Cryopreservation of mouse thymus depletes thymocytes but supports immune reconstitution on transplantation.

Cryopreservation of mouse thymus depletes donor thymocytes but preserves thymus function when transplanted after thawing into athymic mice. No differences in immune reconstitution were observed between fresh and frozen/thawed transplants suggesting that donor thymocyte depletion does not affect outcome. Thus, cryopreservation of thymus may improve outcomes in thymus transplant patients.

Time Trends, Regional Variation and Associations of Low-Allergy Formula Prescribing in England.

BACKGROUND: Cow's milk allergy (CMA) overdiagnosis appears to be increasing and is associated with excessive low-allergy formula prescription. We evaluated recent trends and regional variation in low-allergy formula prescribing for CMA in England, and assessed potential risk factors for higher prescribing rates. METHODS: Data on national and regional prescribing of low-allergy formulas were extracted from England's electronic prescription database using R. Region-level factors were evaluated for potential associations with regional low-allergy formula prescription rates using multivariate linear regression. Analysis of national prescribing trends covered 2007-2023, analysis of regional variation and region-level factors examined 2017-2019, prior to a re-organisation of the regional healthcare structure in England. RESULTS: Low-allergy formula prescribing increased from 6.1 to 23.3 L per birth nationally, between 2007 and 2023. Regional prescribing rate varied from 0.8 to 47.6 L per birth in 2017-2019. We found significant associations between regional low-allergy formula prescribing rate and regional prescribing rates for milk feed thickeners Gaviscon Infant and Carobel Instant (ß = 0.10, p < 0.01), and for other anti-reflux medications used in young children (ß = 0.89 p < 0.01). Inconsistent associations were seen with prescribing junior adrenaline auto-injectors and oral antibiotics. A model including these four variables accounted for 37% of regional variation in low-allergy formula prescribing rate. Region-level socio-economic deprivation, CMA guideline recommendations and paediatric allergy service provision were not associated with low-allergy formula prescribing. CONCLUSIONS: Low-allergy formula prescribing in England is increasing, varies significantly by region and is consistently associated with prescribing rates for milk feed thickeners and other anti-reflux medication for young children. Community prescribing behaviours may be important determinants of CMA overdiagnosis.

Subcutaneous adipose tissue: Implications in dermatological diseases and beyond.

Subcutaneous adipose tissue (SAT) is the deepest component of the three-layered cutaneous integument. While mesenteric adipose tissue-based immune processes have gained recognition in the context of the metabolic syndrome, SAT has been traditionally considered primarily for energy storage, with less attention to its immune functions. SAT harbors a reservoir of immune and stromal cells that significantly impact metabolic and immunologic processes not only in the skin, but even on a systemic level. These processes include wound healing, cutaneous and systemic infections, immunometabolic, and autoimmune diseases, inflammatory skin diseases, as well as neoplastic conditions. A better understanding of SAT immune functions in different processes, could open avenues for novel therapeutic interventions. Targeting SAT may not only address SAT-specific diseases but also offer potential treatments for cutaneous or even systemic conditions. This review aims to provide a comprehensive overview on SAT's structure and functions, highlight recent advancements in understanding its role in both homeostatic and pathological conditions within and beyond the skin, and discuss the main questions for future research in the field.

Lin-CD117+CD34+FcεRI+ progenitor cells are increased in chronic spontaneous urticaria and predict clinical responsiveness to anti-IgE therapy.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is mediated by mast cells which are absent from peripheral blood. However, lineage-CD34hiCD117int/hiFcεRI+ cells in blood have previously been shown to represent a mast cell precursor. METHODS: We enumerated FcεRI-, FcεRI+ and FcεRIhi lineage-CD34+CD117+ cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty-two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single-cell RNA sequencing (scRNA-Seq) on lineage-CD34hiCD117hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4). RESULTS: CSU patients had more lineage-CD34+CD117+FcεRI+ blood cells than controls. Lineage-CD34+CD117+FcεRI+ cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA-Seq revealed that lineage-CD34+CD117+FcεRI+ cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI- and FcεRI+ myeloid progenitors. CONCLUSION: Increased blood CD34+CD117+FcεRI+ cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti-IgE therapy, omalizumab.

