Myeloid-derived suppressor cells mediate tolerance induction in autoimmune disease

In multiple sclerosis (MS) T cells aberrantly recognize self‐peptides of the myelin sheath and attack the central nervous system (CNS). Antigen‐specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non‐specific immunosuppressive drugs, is a promising approach to combat autoimmune disease, but the cellular mechanisms behind successful therapy remain poorly understood. Myeloid‐derived suppressor cells (MDSCs) have been studied intensively in the field of cancer and to a lesser extent in autoimmunity. Because of their suppressive effect on the immune system in cancer, we hypothesized that the development of MDSCs and their interaction with CD4(+) T cells could be beneficial for antigen‐specific immunotherapy. Hence, changes in the quantity, phenotype and function of MDSCs during tolerance induction in our model of MS were evaluated. We reveal, for the first time, an involvement of a subset of MDSCs, known as polymorphonuclear (PMN)‐MDSCs, in the process of tolerance induction. PMN‐MDSCs were shown to adopt a more suppressive phenotype during peptide immunotherapy and inhibit CD4(+) T‐cell proliferation in a cell‐contact‐dependent manner, mediated by arginase‐1. Moreover, increased numbers of tolerogenic PMN‐MDSCs, such as observed over the course of peptide immunotherapy, were demonstrated to provide protection from disease in a model of experimental autoimmune encephalomyelitis

The comorbidity profiles and medication issues of patients with multiple system atrophy:a systematic cross-sectional analysis

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management.OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients.METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®.RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue.CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.</p

The comorbidity and co-medication profile of patients with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients.ObjectivesTo explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease.MethodsCross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik (R).ResultsIn total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions.ConclusionsPSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients

Neuroprotective function for ramified microglia in hippocampal excitotoxicity

<p>Abstract</p> <p>Background</p> <p>Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration.</p> <p>Methods</p> <p>Mouse organotypic hippocampal slice cultures were treated with <it>N</it>-methyl-D-aspartic acid (NMDA) to induce excitotoxic neuronal cell death. This procedure was performed in slices containing resting microglia or slices that were chemically or genetically depleted of their endogenous microglia.</p> <p>Results</p> <p>Treatment of mouse organotypic hippocampal slice cultures with 10-50 μM <it>N</it>-methyl-D-aspartic acid (NMDA) induced region-specific excitotoxic neuronal cell death with CA1 neurons being most vulnerable, whereas CA3 and DG neurons were affected less. Ablation of ramified microglia severely enhanced NMDA-induced neuronal cell death in the CA3 and DG region rendering them almost as sensitive as CA1 neurons. Replenishment of microglia-free slices with microglia restored the original resistance of CA3 and DG neurons towards NMDA.</p> <p>Conclusions</p> <p>Our data strongly suggest that ramified microglia not only screen their microenvironment but additionally protect hippocampal neurons under pathological conditions. Morphological activation of ramified microglia is thus not required to influence neuronal survival.</p

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Synopsis of the second virtual meeting of the Blue Genes community: In search of new ways to increase our connection with Nature

19 pagesOn June 22, 2023, the second online meeting ofthe Blue Genes initiative took place, unitingmembers of the Blue Genes Community. The aimwas to exchange experiences, discuss initiatives,and share insights concerning the Ocean andWaters. Over 30 participants joined this virtual assembly. Following a series of inspiringpresentations delivered by several of the community members, the meetingtransitioned into an interactive session, enabling attendees to activelyparticipate in discussions and to share their viewpoints. Among other relevantconversations, the meeting proposed to target a milestone: to organize aSatellite Event during the 2024 UN Ocean Decade Conference, which will takeplace in Barcelona in April 2024, as an open space to explore how to search fornew ways to increase our connection with Nature, with the ocean as its centralcomponent. The participants felt this in-person meeting would be an excellentvenue to work towards defining the priorities and strategies for the future ofthe Blue Genes community, as well as to engage a wider number of actorsWith the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)Peer reviewe

Blue Genes : Synopsis of the workshop organized by ICM-CSIC and BAU to increase engagement and collaboration for Our Ocean and Waters

