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1.
Neuroimmunomodulation ; 30(1): 268-276, 2023.
Article in English | MEDLINE | ID: mdl-37797587

ABSTRACT

INTRODUCTION: Experimental endotoxemia is a translational model of systemic inflammation that has contributed significantly to our current understanding of sickness behavior and inflammation-associated depression. Previous studies using this model revealed a strong association between cytokine levels, endocrine changes, and psychological sickness symptoms during the acute phase of inflammation. The objective of this randomized, double-blind, placebo-controlled crossover study was to gain insight into potential post-acute physiological and psychological consequences of endotoxin administration that may either persist or newly emerge between 24 and 72 h after injection. The main focus was on associations between serum levels of C-reactive protein (CRP) and affective symptoms as well as alterations in diurnal cortisol profile, the two key features of inflammation-associated depression. METHODS: Healthy male volunteers (N = 18) received an injection of either endotoxin (0.8 ng/kg) or placebo on two separate but otherwise identical study days, 7 days apart. Blood and saliva samples were collected during acute and post-acute phases after injection to measure blood inflammatory markers (interleukin [IL]-6, IL-1 receptor antagonist [ra], CRP) and salivary cortisol levels. In addition, participants completed a comprehensive battery of questionnaires to assess physical and psychological sickness symptoms. RESULTS: Endotoxin treatment induced a short-time rise in plasma IL-6 and a longer increase in IL-1ra. The increase in serum CRP was delayed compared to cytokines, peaking at 24 h and gradually decreasing until 72 h after injection. The inflammatory response was accompanied by bodily and psychological sickness symptoms which occurred only in the acute phase, whereas none of the symptoms persisted or recurred in the post-acute phase. Salivary cortisol levels were significantly increased during the acute phase and exhibited pronounced circadian changes. However, no significant differences in diurnal cortisol profiles were observed between placebo and endotoxin conditions on the days after treatment. CONCLUSION: Our findings suggest that CRP, which is elevated in patients with inflammation-associated depression, does not appear to be responsible for depressive symptomatology. Moreover, a single inflammatory episode is not sufficient to alter diurnal cortisol profiles, as observed in inflammation-associated depression. In addition, the absence of persistent lipopolysaccharide-induced psychological and physiological changes beyond the acute phase further supports the safety of endotoxin administration in humans.


Subject(s)
Endotoxins , Hydrocortisone , Inflammation , Humans , Male , C-Reactive Protein , Cross-Over Studies , Cytokines , Endotoxins/toxicity , Inflammation/chemically induced , Inflammation/immunology , Inflammation/psychology , Interleukin-6 , Double-Blind Method
3.
Clin Immunol ; 226: 108698, 2021 05.
Article in English | MEDLINE | ID: mdl-33639275

ABSTRACT

T follicular helper (TFH) cells are a heterogeneous subset of immunocompetent T helper (TH) cells capable of augmenting B cell responses in lymphoid tissues. In transplantation, exposure to allogeneic tissue activates TFH cells increasing the risk of the emergence of de novo donor-specific HLA-antibodies (dnDSA). These can cause antibody-mediated rejection (AMR) and allograft loss. Follicular regulatory T (TFR) cells counteract TFH cell activity. Here, we investigated the implications of TFH and TFR cells on dnDSA formation after renal transplantation (RTX). Considering TFH cells to be CXCR5+ and IL-21+, we found by flow cytometry that patients with dnDSA produced IL-21 more abundantly compared to healthy volunteers. In in vitro alloreactivity assays, patients with dnDSA featured an enhanced alloreactive TH cell pool in response to donor-specific HLA antigens. Besides, longitudinal investigations suggested enhanced alloreactivity shortly after transplantation increasing the risk of dnDSA development. Taken together, in spite of continuous immunosuppression we report a strong IL-21 response in TFH cells and an expanded reservoir of donor-specific memory TH cells in patients with dnDSA. This warrants further investigations if aberrant TFH cell activation may precede the formation of dnDSA promoting AMR.


