo-HSCT, suggest an interaction of the donor TNFαa-857C/C, TNFRII 196 T/T, IL10-819 C/C, IL10-592 C/C and TGF-509 T/T genotypes on risk of early infection. These results are helpful for predict allo-HSCT outcome, identify more suitable donors and clarify therapy on an individual patient basis. Disclosures No relevant conflicts of interest to declare.

Gvhd Severity Is Regulated by the Adoptive Transfer Low Numbers of NKT Cells by a Mechanism Distinct From CD4+CD25+ Regulatory T Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 229-229
Author(s):  
Dennis Leveson-Gower ◽  
Janelle Olson ◽  
Emanuela I Sega ◽  
Jeanette Baker ◽  
Robert Zeiser ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Adoptive Transfer ◽  
Conflicts Of Interest ◽  
Serum Levels ◽  
Nkt Cells ◽  
Donor Type ◽  
Ifn Γ ◽  
The Impact

Abstract Abstract 229 NKT cells, a subset of which are CD1d reactive, play an important immunoregulatory role in suppressing dysfunctional immune reactions, including graft-versus-host disease (GVHD). To explore the biological activity and mechanism of donor-type NKT in suppression of GVHD, we utilized highly purified (>95%) populations of donor (C57Bl6; H-2b) NKT (DX5+TCR+CD4+) cells adoptively transferred into lethally irradiated recipient (Balb/c; H-2d) animals with T cell depleted bone marrow (TCD-BM). Highly purified (>95%) NKT cells (5.5×105) from luciferase positive (luc+) C57BL/6 mice were infused into lethally irradiated Balb/c recipients with TCD-BM(5×106) from wild-type (WT) C57BL/6 mice, and the animals were monitored by bioluminescence imaging (BLI). By day 4 after transfer, an NKT derived signal was observed in spleen and lymph node (LN) sites, and between days 7 and 10, NKT had also migrated to the skin. Total photons emitted peaked near day 25 after transplantation, followed by a steady decline. To assess the impact of donor-type NKT cells on GVHD induction by conventional CD4+ and CD8+ T cells (Tcon), we co-transferred various doses of highly purified WT NKT at day 0 with TCD-BM, followed by 5×105 luc+Tcon/animal on day 2. As few as 2.5×104 NKT cells significantly improved survival of mice receiving 5×105 Tcon. Animal survival with Tcon only was 20% and for Tcon with NKT cells was 74%(p=0.0023). In contrast to what is observed with CD4+CD25+FoxP3+ regulatory T cells (Treg), the NKT cells did not suppress Tcon proliferation assayed by both in vivo BLI and in a mixed-leukocyte reaction. Analysis of serum cytokines with or without 2.5×104 NKT, following HCT with TCD-BM and Tcon, indicated the addition of NKT cells resulted in elevated levels of INF-γ, IL-5, and IL-6 in serum; significant differences were not observed in serum levels of IL-2, IL-4, IL-10, IL-17, or TNF-α. Intracellular levels of cytokines in Tcon were analyzed from the same groups. At 8 days after HCT, mice receiving NKT had fewer TNFα-positive cells in LNs (CD4: 45% to 27%; CD8 36% to 24%); by day 11, however, TNFαa levels between groups were equivalent. IFN-γ levels, which were high in both NKT treated and untreated groups at day 8 (85%-95%), decreased significantly in NKT treated mice by day 11 (CD4: 40%; CD8: 43%), but were abundant in Tcon only mice (CD4: 78%; CD8: 80%) (p=.0001). No significant changes were found in the intracellular levels of IL-2, IL-4, IL-5, IL-10, or IL-17 of Tcon in the presence or absence of NKT cells. NKT from both IL-4 -/- and IFN-γ -/- mice were less effective at suppressing GVHD than WT NKT, implicating these cytokines in the suppressive mechanism. Finally, we found that NKT do not have a major impact on the graft-versus-tumor effect of Tcon against a luc+ BCL-1 tumor. These studies indicate that NKT persist in vivo upon adoptive transfer and suppress GVHD, even at extremely low cell numbers, which is important given the relative paucity of this cell population. The mechanisms of GVHD suppression appear to be distinct to those of Treg and involve the production of IL-4 and IFN-γ by NKT resulting in a decrease in Tcon, which produce pro-inflamatory cytokines. Disclosures: No relevant conflicts of interest to declare.

Effect of plinabulin, a novel late-clinical stage immunotherapeutic agent on the adaptive and innate immune system.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 8-8
Author(s):  
Ramon W. Mohanlal ◽  
Lan Huang
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Clinical Stage ◽  
Onset Time ◽  
Immune Defense ◽  
Innate Immune ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Post Dose ◽  
The Impact

8 Background: Plinabulin (Plin) is a small molecule Dendritic Cell modulator, which in the presence of antigen, increases T-cell proliferation in an antigen-dependent manner marrow. The addition of Plin to Docetaxel (Doc) improved mOS with 4.6 months vs Docetaxel monotherapy, and prolonged DoR with more than 1 year (p < 0.05), which is indicative of an immune-mediated mechanism of action (Mohanlal, ASCO-SITC 2017). Neutrophils are our first line of innate immune defense against foreign invaders. We previously reported that Plinabulin prevents chemotherapy (Chemo) Induced Neutropenia (CIN) in patients receiving Doc or TAC throughout the cycle (Doc, Doxorubicin, Cyclophosphamide) (Blayney ASH 2018, St Gallen 2019). Here we analyzed the onset time of neutrophil increase following Plin administration. In addition, we analyzed the impact of Plin on plasma haptoglobin, which is an acute phase protein with anti-inflammatory effects together with immune-enhancing effects and is an integral part of innate immunity (Kristiansen Nature 2001). Methods: Absolute neutrophil count (ANC) and haptoglobin data were analyzed from Phase 2 study BPI-2358-106 (NCT03294577) with 10 (n = 15), 20 (n = 15) and 30 mg/m2 (n = 12) Plin in Breast Cancer patients receiving TAC. Plin was administered on Day 1. ANC and Haptoglobin were analyzed by a Central Laboratory (Covance), from blood draws at predose, and post-dose Plin at Day 2,3,6,7,8,9,10,11,12,13 and 15, and changes relative to predose value were evaluated. Results: Plin dose-dependently increased ANC within 1 day (P < 0.001) and Haptoglobin within 3 days (P < 0.03) of dosing. Mean haptoglobin (P < 0.0005) and ANC (P < 0.001) levels increased with ~two-fold vs baseline levels. ANC levels remained increased for approximately 1 week and haptoglobin levels for > 3 weeks. Conclusions: Based on Plinabulin’s ability to stimulate the innate system, together with its previously reported evidence as a potent activator of the adaptive immune system (Mohanlal, ASCO-SITC 2017), it is concluded that Plinabulin is a potent stimulator of the adaptive and innate immune system. Clinical trial information: NCT03294577.

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