Systemic Immune Response In Patients Research Articles

Studying the impact of probiotic agents on the pathogenetic and clinical features of generalized periodontitis

Generalized periodontitis remains one of the most prevalent dental diseases, complications of which significantly deteriorate patients’ quality of life. Currently, the use of probiotic agents is considered a promising direction to enhance the effectiveness of non-surgical treatment of this pathology. Studying the impact of different probiotics on the pathogenetic and clinical features of generalized periodontitis will allow proposing optimized protocols for comprehensive treatment, reducing patient rehabilitation periods and improving the overall dental health of the population. The aim of this study is to examine the influence of various probiotic agents on the pathogenetic and clinical characteristics, treatment effectiveness of generalized periodontitis in adult patients by analyzing professional scientific literature. The literature review provides a brief overview of various probiotic groups and discusses pathogenetic mechanisms of their interaction with the microbiota of oral biofilms. The immunomodulatory mechanisms of probiotics on local and systemic immune responses in patients with generalized periodontitis, inhibition of enzymes responsible for bone tissue resorption, are presented. The analysis results of scientific sources regarding the dynamics of changes in clinical symptoms, microbiological, immunological, and biochemical parameters of saliva and blood serum in individuals with generalized periodontitis receiving comprehensive rehabilitation using probiotic agents compared to patients treated with traditional protocols are provided. The study highlights statistical differences in clinical and laboratory indicators of periodontitis progression at different treatment intervals. Conclusions. The use of probiotic agents for treating patients with generalized periodontitis significantly influences the clinical course of the disease by altering the species composition of dental biofilms and modulating local immune and inflammatory reactions. However, the known results of experimental and clinical studies often have conflicting findings regarding the efficacy of specific probiotic strains and the duration of inflammatory process stabilization over extended periods after treatment, which means a further study is required.

Investigation of parasite genetic variation and systemic immune responses in patients presenting with different clinical presentations of cutaneous leishmaniasis caused by Leishmania aethiopica

BackgroundCutaneous leishmaniasis (CL) is a neglected tropical skin disease, caused by the protozoan parasite Leishmania. In Ethiopia, CL is mainly caused by Leishmania aethiopica and can present in different clinical forms. The aim of this study was to assess whether these different forms are associated with differences in parasite genetic and host systemic immune signatures.MethodsHere we analysed the whole genome sequence data for 48 clinical parasite isolates and the systemic immune signature from a cohort of CL patients, who were recruited in Nefas Mewcha, Northern Ethiopia, from January 2019 to January 2022.ResultsOur results show that parasites from CL cases with different presentations in a single Ethiopian setting are from the same genetic population based on a permutation test of genome-wide similarity. Furthermore, a logistic regression test for genome wide association did not identify any individual genetic variants significantly associated with disease presentation. We also measured plasma chemokine and cytokine levels of 129 CL patients presenting with different forms of CL. None of the chemokine [eotaxin, eotaxin-3, interleukin (IL)-8, interferon (IFN)-γ-induced protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, MCP-4, macrophage-derived chemokines (MDC), macrophage inflammatory protein (MIP)-1α, MIP-1β and thymus- and activation-regulated chemokine (TARC)] or cytokine (IFN-γ, IL-1β, interleukin-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, tumor necrosis factor-α) levels measured were significantly different between the different clinical presentations of CL, as measured by Kruskal–Wallis test. We also compared those with healthy nonendemic controls: our results show a chemokine (IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β and TARC) but not a cytokine immune signature in patients with CL as compared to healthy nonendemic controls, as measured by Mann-Whitney test.ConclusionsThe results of our study did not identify a systemic immune signature or parasite genetic factors associated with different clinical presentation of CL.Graphical abstract

Proteomic and Cytokine Profiling in Plasma from Patients with Normal-Tension Glaucoma and Ocular Hypertension