Subject(s)
Antibodies/immunology , Graft Rejection/immunology , Graft Survival/immunology , HLA Antigens/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adult , Female , Humans , Immune Tolerance/immunology , Interleukins/immunology , Kidney Transplantation , Longitudinal Studies , Male , Middle Aged , Receptors, CXCR5/immunology
4.
Article in English | MEDLINE | ID: mdl-32867664

ABSTRACT

BACKGROUND: Calcineurin-inhibitors (CNI) are used in renal transplant patients (RTX) to prevent rejection. CNI mainly suppress T-cell mediated immunity but very little is known about the impact of long-term treatment with CNI on T-cell function. OBJECTIVE: We investigated the immunological effects of long-term CNI intake in RTX patients in comparison to short-term CNI administration in healthy controls (HC). METHODS: Blood was drawn from 30 RTX patients with long-term CNI treatment. In addition, blood was sampled from HC with short-term CNI treatment (four dosages) before the first and 2 hours after the last CsA intake. T-cells were analyzed for cytokine production, proliferation, and CD25 expression. RESULTS: Short-term CNI reduced T-cell derived IL-2 and IFNγ as well as T-cell proliferation in HC. IFNγ was not suppressed in patients with long-term CNI treatment. IL-2 production, CD25 expression, and T-cell proliferation were enhanced in long-term CNI patients. CONCLUSION: Suppression of IFNγ/IL-2 and T-cell proliferation is weaker during long-term CNI treatment in patients compared to short-term treatment in healthy subjects. Enhanced CD25 expression may lower the threshold for T-cell activation during long-term CNI treatment.


Subject(s)
Calcineurin Inhibitors/administration & dosage , Graft Rejection/prevention & control , Immunosuppressive Agents/administration & dosage , Kidney Transplantation/trends , T-Lymphocytes/drug effects , Adult , Aged , Cell Proliferation/drug effects , Cell Proliferation/physiology , Drug Administration Schedule , Female , Flow Cytometry/methods , Graft Rejection/immunology , Graft Rejection/metabolism , Humans , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Male , Middle Aged , T-Lymphocytes/physiology
5.
Brain Behav Immun ; 88: 283-293, 2020 08.
Article in English | MEDLINE | ID: mdl-32485294

ABSTRACT

Obesity is associated with an increase prevalence of neuropsychiatric symptoms and diseases, such as depression. Based on the facts that pro-inflammatory cytokines are able to modulate behavior, and that obesity is characterized by a chronic low-grade inflammatory state, inflammation has been hypothesized to contribute to the neuropsychiatric comorbidity in obese individuals. However, a causal link between inflammation and the development of neuropsychiatric symptoms is hard to establish in humans. Here, we used an inflammatory stimulus, i.e. the intravenous injection of lipopolysaccharide (LPS), in a double-blind placebo-controlled design, to determine the vulnerability of obese individuals to inflammation-induced behavioral changes. The hypothesis was that obese individuals would show heightened behavioral response compared to normal-weight subjects for the same inflammatory stimulus, reflecting an increased sensitivity to the behavioral effects of pro-inflammatory cytokines. LPS (dose 0.8 ng/kg body weight, adjusted for estimated blood volume in obese subjects) and placebo (saline) were intravenously injected in 14 obese healthy subjects and 23 normal-weight healthy subjects in a within-subject, randomized, crossover design. LPS administration induced, in both groups, an acute increase in blood concentrations of cytokines (interleukin-6, tumor necrosis factor-α, and IL-10), as well as in body temperature, cortisol, norepinephrine, sickness symptoms, fatigue, negative mood, and state anxiety. There were little differences in the immune and behavioral responses to LPS between obese and normal-weight subjects, but the cortisol response to LPS was strongly attenuated in obese individuals. Higher percentage of body fat was related to a lower cortisol response to LPS. Taken together, the population of young and healthy obese individuals in this study did not exhibit an increased behavioral sensitivity to cytokines, but an attenuated cortisol response to the immune challenge. Future studies will need to determine whether additional physiological and psychological factors interact with the state of obesity to increase the risk for inflammation-induced neuropsychiatric symptoms.