HLA-DR+ regulatory T cells and IL-10 are associated with success or failure of desensitization outcomes.

BACKGROUND: Omalizumab (XOLAIR®)-assisted multi-food oral immunotherapy (mOIT) has been shown to safely, effectively, and rapidly desensitize patients with multiple food allergies. In our clinical trial (NCT02626611) on omalizumab-assisted mOIT, different desensitization outcomes (success or failure of desensitization) were observed following a period of either continued or discontinued mOIT. However, the association between the immunological changes induced by omalizumab-assisted mOIT and desensitization outcomes has not yet been fully elucidated. In this study, due to the key roles of regulatory T (Treg) cells and the type 2 helper T cell (Th2) pathway in immune tolerance to food allergens, we aimed to characterize their association with the desensitization outcomes of omalizumab-assisted mOIT. METHODS: Mass cytometry and multiplex cytokine assays were performed on blood samples obtained from participants with allergies to peanut, cashew, or milk in our phase 2 clinical study (NCT02626611). Comprehensive statistical and bioinformatic analyses were conducted on high-dimensional cytometry-based single-cell data and high-throughput multiplex cytokine data. RESULTS: Our results demonstrated that the frequency of HLA-DR+ Treg cells, and the production of Th2 cytokines (IL-4, IL-5, IL-13, and IL-9) as well as the immunoregulatory cytokine IL-10 by peripheral blood mononuclear cells (PBMCs) was significantly increased in cultures with allergen compared to cultures with media alone at baseline (Week 0). We also observed increased frequency of allergen responsive HLA-DR+ Treg cells and enhanced production of IL-10 by PBMCs in participants who achieved successful desensitization compared to those with failure of desensitization. However, the production of Th2 cytokines by PBMCs did not show significant differences between participants with different desensitization outcomes (success vs. failure of desensitization), despite omalizumab-assisted mOIT inducing a significant reduction in the production of Th2 cytokines. CONCLUSIONS: We demonstrated that the frequency of HLA-DR+ Treg cells and IL-10 cytokine production by PBMCs are associated with desensitization outcomes of omalizumab-assisted mOIT. These findings suggest potential immunological parameters that could be targeted to enhance desensitization success rates.

A History of Psycho-Neuro-Endocrine Immune Interactions in Rheumatic Diseases.

BACKGROUND: All active scientists stand on the shoulders of giants and many other more anonymous scientists, and this is not different in our field of psycho-neuro-endocrine immunology in rheumatic diseases. Too often, the modern world of publishing forgets about the collective enterprise of scientists. Some journals advise the authors to present only literature from the last decade, and it has become a natural attitude of many scientists to present only the latest publications. In order to work against this general unempirical behavior, neuroimmunomodulation devotes the 30th anniversary issue to the history of medical science in psycho-neuro-endocrine immunology. SUMMARY: Keywords were derived from the psycho-neuro-endocrine immunology research field very well known to the authors (R.H.S. has collected a list of keywords since 1994). We screened PubMed, the Cochran Library of Medicine, Embase, Scopus database, and the ORCID database to find relevant historical literature. The Snowballing procedure helped find related work. According to the historical appearance of discoveries in the field, the order of presentation follows the subsequent scheme: (1) the sensory nervous system, (2) the sympathetic nervous system, (3) the vagus nerve, (4) steroid hormones (glucocorticoids, androgens, progesterone, estrogens, and the vitamin D hormone), (5) afferent pathways involved in fatigue, anxiety, insomnia, and depression (includes pathophysiology), and (6) evolutionary medicine and energy regulation - an umbrella theory. KEY MESSAGES: A brief history on psycho-neuro-endocrine immunology cannot address all relevant aspects of the field. The authors are aware of this shortcoming. The reader must see this review as a viewpoint through the biased eyes of the authors. Nevertheless, the text gives an overview of the history in psycho-neuro-endocrine immunology of rheumatic diseases.