7 pagesOn October 27th, 2022, the Institut de Ciències del Mar (ICM-CSIC), a marine research institution located in Barcelona, and the College of Arts & Design of Barcelona (BAU), a higher-education centre specialized in arts and design, co-organized the first Blue Genes meeting. This meeting took place virtually in a 3-hour workshop format and counted with more than 50 participants from different locations. Its main goal was to explore in a co-creative way how to reinforce and empower the engagement of people, particularly teenagers and young adults, with our Ocean and Waters and increase networking and collaboration. This meeting was the first workshop of a series of planned activities under the Blue Genes initiativePeer reviewe

Cellular mechanisms of antigen-specific immunotherapy of autoimmune disease

The ideal treatment of autoimmune diseases, such as Multiple Sclerosis, would be to specifically target the disease-causing immune cells without compromising the broader function of the immune system. This could be achieved by either deleting these cells or transform them into regulatory cells able to ameliorate disease. In the TCR-transgenic TG4 mouse model, where CD4+ T cells are specific for the myelin basic protein (MBP) Ac1-9 peptide, immunotherapy based on the administration of cognate peptide in escalating dose immunotherapy (EDI), induces tolerance in these myelin-specific CD4+ T cells and protects the animals from experimental autoimmune encephalomyelitis (EAE). In this thesis, three aspects of this method of tolerance induction are addressed. First, we demonstrate that antigen-specific peptide immunotherapy leads to an increase in the number of CD4+ Foxp3+ Treg cells and IL-10-secreting CD4+ T cells not just in secondary lymphoid structures, but in organs throughout the whole body. In addition to an increase in the number of CD4+ T cells with regulatory properties, effector T cells were prevented from entering the central nervous system (CNS). Analysis of changes to the phenotype of CD4+ T cells during EDI demonstrated that the inhibitory receptors TIM-3, TIGIT and PD-1 were significantly upregulated on both IL-10-secreting cells and Foxp3+ cells but no single receptor or a combination could be regarded as a biomarker for tolerised CD4+ T cells. In the second part, we demonstrate the important principle that tolerised CD4+ T cells can mediate regulation of not only T cells specific for the treatment peptide, but also CD4+ T cells that recognise immunodominant peptides from related proteins. We found that tolerised MBP-specific CD4+ T cells were able to exert linked bystander suppression of MOG35-55-reactive T cells in vivo, most successfully so when both peptides where presented by the same antigen-presenting cell. Finally, we reveal a previously unknown role for a subset of antigen-presenting cells with regulatory properties, known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in limiting immune responses after EDI. Although best known for their detrimental role as immunosuppressors in cancer, PMN-MDSCs could play a beneficial role in the treatment of autoimmune disease. We discovered that the number of PMN-MDSCs increases over the course of EDI. In vitro, these PMN-MDSCs inhibited CD4+ T cell proliferation in a cell contact-dependent manner, mediated by arginase-1. Upon adoptive transfer into untreated mice, PMN-MDSCs suppressed CD4+ T cell activation. The spleen might be a particularly important site for the function of PMN-MDSCs as the removal of the spleen abrogated not only the increase of PMN-MDSCs in other organs, but also reneged tolerance induction. Overall, this body of work not only contributes new insights into the changes in CD4+ T cell phenotype during EDI, it also reveals a new aspect of bystander suppression in autoimmune disease and, most importantly, unveils the discovery of an as-yet undescribed role for PMN-MDSCs in antigen-specific tolerance induction.Die ideale Behandlung von Autoimmunerkrankungen, wie die multiple Sklerose (MS), wäre die krankheitserzeugende Immunzelle anzusteuern ohne die generelle Funktion des Immunsystem zu beeinflussen. Dies könnte erreicht werden durch entweder die Beseitigung der pathogenen Zellen oder die Transformation dieser Zellen in krankheitsregulierende