Subject(s)
Anxiety , Lipopolysaccharides , Cytokines , Humans , Inflammation , Obesity/complications
6.
Brain Behav Immun ; 88: 294-301, 2020 08.
Article in English | MEDLINE | ID: mdl-32531428

ABSTRACT

Impaired extinction of pain-related fear memories can lead to persistent or resurging fear of pain, contributing to the development and maintenance of chronic pain conditions. The mechanisms underlying maladaptive pain-related learning and memory processes remain incompletely understood, particularly in the context of interoceptive, visceral pain. Inflammation is known to interfere with learning and memory, but its effects on the extinction of pain-related fear memories have never been tested. In a randomized, double-blind, placebo-controlled study, we assessed the impact of experimental acute inflammation on the extinction and reinstatement of conditioned visceral pain-related fear. Forty healthy male volunteers underwent differential fear conditioning with visceral pain as clinically relevant unconditioned stimulus (US). Participants then received an intravenous injection of either 0.8 ng/kg lipopolysaccharide (LPS) as inflammatory stimulus or physiological saline as placebo, and extinction training was conducted at the peak of the inflammatory response. Extinction recall and reinstatement test were performed after overnight consolidation. Results showed that visceral pain represents an effective US, eliciting pronounced conditioned pain-related fear responses. Repeated unreinforced presentation of the pain-predictive cue during extinction training resulted in full extinction of the conditioned behavioral response. However, unexpected re-exposure to the US during reinstatement test resulted in return of fear. Despite pronounced LPS-induced effects on inflammatory markers, cortisol, and negative affect, we did not find evidence that acute inflammation resulted in altered fear extinction. The findings support the notion that visceral pain-related fear learning establishes a robust aversive memory trace that remains preserved during inhibitory learning, leaving a latent vulnerability for the return of fear. Inflammation during inhibitory learning did neither weaken nor further amplify this aversive memory trace, suggesting that it is rather resistant to acute inflammation-induced effects, at least in healthy individuals with no additional vulnerability factors.


Subject(s)
Extinction, Psychological , Gastrointestinal Microbiome , Fear , Humans , Inflammation , Magnetic Resonance Imaging , Male
7.
Brain Behav Immun Health ; 8: 100130, 2020 Oct.
Article in English | MEDLINE | ID: mdl-34589881

ABSTRACT

Data from clinical and cross-sectional studies suggest that inflammation contributes to psychomotor slowing and attentional deficits found in depressive disorder. However, experimental evidence is still lacking. The aim of this study was to clarify the effect of inflammation on psychomotor slowing using an experimental and acute model of inflammation, in which twenty-two healthy volunteers received an intravenous injection of lipopolysaccharide (LPS, dose: 0.8 â€‹ng/kg body weight) and of placebo, in a randomized order following a double-blind within-subject crossover design. A reaction time test and a go/no-go test were conducted 3 â€‹h after the LPS/placebo injection and interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations were assessed. No effect of experimental inflammation on reaction times or errors for either test was found. However, inflammation was related to worse self-rated performance and lower effort put in the tasks. Exploratory analyses indicated that reaction time fluctuated more over time during acute inflammation. These data indicate that acute inflammation has only modest effects on psychomotor speed and attention in healthy subjects objectively, but alters the subjective evaluation of test performance. Increased variability in reaction time might be the first objective sign of altered psychomotor ability and would merit further investigation.