Primary open-angle glaucoma (POAG) is subdivided depending on eye pressure. Patients with normal-tension glaucoma (NTG) have never had high intraocular pressure (IOP) measured while patients with ocular hypertension (OHT) have high eye pressure but no signs of glaucoma. Although IOP is considered to be a risk factor for all glaucoma patients, it is reasonable to assume that other risk factors such as inflammation play a role. We aimed to characterize the proteome and cytokine profile during hypoxia in plasma from patients with NTG (n = 10), OHT (n = 10), and controls (n = 10). Participants were exposed to hypoxia for two hours, followed by 30 min of normoxia. Samples were taken before (“baseline”), during (“hypoxia”), and after hypoxia (“recovery”). Proteomics based on liquid chromatography coupled with mass spectrometry (LC–MS) was performed. Cytokines were measured by Luminex assays. Bioinformatic analyses indicated the involvement of complement and coagulation cascades in NTG and OHT. Regulation of high-density lipoprotein 3 (HDL3) apolipoproteins suggested that changes in cholesterol metabolism are related to OHT. Hypoxia decreased the level of tumor necrosis factor-α (TNF-α) in OHT patients compared to controls. Circulating levels of interleukin-1β (IL-1β) and C-reactive protein (CRP) were decreased in NTG patients compared to controls during hypoxia. After recovery, plasma interleukin-6 (IL-6) was upregulated in patients with NTG and OHT. Current results indicate an enhanced systemic immune response in patients with NTG and OHT, which correlates with pathogenic events in glaucoma. Apolipoproteins may have anti-inflammatory effects, enabling OHT patients to withstand inflammation and development of glaucoma despite high IOP.Graphical

Irreversible electroporation of localised prostate cancerdownregulates immune suppression andinduces systemic anti-tumour T-cell activation - IRE-IMMUNO study.

To prospectively compare systemic anti-tumour immune responses induced by irreversible electroporation (IRE) and robot-assisted radical prostatectomy (RARP) in patients with localised intermediate-risk prostate cancer (PCa). Between February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2-3, clinical cancer stage ≤T2c, prostate-specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa-specific T-cell responses to prostatic acid phosphatase(PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY-ESO-1]) were determined by interferon-γ enzyme-linked immunospot assay (ELISpot). Repeated-measures analysis of variance and two-sided Student's t-tests were used to compare immune responses over time and between treatment cohorts. Patient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory Tcells (P = 0.0001) and a simultaneous increase in activated cytotoxic T-lymphocyte antigen 4 (CTLA-4)+ cluster of differentiation (CD)4+ (P < 0.001) and CD8+ (P = 0.032) Tcells, consistent with reduction of systemic immune suppression allowing for effector T-cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY-ESO-1 specific T-cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP. Irreversible electroporation induces a PCa-specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA-4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high-risk localised or (oligo)metastatic disease.

Association of gut microbiome with immune microenvironment in surgically treated colorectal cancer patients

This study explored the relationship between faecal microbiota distribution and local or systemic immune response in patients with colorectal cancer (CRC). The study population included 114 surgically treated CRC patients. Faeces were analysed using 16S rRNA gene sequencing. The immune score in tumour microenvironment was evaluated using CD3 and CD8 immunohistochemistry. Genetic alterations, microsatellite instability status and five systemic inflammatory markers were also analysed. Thirty of 114 (26.3%) CRC patients were categorised as the 'immune type' with a high density of T-cells. The immune type CRC cases showed lower angiolymphatic invasion and longer overall survival. Of the 123 selected bacterial species, Bacteroides fragilis and Collinsella aerofaciens were prevalent in immune CRC cases, whereas Odoribacter splanchnicus and Phascolarctobacterium succinatutens were prevalent in non-immune CRC patients. Bacteroides fragilis was associated with shorter disease free survival in univariable and multivariable survival analyses. Regarding systemic immunity, a high prevalence of C.aerofaciens was associated with a high modified Glasgow prognostic score. This study revealed a potential relationship among the gut microbiome, immune microenvironment, and disease progression in patients with CRC. Our findings suggest that abundant B.fragilis in patients with CRC is associated with a 'cold immune' tumour microenvironment.

Microwave ablation enhances the systemic immune response in patients with lung cancer.