Assessment of the first presentations of common variable immunodeficiency in a large cohort of patients.

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations. METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated. RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) and diarrhea (19.1%). Patient sex, age of onset, and family history did not make significant differences in first presentations of this disease. CONCLUSION: pneumonia is the most common first presentation of CVID. Family history of CVID, the age of symptom onset, and sex made no differences in the first presentations of CVID.

Inborn Errors of Immunity and Efforts to Diagnose Affected Children in the Absence of Training and Specialty Practice in Clinical Immunology in Ethiopia: a Brief Report.

Four in five children with inborn errors of immunity globally remain undiagnosed. These figures are disproportionally high in low-income countries like Ethiopia. Apart from the inclusion of basic overviews of these disorders in to postgraduate pediatric curricula, little effort has been placed in to establishing clinical immunology training programs. This report summarizes the existing epidemiology of inborn errors of immunity in Ethiopia, unique presentations in Ethiopian children, challenges faced in diagnosing them, and efforts to improve their management.

From trained immunity in allergy to trained immunity-based allergen vaccines.

Innate immune cells experience long lasting metabolic and epigenetic changes after an encounter with specific stimuli. This facilitates enhanced immune responses upon secondary exposition to both the same and unrelated pathogens, a process termed trained immunity. Trained immunity-based vaccines (TIbV) are vaccines able to induce innate immune memory, thus conferring heterologous protection against a broad range of pathogens. While trained immunity has been well documented in the context of infections and multiple immune-mediated diseases, the role of innate immune memory and its contribution to the initiation and maintenance of chronic allergic diseases remains poorly understood. Over the last years, different studies attempting to uncover the role of trained immunity in allergy have emerged. Exposition to environmental factors impacting allergy development such as allergens or viruses induces the reprogramming of innate immune cells to acquire a more pro-inflammatory phenotype in the context of asthma or food allergy. Several studies have convincingly demonstrated that prevention of viral infections using TIbV contributes to reduce wheezing attacks in children, which represent a high-risk factor for asthma development later in life. Innate immune cells trained with specific stimuli might also acquire anti-inflammatory features and promote tolerance, which may have important implications for chronic inflammatory diseases such as allergies. Recent findings showed that allergoid-mannan conjugates, which are next generation vaccines for allergen-specific immunotherapy (AIT), are able to reprogram monocytes into tolerogenic dendritic cells by mechanisms depending on metabolic and epigenetic rewiring. A better understanding of the underlying mechanisms of trained immunity in allergy will pave the way for the design of novel trained immunity-based allergen vaccines as potential alternative strategies for the prevention and treatment of allergic diseases.

Scalp biomarkers during dupilumab treatment support Th2 pathway pathogenicity in alopecia areata.

BACKGROUND: The mechanisms driving alopecia areata (AA) are still unclear, hindering development of targeted therapeutics. Specific Th2 targeting with dupilumab in AA provides a unique opportunity to dissect its pathogenesis and explore the role of Th2 pathway. METHODS: We evaluated changes in scalp biomarkers in AA patients (with and without concomitant atopy) randomized to weekly dupilumab or placebo for 24 weeks, followed by open-label dupilumab for 24 weeks. Changes in biomarker levels were measured at weeks 12, 24, and 48 and were also correlated with clinical hair regrowth. RESULTS: At week 24, preceding clinical hair regrowth outcomes, only dupilumab-treated patients presented significant suppression of cellular infiltrates, and multiple Th2-related, markers (CCL13/MCP-4, CCL18/PARC, CCL26/eotaxin-3, CCL24/Eotaxin-2), coupled with significant upregulation in the hair keratins. Th1-related suppression was evident later (week 48) when all patients received open-label dupilumab. Results were more pronounced in atopic AA patients, that showed 48% and 97% improvements in the lesional AA scalp profile at weeks 24 and 48, respectively, while 2% worsening was seen in the placebo arm at week 24. Moreover, placebo-treated patients presented 54% worsening in hair keratins when compared with baseline at week 24. At week 24, increases in hair keratins showed significant correlations only with decreases in Th2-related markers. CONCLUSIONS: Scalp biomarkers provide evidence of dupilumab efficacy in AA, detected even prior to clinical response, with exclusive correlations between early suppression of Th2 markers and increased hair keratins. These findings strengthen previous reports suggesting a possible role for Th2 cytokines as AA drivers.