8.
Biosci Rep ; 39(5)2019 05 31.
Article in English | MEDLINE | ID: mdl-30962268

ABSTRACT

Recently, B cells with regulatory functions suppressing T-cell immunity were identified. Inflammation in the context of sepsis is characterized by a profound immune dysfunction increasing the patient's risk for additional infections. The impact of endotoxemia on B-cell dynamics, regulatory B cells (Breg) and its contribution to immune dysfunction is unknown. It is the aim of the present study to characterize the dynamics of the B-cell compartment and Breg in an experimental human endotoxemia model.In this randomized placebo-controlled cross-over study, 20 healthy males received an intravenous injection of endotoxin (Escherichia coli lipopolysaccharide, LPS, 0.8 ng/kg body weight) or placebo (saline 0.9%) on two otherwise identical study days. B cells were analyzed by flow cytometry at baseline and repeatedly up to 72 h after endotoxin/placebo injection.Absolute CD19+ B cells counts showed a significant decrease 3 h after endotoxin injection. Memory B cells were partially depleted from the circulation; the total number of Breg was significantly diminished 3 h after LPS challenge. Production of anti-inflammatory interleukin (IL)-10 (IL-10) by Breg was unaltered after LPS challenge. Systemic B-cell activating factor (BAFF) levels were significantly increased with a maximum after 24 h and remained increased up to 72 h post-injection.Endotoxemia causes a transient depletion of memory B cells and Breg from the circulation. However, the functional capacity of B cells to produce IL-10 is not impaired.


Subject(s)
B-Lymphocytes/immunology , Endotoxemia/immunology , Adolescent , Adult , Cross-Over Studies , Cytokines/immunology , Endotoxins/immunology , Humans , Inflammation/immunology , Interleukin-10/immunology , Lipopolysaccharides/immunology , Male , Sepsis/immunology , Single-Blind Method , Young Adult
9.
J Clin Virol ; 113: 14-19, 2019 04.
Article in English | MEDLINE | ID: mdl-30771597

ABSTRACT

BACKGROUND: After reactivation the BK-polyomavirus (BKPyV) associated nephropathy (PyVAN) is observed in 1-10% of renal transplant recipients, of which up to 80% undergo graft failure. BKPyV reactivation after renal transplantation was associated with donor-derived serotypes against which the recipient has no immunological protection. However, PyVAN risk assessment seroactivity testing is a time-consuming and cost intensive process. OBJECTIVES: Since BKPyV serotypes can be attributed to distinct genotypes I to IV, in the present study we retrospectively analyzed whether a simple PCR-based BKPyV genotyping assay might be a fast and inexpensive method to assess the risk for PyVAN and transplant outcome already at early stages of BKPyV reactivation. STUDY DESIGN: 56 patients who were renal transplanted and tested positive for BKPyV viremia were included into the study. The BKPyV-VP1-coding sequences were PCR-amplified, sequenced, and subjected to genotyping. For group specific analysis patients were grouped in genotype I (n = 46) and a second group including genotype II and IV (n = 10) and associated with their clinical outcomes. RESULTS: The most abundant genotype I was detected in 46 of 56 (82%) patients, however, in the genotype II and IV group PyVAN was twice as frequent as compared to the genotype I group 24 months after transplantation (8 of 10 (80%) vs. 17 of 46 (37%); p = 0.001). Accordingly, graft failure was significantly more frequent in the genotype II and IV group (3 of 10 (30%) vs. 2 of 46 (4%); p = 0.007). CONCLUSION: PCR-based BKPyV genotyping might represent a fast and inexpensive method to assess the risk for PyVAN and transplant outcome already at early stages of BKPyV reactivation even if matched samples of the donor are not available.