Microwave ablation (MWA) is a key alternative therapy to conventional surgery for the treatment of lung cancer. In addition to eliminating local tumors, MWA may promote antitumor immunological responses, such as abscopal effects in distant lesions. However, the intensity of MWA is limited and the underlying mechanisms are not well-defined. The present study assessed the impact of MWA on immune cell subsets and cytokines in patients with lung cancer. A total of 45 patients with lung cancer who underwent percutaneous lung tumor MWA were enrolled. Peripheral blood samples were collected before and 24 h after MWA and changes in immune cell subsets [lymphocytes, CD3+, CD4+ and CD8+ T cells, B cells and natural killer (NK) cells] and serum cytokine levels (IL-1β, IL-2, IL-4-6, IL-8, IL-10, IL-12p70, IL-17A and F, IL-22, TNF-α, TNF-β and IFN-γ) were assessed by flow cytometry and ELISA. The number of total lymphocytes, CD4+ T and NK cells in the peripheral blood significantly decreased 24 h after MWA, while number of CD8+ T cells remained stable, leading to a higher proportion of CD8+ T cells. In addition, the serum levels of IL-2, IL-1β, IL-6, IL-12p70, IL-22, TNF-α and IFN-γ were significantly increased 24 h after MWA, indicating a T helper 1 type immune response. The immune response in patients with advanced stage disease was comparable with patients in the early stage group; however, the number of total lymphocytes and CD3+ T cells significantly decreased and the ratio of CD4/CD8 and IL-2 levels significantly increased. The early immune response after MWA may contribute to systemic antitumor immunity in patients with both early and advanced disease. Thus, MWA may exhibit potential as a local therapy and trigger abscopal effects in distant lesions in patients with lung cancer.

Tissue Resistance Decrease during Irreversible Electroporation of Pancreatic Cancer as a Biomarker for the Adaptive Immune Response and Survival

PurposeTo correlate irreversible electroporation (IRE) procedural resistance changes with survival outcomes and the IRE-induced systemic immune response in patients with locally advanced pancreatic cancer (LAPC). Materials and MethodsData on IRE procedural tissue resistance (R) features and survival outcomes were collected from patients with LAPC treated within the context of 2 prospective clinical trials in a single tertiary center. Preprocedural and postprocedural peripheral blood samples were prospectively collected for immune monitoring. The change (ie, decrease) in R during the first 10 test pulses (ΔR10p) and during the total procedure (ΔRtotal) were calculated. Patients were divided in 2 groups on the basis of the median change in R (large ΔR vs small ΔR) and compared for differences in overall survival (OS) and progression-free survival and immune cell subsets. ResultsA total of 54 patients were included; of these, 20 underwent immune monitoring. Linear regression modeling showed that the first 10 test pulses reflected the change in tissue resistance during the total procedure appropriately (P < .001; R2 = 0.91). A large change in tissue resistance significantly correlated with a better OS (P = .026) and longer time to disease progression (P = .045). Furthermore, a large change in tissue resistance was associated with CD8+ T cell activation through significant upregulation of Ki-67+ (P = .02) and PD-1+ (P = .047). Additionally, this subgroup demonstrated significantly increased expression of CD80 on conventional dendritic cells (cDC1; P = .027) and PD-L1 on immunosuppressive myeloid-derived suppressor cells (P = .039). ConclusionsIRE procedural resistance changes may serve as a biomarker for survival and IRE-induced systemic CD8+ T cell and cDC1 activation.

Assessment of the systemic immune response in patients with inflammatory complications of large joint implants.

One of the most common reasons for the progressing of aseptic instability of implanted structures in patients with end-stage osteoarthrosis is a disorder of immunogenulatory processes of bone tissue remodeling along with chronic inflammatory response influenced by endoprosthesis wear components. This research features the specifics of systemic immune response in patients with inflammatory complications in late postoperative period after total replacements of large joints. The factor analysis enabled determining the most significant immunological mechanisms associated with the progressing of implant aseptic instability. Pathogenetically significant components involved in the formation of cellular and humoral immune responses in patients with signs of inflammatory activity in late postoperative period have been identified. Our findings can be used in designing diagnostic and prognostic criteria for systemic inflammatory response severity in preoperative monitoring of the condition of patients in need of large joint arthroplasties, and also in detecting the progress of implant aseptic instability.