Adoptive transfer of ex vivo expanded regulatory T cells improves immune cell engraftment and therapy-refractory chronic GvHD.

Graft-versus-host disease (GvHD) is still the major non-relapse, life-limiting complication after hematopoietic stem cell transplantation. Modern pharmacologic immunosuppression is often insufficient and associated with significant side effects. Novel treatment strategies now include adoptive transfer of ex vivo expanded regulatory T cells (Tregs), but their efficacy in chronic GvHD is unknown. We treated three children suffering from severe, therapy-refractory GvHD with polyclonally expanded Tregs generated from the original stem cell donor. Third-line maintenance immunosuppression was tapered to cyclosporin A and low-dose steroids shortly before cell transfer. Regular follow-up included an assessment of the subjective and objective clinical development, safety parameters, and in-depth immune monitoring. All patients showed marked clinical improvement with substantially decreased GvHD activity. Laboratory follow-up showed a significant enhancement of the immunologic engraftment, including lymphocytes and dendritic cells. Monitoring the fate of Tregs by next-generation sequencing demonstrated clonal expansion. In summary, adoptive transfer of Tregs was well tolerated and able to modulate an established undesired T cell mediated allo-response. Although no signs of overimmunosuppression were detectable, the treatment of patients with invasive opportunistic infections should be undertaken with caution. Further controlled studies are necessary to confirm these encouraging effects and eventually pave the way for adoptive Treg therapy in chronic GvHD.

Effects of in-house and commercial extracts of the allergenic mite Tyrophagus putrescentiae on murine and human cell responses.

Mites are among the major sources of domestic and occupational allergens worldwide, and continuous exposure to these allergens leads to chronic airway inflammation. One of the most allergenic species is the storage mite Tyrophagus putrescentiae (Schrank). Protein extracts are produced from this mite for tests that help the clinical diagnosis (via prick test), treatment, and monitoring of disease progression in patients who had positive results for allergic reactions. Therefore, the aim of the present study was to evaluate the cell viability of RAW 264.7 and L929 cells when exposed to in-house raw protein extracts of T. putrescentiae compared to a commercial product, as well as quantify TNF-α secretion by RAW 264.7. Additionally, this study quantified the effect of these extracts in IgE secretion in total blood of people affected by this mite. The study found similarity between the in-house extract and the commercial extract as they had equivalent TNF-α secretion. Additionally, viabilities of RAW 264.7 and L929 exposed to the in-house extract were compatible with viabilities of cells exposed to the commercial extract, with no cytotoxicity at the concentrations tested. Results corroborated the hypothesis that the extract produced in-house would be equivalent to the commercial extract in allergic patients when the IgE was quantified. This study is the first to show the cytotoxicity of T. putrescentiae extracts, and to provide a quantitative analysis of TNF-α and IgE.

Frequency of guideline-defined cow's milk allergy symptoms in infants: Secondary analysis of EAT trial data.