Subject(s)
BK Virus/genetics , Genotype , Kidney Diseases/virology , Kidney Transplantation , Polyomavirus Infections/diagnosis , Virus Activation , Adult , Aged , BK Virus/isolation & purification , BK Virus/physiology , Biopsy , Capsid Proteins/genetics , Cross-Sectional Studies , Female , Humans , Kidney/pathology , Kidney/virology , Kidney Diseases/diagnosis , Kidney Diseases/prevention & control , Male , Middle Aged , Polyomavirus Infections/blood , Polyomavirus Infections/virology , Retrospective Studies , Risk Assessment , Tumor Virus Infections/diagnosis , Tumor Virus Infections/virology
10.
Front Immunol ; 10: 2843, 2019.
Article in English | MEDLINE | ID: mdl-31921121

ABSTRACT

Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV). Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3+CD4-CD8-. To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied. Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3+CD4-CD8-). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC. Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.


Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/etiology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/metabolism , Disease Susceptibility , Receptors, Immunologic/genetics , Th17 Cells/immunology , Th17 Cells/metabolism , Adult , Aged , Aged, 80 and over , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pathology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Female , Gene Expression , Humans , Male , Middle Aged , Receptors, Immunologic/metabolism , Recurrence , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Young Adult
11.
Clin Ther ; 40(11): 1868-1877, 2018 11.
Article in English | MEDLINE | ID: mdl-30376962

ABSTRACT

PURPOSE: The learned immunosuppressive placebo response has been demonstrated in experimental animals, healthy humans, and patients, and is suggested as a therapy for improving immunopharmacologic treatment. It remains unclear, however, whether potential adverse events induced by the drug are also behaviorally conditioned. Employing an established taste-immune learning paradigm in healthy humans using the calcineurin inhibitor and immunosuppressive drug cyclosporine A (CsA) as an unconditioned stimulus, we investigated whether and to what extent perceived adverse events induced by acute CsA administration are behaviorally conditioned. METHODS: A total of 68 healthy male subjects were exposed to the established taste-immune learning paradigm, receiving either placebo or CsA (10 mg/kg) as an unconditioned stimulus, and a novel-tasting drink as a conditioned stimulus. FINDINGS: Subjects repeatedly receiving CsA during acquisition reported significantly more adverse events than did placebo-receiving subjects. However, during reexposure to the conditioned stimulus, the reported adverse events did not differ from those in the placebo control condition. IMPLICATIONS: These data indicate that acute adverse events are not behaviorally conditioned during the learned immunosuppressive response. Our results further strengthen the great potential clinical relevance of employing the learned immunosuppressive placebo response as a therapy to support immunopharmacologic regimens, ultimately aiming to reduce the medical dosages required, thereby minimizing adverse drug events while maximizing the therapeutic benefit in patients. German Clinical Trial Register (www.drks.de) identifier: DRKS00007693.


Subject(s)
Calcineurin Inhibitors/administration & dosage , Cyclosporine/administration & dosage , Immunosuppressive Agents/administration & dosage , Adult , Animals , Calcineurin Inhibitors/adverse effects , Conditioning, Classical , Cyclosporine/adverse effects , Cyclosporine/pharmacology , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/pharmacology , Male , Taste/physiology , Young Adult
12.
Antiviral Res ; 159: 68-76, 2018 11.
Article in English | MEDLINE | ID: mdl-30268912

ABSTRACT

BACKGROUND: Reactivation of the BK-Polyomavirus (BKPyV) can cause a polyomavirus associated nephropathy in approx. 10% of kidney transplant recipients. In these cases, current therapy is based on the reduction of immunosuppression. Since BKPyV-transcription is driven by the Non-Coding-Control-Region (NCCR) we were interested whether NCCR-activity is affected by immunosuppressive agents. METHODS: Plasma samples from 45 BKPyV-positive patients after renal transplantation were subjected to PCR-analysis. NCCR-amplicons were cloned into a plasmid that allows the quantification of early and late NCCR-activity by tdTomato and eGFP expression, respectively. HEK293T-cells were transfected with the reporter-plasmids, treated with immunosuppressive agents, and subjected to FACS-analysis. In addition, H727-cells were infected with patient derived BKPyV, treated with mTOR-inhibitors, and NCCR activity was analysed using qRT-PCR. RESULTS: While tacrolimus and cyclosporine-A did not affect NCCR-promoter-activity, treatment with mTOR1-inhibitor rapamycin resulted in the reduction of early, but not late-NCCR-promoter-activity. Treatment with dual mTOR1/2 inhibitors (INK128 or pp242) led to significant inhibition of early, however, concomitantly enhanced late-promoter-activity. In BKPyV infected cells both rapamycin and INK128 reduced early expression, however, INK128 resulted in higher late-mRNA levels when compared to rapamycin treatment. CONCLUSIONS: Our results demonstrate that mTOR1-inhibitors are able to reduce early-expression of wildtype and rearranged NCCRs, which might contribute to previously described inhibition of BKPyV-replication. Dual mTOR1/2-inhibitors, however, additionally might shift viral early into late-expression promoting synthesis of viral structural proteins and particle production.