Late Breaking Abstracts

Late Breaking Abstracts

Impact of Endoluminal Radiofrequency Ablation on Immunity in Pancreatic Cancer and Cholangiocarcinoma

Radiofrequency ablation (RFA) is a mini-invasive loco-regional ablation technique that is increasingly being used as a palliative treatment for pancreatic cancer and cholangiocarcinoma. Ablation-triggered immune system stimulation has been proposed as a mechanism behind the systemic effects of RFA. The aim of our study was to investigate the immune response to endoluminal biliary RFA. Peripheral blood samples were collected from patients with pancreatic cancer and cholangiocarcinoma randomised to receive endoluminal biliary radiofrequency ablation + stent (19 patients) or stent only (21 patients). We observed an early increase in IL-6 levels and a delayed increase in CXCL1, CXCL5, and CXCL11 levels as well as an increase in CD8+ and NK cells. However, these changes were not specific to RFA treatment. Explicitly in response to RFA, we observed a delayed increase in serum CXCL1 levels and an early decrease in the number of anti-inflammatory CD206+ blood monocytes. Our study provides the first evidence of endoluminal biliary RFA-based regulation of the systemic immune response in patients with pancreatic cancer and cholangiocarcinoma. These changes were characterised by a general inflammatory response. RFA-specific activation of the adaptive immune system was not confirmed.

Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis.

ObjectiveBased on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS.MethodsWe investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing.ResultsWe show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction (r = −0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001).ConclusionsGut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS.

Immunological effect of irreversible electroporation on hepatocellular carcinoma

BackgroundThis study intends to investigate the immunological effects of tumor ablation with irreversible electroporation (IRE).MethodsWe evaluated the systemic immune response in patients with hepatocellular carcinoma (HCC) after IRE treatment. Furthermore, we analyzed the tumor infiltrating T lymphocytes and the level of serum cytokines in IRE and control groups of tumor-bearing mice.ResultsWe observed that IRE induced an increase in WBC, neutrophil and monocyte counts and a decrease in lymphocyte count 1 day post-IRE and returned to baseline values within 7 days in the patients. Meanwhile, circulating CD4+ T cell subsets, but not CD8+, decreased 1 day post-IRE. The activated T cells and natural killer (NK) cells increased, and regulatory T (Treg) cells decreased. Furthermore, a significant increase in cytotoxic CD8+ T cells infiltration was observed on ablative tumors in mice. The level of serum IFN-γ also significantly increased in the IRE group.ConclusionsOur study demonstrated that IRE upregulated activated T cells and downregulated Tregs in the peripheral blood of patients. Meanwhile, the results from the animal model indicated that IRE could induce antitumor adaptive immunity dominated by the infiltration of cytotoxic CD8+ T cells into the tumors, accompanied by reduced Tregs.

Discoordination of the processes of activation and suppression of immunocompetent cells during mesotherapy with hyaluronic acid

Objective. The study aimed to assess the dynamics of the systemic immune response in patients during mesotherapy with hyaluronic acid (HA).Materials and methods. The observation group included 26 women who received the first-time mesocorrection with drugs based on hyaluronic acid (HA). Injections of low molecular weight HA were carried out according to standard methods in a course of 5 procedures with an interval of 14 days. The parameters of the innate and adaptive immune response were studied before and two weeks after the end of the course. The skin condition was assessed by dermatoscopy (Aramo Smart Lite 300, Southern Korea).Results. The clinical effect of the course of procedures was reflected in the subjective improvement in the appearance. The improvement was confirmed by hardware analysis, which recorded an increase in hydration, a smoothing of the skin relief, and a decrease in the depth of wrinkles. At the end of the course, redistribution of lymphocyte populations towards natural killer cells and B-lymphocytes was revealed with a decrease in the total number of T cells. The antibody production of immunoglobulins of classes M and G was increased, the serum content of Ig A and IgE was reduced, the number of both T-effectors and T-lymphocytes with immunosuppressive activity increased. Changes in the neutrophil system were characterized by the inhibition of the production of reactive oxygen intermediates; the dynamics of the expression of Toll-like receptors by monocytes was ambiguous.Conclusion. The results of the study confirmed the active involvement of the factors of innate and adaptive systemic response in the cosmetic effect, which manifested itself immediately after mesotherapy as systemic dysregulatory immune changes.