BACKGROUND: Non-IgE-mediated Cow's Milk Allergy (CMA) has a prevalence of less than 1% in children. Guidelines developed to help non-specialists diagnose CMA may lead to misattribution of normal symptoms and contribute to overdiagnosis of CMA. We sought to establish the frequency of symptoms during infancy associated with non-IgE-mediated CMA, using the international Milk Allergy in Primary Care (iMAP) guideline as representative of CMA guidelines more generally. METHOD: Secondary analysis of the Enquiring About Tolerance (EAT) randomized controlled trial (ISRCTN 14254740; 1303 exclusively breastfed 3-month-old healthy infants). Key outcomes were ≥2 iMAP symptoms associated with 'mild-moderate' and 'severe' non-IgE-mediated CMA. RESULTS: Whilst breastfeeding and parental atopy rates were higher than the general population, participants were otherwise similar to the population of England and Wales. Two or more non-IgE CMA symptoms were reported by 25% families for mild-moderate and 1.4% for severe symptoms each month between ages 3 and 12 months, peaking at 38% with ≥2 mild-moderate and 4.3% ≥2 severe symptoms at three months, when participants were not directly consuming cow's milk. 74% of participants reported ≥2 mild-moderate symptoms and 9% ≥2 severe symptoms in at least one month during this period. At six months there was no evidence of difference in the proportion of children with ≥2 symptoms between those consuming (29.5% mild-moderate, 1.8% severe) and not consuming cow's milk (35.3% mild-moderate, 2.2% severe). Mean monthly reporting of ≥2 symptoms was also no different between those with (15.8% mild-moderate, 1.1% severe) or without eczema at baseline (16.7% mild-moderate, 1.3% severe). CONCLUSIONS: Guideline-defined symptoms of non-IgE-mediated CMA are very common in infants. Guidelines may promote milk allergy overdiagnosis by labelling normal infant symptoms as possible milk allergy.

National Survey of United Kingdom Paediatric Allergy Services.

BACKGROUND: Comprehensive national assessments of paediatric allergy services are rarely undertaken, and have never been undertaken in the United Kingdom. A 2006 survey estimated national capacity at 30,000 adult or paediatric new allergy appointments per year and identified 58 hospital clinics offering a paediatric allergy service. OBJECTIVE: The UK Paediatric Allergy Services Survey was the first comprehensive assessment of UK paediatric allergy service provision. METHODS: All 450 UK hospitals responded to a survey. Paediatric allergy services are provided in 154 lead hospitals with 75 further linked hospitals. All 154 lead paediatric allergy services completed a detailed questionnaire between February 2019 and May 2020. RESULTS: The 154 paediatric allergy services self-define as secondary (126/154, 82%) or tertiary (28/154, 18%) level services. The annual capacity is 85,600 new and 111,400 follow-up appointments. Fifty-eight percent (85/146) of services offer ≤10 new appointments per week (no data provided from 8 services-2 no response, 6 unknown) and 50% (70/139) of the services undertaking challenges undertake ≤2 food or drug challenges per week (no data from 3 challenge services). Intramuscular adrenaline is rarely used during challenges-median annual frequency 0 in secondary services and 2 in tertiary services. Allergen-specific immunotherapy is offered in 39% (60/154) of services, with 71% (41/58) of these centres treating ≤10 patients per annum (no data from 2 immunotherapy services). The 12 largest services see 31% of all new paediatric allergy appointments, undertake 51% of new immunotherapy patient provision and 33% of food or drug challenges. Seventy percent (97/126) of secondary and all tertiary services are part of a regional paediatric allergy network. Only nine services offer immunotherapy for any food (3 for peanut), 10 drug desensitization and 18 insect venom immunotherapy. CONCLUSIONS: There has been a fourfold increase in paediatric allergy clinics and an approximately sevenfold increase in new patient appointment numbers in the United Kingdom over the past 15 years. Most services are small, with significant regional variation in availability of specific services such as allergen immunotherapy. Our findings emphasize the need for national standards, local networks and simulation training to ensure consistent and safe service provision.

Cluster analysis of nasal cytokines during rhinovirus infection identifies different immunophenotypes in both children and adults with allergic asthma.