Subject(s)
BK Virus/drug effects , BK Virus/genetics , Immunosuppressive Agents/pharmacology , RNA, Untranslated/genetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , Cyclosporins/pharmacology , DNA, Viral/genetics , Gene Expression Regulation, Viral/drug effects , HEK293 Cells , Humans , Immunosuppression Therapy , Kidney Transplantation , Open Reading Frames , Polyomavirus Infections/virology , Sirolimus/pharmacology , Tacrolimus/pharmacology , Transplant Recipients , Tumor Virus Infections/virology , Virus Replication/drug effects
13.
Front Behav Neurosci ; 12: 183, 2018.
Article in English | MEDLINE | ID: mdl-30186124

ABSTRACT

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences.

14.
Front Immunol ; 9: 1133, 2018.
Article in English | MEDLINE | ID: mdl-29868038

ABSTRACT

Objective: Sepsis is one of the leading causes of the deaths in hospitals. During sepsis, patients are exposed to endotoxemia, which may contribute to the dysregulation of the immune system frequently observed in sepsis. This dysregulation leads to impaired pro-inflammatory responses and may increase the risk for secondary infections in sepsis. The experimental human endotoxemia model is widely used as a model system to study the acute effects of endotoxemia. Under physiological circumstances, the immune system is tightly regulated. Effector T-cells exert pro-inflammatory function and are restrained by regulatory T-cells (Tregs), which modulate pro-inflammatory effector responses. Endotoxemia may induce inadequate Treg activity or render effector T-cells dysfunctional. It was the aim of the study to investigate effector T-cell and Treg responses in an experimental human endotoxemia model. Methods: In a cross-over designed placebo-controlled study, 20 healthy male volunteers received an intravenous injection of either lipopolysaccharide (LPS) (0.8 ng/kg body weight) or a placebo (saline 0.9%). CD3+ T-cells, CD4+ T-cells, CD8+ T-cells, and intracellular cytokine profiles were measured with flow cytometry at baseline and at repeated points after LPS/placebo injection. Complete blood cell counts were obtained with an automated hematology analyzer and cytokines were quantified by ELISA. Results: Circulating neutrophils were significantly increased 2 h after LPS injection (p < 0.001) while absolute number of CD3+ T-cells, CD4+ T-cells, and CD8+ T-cells decreased (p < 0.001). Effector T-helper-cells (THs) showed a significant-but transient-decrease of pro-inflammatory IFNγ, interleukin (IL)-2, TNFα, and IL-17A production after LPS injection (p < 0.001). In contrast, the frequency of Treg and the capacity to produce IL-10 were unchanged (p = 0.21). Conclusion: Effector THs fail to produce pro-inflammatory Th1-/Th17-associated cytokines after LPS challenge. In contrast, IL-10 production by Treg is not affected. Thus, endotoxemia-induced suppression of pro-inflammatory THs might be considered as a contributing factor to immunoparalysis in sepsis.