Systemic immune responses in patients with early localized or early disseminated Borrelia afzelii lyme borreliosis.

IntroductionThe role of host immune responses in the pathogenesis of borrelial dissemination in early Lyme borreliosis (LB) in the form of multiple erythema migrans (MEM) or LB‐associated symptoms is incompletely understood.MethodsIn this study, fifteen cytokine or chemokine levels, representative of innate, Th1, and Th17 immune responses, were assessed using a bead‐based Luminex multiplex assay in acute sera from 76 adult patients with skin culture‐positive Borrelia afzelii solitary erythema migrans (SEM) and 58 patients with MEM at a single‐center university hospital. Differences between the groups were tested by modeling each cytokine or chemokine concentration by means of left‐censored regression using the classic Tobit model.ResultsMean serum cytokine or chemokine levels were low. When taking into account the proportion of patients with cytokine or chemokine concentrations below the lowest detectable limit, only levels of CXCL10 (p = .03) and CCL19 (p = .02), representatives of the Th1 immune response, differed between patients with SEM and those with MEM; however, the differences did not reach statistical significance when adjusted for multiple comparisons. In addition, we did not find differences in systemic inflammatory responses when comparing patients with and those without LB‐associated constitutional symptoms.ConclusionNo significant differences in systemic immune responses represented by selected cytokines or chemokines in serum samples of patients with EM infected with B. afzelii suggest that systemic mediators are not pivotal in the pathogenesis of dissemination of early infection in the form of MEM or LB‐associated symptoms. Localized immune responses in the skin or other pathogenetic mechanisms may be more important in this regard.

Is there a link between very early changes of primary and secondary lymphoid organs in 18F-FDG-PET/MRI and treatment response to checkpoint inhibitor therapy?

Response assessment or prediction to checkpoint inhibitor therapy (CIT) is an unsolved problem in current routine diagnostics of patients with melanoma. Here, we evaluated very early changes of primary and secondary lymphoid organs under CIT in multiparametric [18F]-labeled fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)/MRI as possible predictors of treatment response and investigated their correlation with baseline blood immune biomarkers. Between October 2014 and November 2017, 17 patients with unresectable melanoma (8 females; 65±11 years) undergoing CIT were prospectively evaluated using whole-body 18F-FDG-PET/MRI before CIT start (t0), 2 weeks (t1) and 3 months after CIT initiation (t2). At each time point, the volume, the 18F-FDG-uptake and the mean apparent diffusion coefficient (ADC) of the spleen as well as the 18F-FDG uptake of the bone marrow were assessed. Relative lymphocyte count (RLC), relative eosinophil count (REC) and neutrophil-lymphocyte ratio (NLR) were assessed at baseline. Response Evaluation Criteria in Solid Tumours modified for immune-based therapeutics (iRECIST) and decisions from an interdisciplinary tumor board were used for treatment response evaluation at t2. iRECIST was compared with PET response criteria in solid tumors for image-based response evaluation at different time points. Comparative analysis was conducted with Mann-Whitney U test with false discovery rate correction for multiple testing and correlation coefficients were computed. In lymphoid organs, significant differences (p<0.05) between responders (9/17) and non-responders were found for the 18F-FDG-uptake in the spleen at t1 and the increase of the uptake t1-t0 (responders/non-responders: standardized uptake value lean body mass 1.19/0.93; +49%/−1%). The best correlation coefficients to baseline biomarkers were found for the 18F-FDG-uptake in the spleen at t1: NLR, r=−0.46; RLC, r=0.43; REC, r=0.58 (p<0.05), respectively. Compared with the non-responder group, the responder group showed marked increases also in the volume of the spleen (+22%/+10%), the 18F-FDG-uptake of bone marrow (+31%/−9%) at t1 and the ADCmean at t2 (+46%/+15%) compared with t0, however, not reaching significance. Our findings indicate that an effective systemic immune response in patients undergoing CIT can be detected as a significantly increased spleen activity in 18F-FDG-PET as early as 2 weeks after treatment initiation.Trial registration number NCT03132090, DRKS00013925.