Immunzellen, die in der Lage sind die Krankheit zu mildern. In dem T-Zell-Antigenrezeptor transgenen Mausmodel Tg4, in dem die CD4+ T-Zellen spezifisch das Myelin-Basische-Proteinpeptid (MBP) Ac1-9 erkennen, Immuntherapie basierend auf der Verabreichung des Peptids MBPAc1-9 in steigenden Dosen (EDI) induziert Toleranz in diesen myelinspezifischen T-Zellen und verhindert die Entwicklung von experimenteller autoimmune Enzephalomyelitis (EAE), dem Tiermodell für MS. In dieser Dissertation werden drei Aspekte dieser Methode, Toleranz zu erreichen, addressiert. Als Erstes zeigten wir, dass antigen-spezifische Peptideimmuntherapie zu einem Anstieg in der Anzahl der CD4+ Foxp3+ regulatorischen T-Zellen und der Interleukin 10 (IL-10)-produzierenden CD4+ T-Zellen nicht nur in sekundären lymphoiden Strukturen führt sondern auch in Organen im ganzen Körper. Zusätzlich zu dem Anstieg von CD4+ T-Zellen mit regulierenden Eigenschaften, verhinderte die Behandlung die Migration von Effektor-T-Zellen in das zentrale Nervensystem (CNS). Die genauere Analyse des CD4+ T-Zellphänotyps während EDI zeigte, dass die Zelloberflächenrezeptoren TIM-3, TIGIT und PD-1 signifikant hochreguliert wurden in beiden IL-10-produzierenden Zellen und Foxp3+ T-Zellen aber das keiner der Rezeptoren oder eine Kombination der Rezeptoren als Biomarker für tolerisierte CD4+ T-Zellen fungieren kann. Im zweiten Teil weisen wir das wichtige Prinzip nach, dass tolerisierte CD4+ T-Zellen nicht nur T-Zellen regulieren, die spezifisch sind für das Peptid welches für die Behandlung gebraucht wurde, sondern auch CD4+ T-Zellen regulieren, die immundominante Peptide von verwandten Proteinen erkennen. Wir beobachteten, dass tolerisierte MBP-spezifische CD4+ T-Zellen in der Lage waren Bystander-Unterdrückung von MOG35-55-spezifischen CD4+ T-Zellen in vivo auszuüben, zumeist besser wenn beide Peptide von der gleichen antigenpräsentierenden Zelle präsentiert wurden. Zum Schluss deckten wir eine bisher noch nicht bekannte Rolle von einer Subpopulation von antigenpräsentierenden Zellen mit regulierenden Eigenschaften auf, bekannt als polymorphonukleare myeloide Unterdrückerzellen (PMN-MDSCs), die Immunantworten nach EDI hemmen. Obwohl bestens bekannt für ihre nachteilige Rolle als Immununterdrücker in Krebs, diese PMN-MDSCs könnten eine förderliche Rolle in der Behandlung von Autoimmunerkrankungen spielen. Wir stellten fest, dass die Anzahl von PMN-MDSCs steigt im Verlauf von EDI. In vitro Experimente zeigten, dass diese PMN-MDSCs zellkontaktabhängige CD4+ T-Zellenproliferation inhibieren, vermittelt durch das Enzym Arginase 1. PMN-MDSCs verhinderten T-Zellenaktivierung nach adoptiven Transfer in unbehandelte Mäuse. Die Milz könnte ein wichtiger Ort sein für die Funktion von PMN-MDSCs, weil die Entfernung der Milz nicht nur die Expansion der PMN-MDSCs in anderen Organen verhindert, sondern auch Toleranzinduzierung. Insgesamt liefert diese Dissertation nicht nur neue Einblicke in die Veränderungen des CD4+ T-Zellphänotyps im Verlauf von EDI, sondern zeigt auch einen neuen Aspekt von Bystander-Unterdrückung in Autoimmunerkrankungen auf. Aber noch viel bedeutender ist die Entdeckung einer noch nicht beschriebenen Rolle für PMN-MDSCs in antigenspezifischer Toleranzinduzierung

Fish Architecture : A framework to create Interspecies Spaces

Fish Architecture embraces the common spaces that we inhabit with aquatic animals. Here, we develop an approach to redesign these spaces as an interspecies collaboration. First, we should empathise with the non-human perspectives, while acknowledging limitations in understanding non-human perspectives of our mutual Umwelt. Next, we imagine new spaces that do not follow pre-existing human concepts. To achieve this in the framework of Fish Architecture, we merge the two disciplines art and science and apply their complementary methods to understand and imagine Interspecies Spaces. The Fishy Manifesto captures our process and explorations, as well as, offering a practical approach to coexistence. Fish Architecture is divided into three distinct phases, each offering room for observation and experimentation in different ecosystems. The third phase allows us to join aquatic and terrestrial life at the surface, paving a path to genuine ecological coexistence.publishe