Subject(s)
Cytokines/metabolism , Endotoxemia/etiology , Endotoxemia/metabolism , Inflammation Mediators/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Adolescent , Adult , Biomarkers , Cross-Over Studies , Healthy Volunteers , Humans , Immunophenotyping , Interleukin-10/metabolism , Leukocyte Count , Lipopolysaccharides/immunology , Male , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Young Adult
15.
Proc Natl Acad Sci U S A ; 115(16): 4223-4227, 2018 04 17.
Article in English | MEDLINE | ID: mdl-29610294

ABSTRACT

Patients after organ transplantation or with chronic, inflammatory autoimmune diseases require lifelong treatment with immunosuppressive drugs, which have toxic adverse effects. Recent insight into the neurobiology of placebo responses shows that associative conditioning procedures can be employed as placebo-induced dose reduction strategies in an immunopharmacological regimen. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. Thus, 30 renal transplant patients underwent a taste-immune conditioning paradigm, in which immunosuppressive drugs (unconditioned stimulus) were paired with a gustatory stimulus [conditioned stimulus (CS)] during the learning phase. During evocation phase, after patients were reexposed to the CS, T cell proliferative capacity was significantly reduced in comparison with the baseline kinetics of T cell functions under routine drug intake (ƞp2 = 0.34). These data demonstrate, proof-of-concept, that learned immunosuppressive placebo responses can be used as a supportive, placebo-based, dose-reduction strategy to improve treatment efficacy in an ongoing immunopharmacological regimen.


Subject(s)
Conditioning, Classical , Cyclosporine/administration & dosage , Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Lymphocyte Activation , Placebo Effect , T-Lymphocyte Subsets/immunology , Tacrolimus/administration & dosage , Administration, Oral , Adult , Affect , Association , Catecholamines/metabolism , Dose-Response Relationship, Drug , Dose-Response Relationship, Immunologic , Female , Hemodynamics , Humans , Hydrocortisone/metabolism , Interferon-gamma Release Tests , Learning , Lymphocyte Activation/drug effects , Male , Middle Aged , Placebos , Proof of Concept Study , Taste
16.
Transpl Infect Dis ; 20(1)2018 Feb.
Article in English | MEDLINE | ID: mdl-29156086

ABSTRACT

BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy (PyVAN) is a significant cause of premature renal transplant failure. High-level BKPyV viremia is predictive for PyVAN; however, low-level BKPyV viremia does not necessarily exclude the presence of PyVAN. As data are limited regarding whether or not low-level BKPyV viremia has an effect on intermediate-term graft outcome, this study analyzes the impact of low-level BKPyV viremia on intermediate-term graft function and outcome compared with high-level viremia and non-viremic patients. METHODS: All renal transplant patients received follow-up examinations at the Department of Nephrology, University Hospital Essen. Patients were screened for BKPyV viremia and stratified into three groups according to their maximum BKPyV load in serum (low-level viremia, high-level viremia, and no viremia). RESULTS: In 142 of 213 (67%) patients, BKPyV was never detected in serum; 42 of 213 (20%) patients were found positive for low-level viremia (≤104 copies/mL); and 29 of 213 (13%) patients showed high-level viremia (>104 copies/mL). No significant differences regarding transplant function and graft failure were observed between patients without BKPyV viremia (delta estimated glomerular filtration rate [eGFR] +0.1 mL/min [month 1 vs last visit at month 44]) and patients with low-level BKPyV viremia (delta eGFR -1.7 mL/min). In patients with high-level viremia, transplant function was significantly restricted (delta eGFR -6.5 mL/min) compared with low-level viremia until the last visit at 44 ± 9.7 months after transplantation. Although the graft function and graft loss were worse in the high-level viremia group compared with no viremia (eGFR 37 vs 45 mL/min), the difference was not significant. CONCLUSIONS: High-level viremia was associated with impaired graft function. In contrast, low-level BKPyV viremia had no significant impact on intermediate-term graft function.