Irreversible Electroporation versus Radiofrequency Ablation: Comparison of Systemic Immune Responses in Patients with Hepatocellular Carcinoma

PurposeIrreversible electroporation (IRE) differs from thermal radiofrequency (RF) ablation, especially in terms of the reparative process in the ablation zone induced. To elucidate this, the systemic immune responses after 2 mechanistically different types of ablation (IRE and RF ablation) were evaluated in patients with hepatocellular carcinoma (HCC). Materials and MethodsTwenty-one patients with HCC who underwent either RF ablation (n = 11) or IRE (n = 10) were studied. Peripheral blood samples were collected from all patients at 4 timepoints: before ablation, within 1 hour after ablation, 1 day after ablation, and 4 days after ablation. The phenotypes and functions of immune cells in peripheral blood and serum levels of cytokines and chemokines were monitored and analyzed using the mixed-effects model. Follow-up radiological images were also obtained to assess temporal changes in the ablation zone. ResultsThe most significant difference was seen in the levels of macrophage migration inhibitory factor (MIF) in the IRE group compared to the RF ablation group (P = .0011): the serum levels of MIF in the IRE group significantly increased immediately after IRE and then rapidly decreased to the pre-ablation range 1 day after IRE, but, in contrast, no consistent trend was observed in the RF ablation group. The axial diameter (P = .0009) and area (P = .0192) of the ablation zone of IRE were significantly smaller than those of RF ablation 1 year after ablation. ConclusionsIRE was found to be associated with a significant early increase in MIF levels, which may facilitate the early reparative process and result in significant shrinkage of the ablation zone.

Abstract 3034: 18F-FDG-positron emission tomography (PET)/CT enables the identification of checkpoint inhibitor immunotherapy (CIT) responders by determination of CIT-induced metabolic changes in secondary lymphatic organs

Abstract Although the majority of patients with metastatic melanoma achieve a prolongation of overall survival by using checkpoint inhibitor based immunotherapy (CIT), there is still a larger number of patients who do not benefit from this therapy. As a CIT-induced systemic immune response is required to promote the anti-tumor effect we analyzed the glucose metabolism in secondary lymphoid organs such as the spleen by 18F-FDG-Positron Emission Tomography (PET). In preclinical studies, we were able to distinguish responders from non responders by focusing on the spleen 18F-FDG-uptake of mice with CIT in experimental tumor models. Thus, we aimed to gain deeper insights into impact of CIT on the metabolism in secondary lymphatic organs to identify responders and to stratify patients for differential treatment strategies. We retrospectively analyzed 18F-FDG-PET/CT scans (baseline and post-therapy) of 38 patients with metastatic melanoma with CTLA-4 or PD-1 Ab treatment as third line therapy (21 responder: 5x nivolumab; 7x pembrolizumab; 9x ipilimumab; 17 non-responder: 2x nivolumab; 11x pembrolizumab; 4x ipilimumab). Spleen regions of interest (ROI) were defined in the CT data, copied to the coregistered PET and analyzed semiquantitatively. Total lesion glycolysis (TLG) was calculated by multiplication of the spleen volume and the SUVmean. We determined in the baseline 18F-FDG-PET/CT-scans (prior to CIT), no significant differences in spleen volume (221±18 cm3 vs. 209 ±22 cm3) and in the spleen 18F-FDG-uptake (SUVmean: 1,74±0,06vs.1,72±0,05; TLG: 384±37 vs. 359±36) between responders and non-responders. In the follow up 18F-FDG-PET/CT-scans 110±68 days after onset of CIT we measured a similar increase in spleen volume in responders (+8±6%) and non-responders (+7±5%). 15 out of 21 responders revealed an enhanced spleen 18F-FDG uptake when compared to the baseline 18F-FDG-PET/CT-scans. The mean standard uptake values in the spleen of responders increased by +10±9% SUVmean. In sharp contrast, we determined hardly any change in the spleen 18F-FDG uptake of non-responders (SUVmean -1,3±2,6%). Additionally, the total lesion glycolysis (TLG) in the CIT-responders increased stronger (+25±22%) than in non-responders (+6±6%). Our results suggest that CIT-induced metabolic changes in secondary lymphatic organs are associated with therapy responds. Thus, non invasive 18F-FDG-PET/CT investigations might represent a powerful tool to monitor CIT-induced systemic immune responses in patients. Consequently, preclinical research is prerequisite to uncover the exact mode of action of CIT-induced systemic immune response in secondary lymphatic organs. Moreover, prospective clinical studies are essential to evaluate the prognostic value of our method. Citation Format: Johannes Schwenck, Barbara Schörg, Francesco Fiz, Kilian Wistuba-Hamprecht, Andrea Forschner, Thomas Eigentler, Benjamin Weide, Claus Garbe, Martin Röcken, Christina Pfannenberg, Bernd J. Pichler, Christian la Fougere, Manfred Kneilling. 18F-FDG-positron emission tomography (PET)/CT enables the identification of checkpoint inhibitor immunotherapy (CIT) responders by determination of CIT-induced metabolic changes in secondary lymphatic organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3034.