BACKGROUND: Infection with rhinovirus (RV) is a major risk factor for disease exacerbations in patients with allergic asthma. This study analysed a broad set of cytokines in the noses of children and adults with asthma during RV infection in order to identify immunophenotypes that may link to virus-induced episodes. METHODS: Nasal wash specimens were analysed in children (n = 279 [healthy, n = 125; stable asthma, n = 64; wheeze, n = 90], ages 2-12) who presented to a hospital emergency department, and in adults (n = 44 [healthy, n = 13; asthma, n = 31], ages 18-38) who were experimentally infected with RV, including a subset who received anti-IgE. Cytokines were measured by multiplex bead assay and data analysed by univariate and multivariate methods to test relationships to viral load, allergic status, airway inflammation, and clinical outcomes. RESULTS: Analysis of a core set of 7 cytokines (IL-6, CXCL8/IL-8, IL-15, EGF, G-CSF, CXCL10/IP-10 and CCL22/MDC) revealed higher levels in children with acute wheeze versus those with stable asthma or controls. Multivariate analysis identified two clusters that were enriched for acutely wheezing children; one displaying high viral load ("RV-high") with robust secretion of CXCL10, and the other displaying high IgE with elevated EGF, CXCL8 and both eosinophil- and neutrophil-derived mediators. Broader assessment of 39 cytokines confirmed that children with acute wheeze were not deficient in type 1 anti-viral responses. Analysis of 18 nasal cytokines in adults with asthma who received RV challenge identified two clusters; one that was "RV-high" and linked to robust induction of anti-viral cytokines and anti-IgE; and the other associated with more severe symptoms and a higher inflammatory state featuring eosinophil and neutrophil factors. CONCLUSIONS: The results confirm the presence of different immunophenotypes linked to parameters of airway disease in both children and adults with asthma who are infected with RV. Such discrepancies may reflect the ability to regulate anti-viral responses.

Physical exercise, immune response, and susceptibility to infections-current knowledge and growing research areas.

This review presents state-of-the-art knowledge and identifies knowledge gaps for future research in the area of exercise-associated modifications of infection susceptibility. Regular moderate-intensity exercise is believed to have beneficial effects on immune health through lowering inflammation intensity and reducing susceptibility to respiratory infections. However, strenuous exercise, as performed by professional athletes, may promote infection: in about half of athletes presenting respiratory symptoms, no causative pathogen can be identified. Acute bouts of exercise enhance the release of pro-inflammatory mediators, which may induce infection-like respiratory symptoms. Relatively few studies have assessed the influence of regularly repeated exercise on the immune response and systemic inflammation compared to the effects of acute exercise. Additionally, ambient and environmental conditions may modify the systemic inflammatory response and infection susceptibility, particularly in outdoor athletes. Both acute and chronic regular exercise influence humoral and cellular immune response mechanisms, resulting in decreased specific and non-specific response in competitive athletes. The most promising areas of further research in exercise immunology include detailed immunological characterization of infection-prone and infection-resistant athletes, examining the efficacy of nutritional and pharmaceutical interventions as countermeasures to infection symptoms, and determining the influence of various exercise loads on susceptibility to infections with respiratory viruses, including SARS-CoV-2. By establishing a uniform definition of an "elite athlete," it will be possible to make a comparable and straightforward interpretation of data from different studies and settings.

High-dose pollen intralymphatic immunotherapy: Two RDBPC trials question the benefit of dose increase.

BACKGROUND: The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies evaluated if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. METHODS: Two randomized double-blind placebo-controlled trials of ILIT for grass pollen-induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000-3000-10,000 (5000 + 5000 with 30 minutes apart) SQ-U with 1 month in between was evaluated. RESULTS: Doses up to 10,000 SQ-U were safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass-specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified up-dosing schedule; 1000-3000-3000 SQ-U appeared to be safe but failed to improve the CSMS. Flow cytometry analyses showed increased activation of lymph node-derived dendritic but not T cells. Quality of life and nasal provocation response did not improve in any study. CONCLUSION: Intralymphatic immunotherapy in high doses after SCIT appears to further reduce grass pollen-induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3000 SQ-U should be avoided.