Subject(s)
Kidney Diseases/virology , Kidney Transplantation/adverse effects , Polyomavirus Infections/blood , Transplantation, Homologous/adverse effects , Viremia/virology , Adult , Aged , BK Virus , Female , Humans , Male , Middle Aged , Tumor Virus Infections/blood , Viremia/etiology
17.
Transl Psychiatry ; 7(12): 1281, 2017 12 11.
Article in English | MEDLINE | ID: mdl-29225332

ABSTRACT

Experimental endotoxemia is a translational model to study inflammatory mechanisms involved in the pathophysiology of mood disorders including depression. Disturbed affective cognition constitutes a core aspect in depression, but has never been studied in the context of inflammation. We combined experimental endotoxemia with an established experimental mood induction procedure to assess the interaction between acute inflammation and sad mood and their effects on affective cognition. In this randomized cross-over study, N = 15 healthy males received endotoxin (0.8 ng/kg lipopolysaccharide iv) on one study day and placebo an otherwise identical study day. The affective Go/Nogo task was conducted after experimental induction of neutral and sad mood. Inflammatory markers were assessed hourly. Endotoxin application induced a transient systemic inflammation, characterized by increased leukocyte counts, TNF-alpha and interleukin-6 plasma concentrations (all p < 0.01, interaction effects). Mood induction led to greater sadness ratings, with highest ratings when sad mood was induced during inflammation (p < 0.05, interaction effect). Based on a 2 (endotoxin vs. placebo) × 2 (sad vs. neutral mood) × 2 (sad vs. happy Go/Nogo target words) factorial design, we observed a significant target × endotoxin condition interaction (p < 0.01) reflecting slower responses to sad targets during endotoxemia. Additionally, we found a valence × mood interaction (p < 0.05), reflecting slower reaction times to sad targets in sad mood. In summary, acute inflammation and sad mood are risk factors for disturbed affective cognition. The results may reflect a mood-congruency effect, with prolonged and sustained processing of mood-congruent information during acute inflammation, which may contribute to depression risk.


Subject(s)
Affect , Cognition , Depression/etiology , Inflammation/psychology , Adult , Cross-Over Studies , Double-Blind Method , Endotoxemia/chemically induced , Endotoxemia/psychology , Humans , Inflammation/chemically induced , Lipopolysaccharides/administration & dosage , Male , Young Adult
18.
Clin Immunol ; 184: 48-53, 2017 11.
Article in English | MEDLINE | ID: mdl-28461110

ABSTRACT

OBJECTIVES: A separate subset of Granzyme B (GrB) producing B-cells regulating T-cell mediated immunity has been identified. In the present study, we investigated the role of GrB+ B-cells in renal transplant patients (RTX). METHODS: 12 healthy controls (HC) and 26 RTX patients were enrolled. In addition, 19 healthy volunteers treated with cyclosporine A (CsA) were enrolled. GrB+ B-cells were determined via flow cytometry. RESULTS: RTX Patients showed a diminished fraction of GrB+ B-cells as compared to HC. CsA treatment of healthy volunteers had no impact on the development of GrB+ B-cells. RTX patients with a history of allograft rejection showed an increased frequency of GrB+ B-cells. RTX patients with at least one episode of CMV viremia tended to have lower GrB+ B-cells as compared to patients without viremic episodes. CONCLUSION: We demonstrate that treatment with CsA does not impair the development of GrB+ B-cells. GrB+ B-cells may have a dual role in renal transplantation as regulatory cells to maintain allospecific tolerance and as effector cells enhancing viral control.


Subject(s)
B-Lymphocytes/metabolism , Granzymes/metabolism , Kidney Transplantation , Adrenal Cortex Hormones/therapeutic use , Aged , B-Lymphocytes/drug effects , Case-Control Studies , Cyclosporine/pharmacology , Cyclosporine/therapeutic use , Female , Graft Rejection/prevention & control , Granzymes/drug effects , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Interleukins/pharmacology , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Tacrolimus/therapeutic use
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