Immunomodulation in Patients with Chronic Hand Eczema Treated with Oral Alitretinoin

Background: Oral alitretinoin (9-cis-retinoic acid; 9-cis-RA) has shown clinical efficacy in patients with chronic hand eczema (CHE). Herein, we investigated the impact of oral 9-cis-RA on the local and systemic immune response in patients with CHE. Methods: Twenty patients with CHE were treated with oral alitretinoin (10 or 30 mg/day) for at least 24 weeks. Blood samples were taken for flow cytometry, and serum samples were assessed by ELISA to determine immunoglobulin (Ig) levels. Skin biopsies from lesional skin were evaluated immunohistochemically. Results: Upon 9-cis-RA treatment, improvement of the CHE was observed in all patients. A significant decrease in plasmablasts in the peripheral blood and a significant reduction of serum IgE levels were determined. Furthermore, we detected a significant reduction of CD4+ cells and regulatory T cells in the peripheral blood upon treatment. By contrast, these cell subsets were significantly increased in the affected skin. Cytokine analysis of activated CD154-positive T cells showed a reduction of interleukin (IL)-17 but not of IL-4 or IFN-γ production. Conclusions: Overall, our data indicate a disease-modifying effect of 9-cis-RA, including a systemic decrease in IL-17-positive cells, but decreased serum IgE and CD23 expression. The increased frequency of FoxP3-positive cells in the skin upon treatment may suggest a mechanism by which hand eczema is therapeutically targeted by 9-cis-RA, but this will need to be proven in the future studies.

Activation of immune responses to brain antigens after stroke.

Infection is common after stroke and is independently associated with a worse outcome. The predisposition to infection following stroke is in part related to a sympathetically mediated suppression of the peripheral immune response. The teleological explanation for this immune dysfunction is that it serves to prevent autoimmune responses to brain antigens. We believe that the systemic immune response in patients who develop infection, however, thwarts this seemingly protective response and predisposes to central nervous system autoimmunity. These autoimmune responses may mediate, at least in part, the worse outcome associated with post-stroke infection.

Alterations of T cell subsets in ALS: a systemic immune activation?

There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Few studies to date have explored the status of the systemic immune response in patients with ALS. In order to examine whether systemic immune activation is observed in patients with ALS, we measured the number of T cell subsets by flow cytometry in 36 patients with ALS and 35 normal controls. CD8 cytotoxic T cells and natural killer (NK) T cells were significantly increased in our patients with ALS compared with the control group (P = 0.02 and P = 0.04, respectively). Treg cells were significantly reduced compared with normal controls (P = 0.01). Treg cells were also negatively correlated with progression of the disease (P = 0.017). Our results suggest a systemic immune activation in patients with ALS. The high production of CD8(+) T and NKT cells may suggest an immunological reaction to some unknown or undetected endogenous proteins or viruses. A probably dual (neurodestructive or neuroprotective) inflammatory function of Treg cells cannot be excluded.