Humoral and cellular immune response to severe acute respiratory syndrome coronavirus-2 vaccination in haemodialysis and kidney transplant patients.

End-stage renal disease (ESRD) patients are amongst the vulnerable groups and thus prioritized in the Coronavirus disease-2019 vaccination programmes. However, this cohort was excluded from vaccine-trials and yet shares the same vaccination scheme with the general population. Here, we explore trends of immune response-proportions amongst ESRD patients on renal replacement therapy for up to 4 weeks post-vaccination completion with Pfizer/Moderna vaccines. From inception to 10 July 2021, we searched six online-databases for articles reporting humoral and cellular immune response proportions for up to 4 weeks post booster-vaccination. We pooled the responders' proportions by meta-analysis and conducted a meta-regression stratifying outcomes by significant confounders. Twenty-seven eligible studies reported 2789 ESRD patients. 1337, 1452 and 477 were on haemodialysis, received kidney transplantation, and healthy controls, respectively. Haemodialysis patients' proportions of humoral and cellular immune responses varied from 87.29% (80.77-93.81)-88.78% (86.76-90.80) and 62.86% (56.56, 69.17)-85.78% (78.99, 92.57), respectively, between first- and fourth-weeks. Kidney transplant patients' proportions of humoral and cellular immune responses ranged from 2.6% (0.06-13.48)-29.87% (27.68, 32.07) and 5.13% (0.63-17.3)-59.84% (54.57-65.10), respectively, between first- and fourth-weeks. All healthy controls maintained ≥93% proportions of both responses throughout the follow-up. Study design and country of study influenced the pooled response proportions. Conclusively, haemodialysis and kidney transplant patients have lower proportions of humoral and cellular immune responses than healthy controls. However, haemodialysis patients' response proportions improve, reaching near healthy-control levels by the fourth week. Kidney transplant patients' lower responses' proportions also improve but remain significantly lower than healthy controls throughout four-weeks. The "one-size-fits-all" vaccination scheme might be inadequate for kidney transplant patients.

Antibody and T Cell Response to SARS-CoV-2 Messenger RNA BNT162b2 Vaccine in Kidney Transplant Recipients and Hemodialysis Patients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in patients with ESKD, and vaccination is hoped to prevent infection. METHODS: Between January 18 and February 24, 2021, 225 kidney transplant recipients (KTRs) and 45 patients on hemodialysis (HDPs) received two injections of mRNA BNT162b2 vaccine. The postvaccinal humoral and cellular response was explored in the first 45 KTRs and ten HDPs. RESULTS: After the second dose, eight HDPs (88.9%) and eight KTRs (17.8%) developed antispike SARS-CoV-2 antibodies (P<0.001). Median titers of antibodies in responders were 1052 AU/ml (IQR, 515-2689) in HDPs and 671 AU/ml (IQR, 172-1523) in KTRs (P=0.40). Nine HDPs (100%) and 26 KTRs (57.8%) showed a specific T cell response (P=0.06) after the second injection. In responders, median numbers of spike-reactive T cells were 305 SFCs per 106 CD3+ T cells (IQR, 95-947) in HDPs and 212 SFCs per 106 CD3+ T cells (IQR, 61-330) in KTRs (P=0.40). In KTRs, the immune response to BNT162b2 seemed influenced by the immunosuppressive regimen, particularly tacrolimus or belatacept. CONCLUSION: Immunization with BNT162b2 seems more efficient in HDPs, indicating that vaccination should be highly recommended in these patients awaiting a transplant. However, the current vaccinal strategy for KTRs may not provide effective protection against COVID-19 and will likely need to be improved.

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury.

BACKGROUND: The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI). METHODS: We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of ß2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling. RESULTS: In vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue. CONCLUSIONS: The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.