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.

Limited beneficial effects of systemic steroids when added to standard of care treatment of seasonal allergic rhinitis.

Intramuscular injections with methylprednisolone treating allergic rhinitis (AR) have a long history. Modern guidelines are designed to dissuade this treatment, but it´s frequently used, especially in primary care. This despite of concern for side effects and lack of modern placebo-controlled studies. This study was designed to evaluate if methylprednisolone, could significantly improve symptoms of birch pollen induced AR and reduce the concomitant use of standard of care medication. Forty-two patients with birch pollen induced AR were randomized to treatment with methylprednisolone (80 mg) or placebo (NaCl 0.9%). Daily symptom- and medication scores was registered for 3 weeks. Quality of life questionnaires Sino-nasal Outcome Test-22 (SNOT-22) and Juniper Rhinoconjunctivitis Quality of Life Questionaire (Juniper RQLQ) were registered at trial start and at the end of the 3 weeks period. The combined symptom- and medication scores indicate that the methylprednisolone treated group [mean Area Under the Curve (AUC) 37.1 (SD 16.2 (95% CI 29.9-44.6))] was significantly better off than the placebo group [mean AUC 49.1 (SD 10.1 (95% CI 44.5-53.7))], p = 0.008. No significant difference between the groups were found in the SNOT-22 and Juniper RQLQ analysis. Registered side effects were few and mild. The limited beneficial effects of systemic steroids when added to standard of care in combination of its potential risk for side effects, speaks against its use for treatment of severe seasonal allergic rhinitis. The lack of difference in quality-of-life further underscores this result.

A prolonged innate systemic immune response in COVID-19.

Despite the introduction of vaccines, COVID-19 still affects millions of people worldwide. A better understanding of pathophysiology and the discovery of novel therapies are needed. One of the cells of interest in COVID-19 is the neutrophil. This cell type is being recruited to a site of inflammation as one of the first immune cells. In this project, we investigated a variety of neutrophils phenotypes during COVID-19 by measuring the expression of markers for migration, maturity, activation, gelatinase granules and secondary granules using flow cytometry. We show that neutrophils during COVID-19 exhibit altered phenotypes compared to healthy individuals. The activation level including NETs production and maturity of neutrophils seem to last longer during COVID-19 than expected for innate immunity. Neutrophils as one of the drivers of severe cases of COVID-19 are considered as potential treatment targets. However, for a successful implementation of treatment, there is a need for a better understanding of neutrophil functions and phenotypes in COVID-19. Our study answers some of those questions.

Increased IL-26 associates with markers of hyperinflammation and tissue damage in patients with acute COVID-19.

Interleukin-26 (IL-26) is released by several immune and structural cells following stimulation of toll-like receptors (TLRs), whereupon it can directly inhibit viral replication and enhance neutrophil chemotaxis. Given these unique properties, IL-26 has emerged as an intriguing mediator of host defense in the lungs. However, the role of IL-26 in COVID-19 has not been thoroughly investigated. Here, we characterized the involvement of IL-26 in the hyperinflammation and tissue damage that occurs in patients with acute COVID-19. We found that IL-26 is markedly increased in blood samples from these patients, and that the concentration of IL-26 correlates with those of the neutrophil-mobilizing cytokines IL-8 and TNFα, respectively. Moreover, the increase in blood IL-26 correlates with enhanced surface expression of the "don't eat me" signal CD47 on blood neutrophils isolated from patients with acute COVID-19. Finally, we found that the blood concentration of IL-26 correlates with that of increased lactate dehydrogenase, an established marker of tissue damage, and decreased mean corpuscular hemoglobin (MCH), a previously verified hematological aberration in COVID-19, both of which are associated with severe disease. Thus, our findings indicate that increased systemic IL-26 associates with markers of hyperinflammation and tissue damage in patients with acute COVID-19, thereby forwarding the kinocidin IL-26 as a potential target for diagnosis, monitoring, and therapy in this deadly disease.

Intra-colonic administration of the TLR7 agonist R-848 induces an acute local and systemic inflammation in mice.

Imidazoquinoline compounds, such as resiquimod (R-848), are well known topically active immune modifiers that bind to toll-like receptor 7 (TLR7). The aim of this study was to characterize the R-848 induced inflammatory response in mice and to validate the response using methyl-prednisolone and anti-TNF antibody. Intra-colonic application of R-848 to BALB/c mice induced a systemic transient elevation of TNF, CXCL1, IL-6, and IL-12p40 and a colonic elevation of cytokines/chemokines and iNOS, without infiltration of immune cells or epithelial destruction. Treatment with methyl-prednisolone or anti-TNF antibody attenuated the systemic (TNF, IL-6, IL-12p40, and CXCL1) and local (colonic TNF and iNOS mRNA expression) response induced by R-848. In summary, intra-colonic administration of R-848 induces an acute systemic and local inflammatory response, which can be attenuated by steroids or anti-TNF antibody. We suggest that the R-848 inflammatory model can be useful in future validation of new drugs for gastrointestinal inflammatory conditions.

Dextran sulphate sodium induces acute colitis and alters hepatic function in hamsters.

Dextran sulphate sodium (DSS)-induced colitis in rodents is an experimental model for human inflammatory bowel disease (IBD). The aim of this study was to characterize the effect of DSS in hamster colon and liver. DSS (2-5%) was administrated in the drinking water for 4-6 days. Clinical symptoms were recorded daily, inflammatory and fatty acid-related metabolic markers were assessed in plasma, colon and liver. Six days of 3 or 5% DSS induced a severe wasting disease, whereas 2.5% DSS induced a colonic inflammation without severe systemic adverse effects. The systemic inflammatory response was characterized by an inverse production of albumin and the acute phase protein haptoglobin. The colonic inflammatory response was confined to the proximal colon, manifested by a high macroscopic inflammatory score, increased colon weight and expression of IL-1beta, IL-6 and iNOS, infiltration of inflammatory cells and epithelial disruption. In contrast, only a low/mild inflammatory response was observed in the distal colon of DSS-exposed hamsters. Significant hepatic-related metabolic alterations were also observed, with elevation of plasma triglycerides and increased liver expression of lipoprotein lipase and reduced expression of acyl-CoA oxidase and cytochrome P450A. Although liver weight was significantly reduced, no histopathological signs of inflammation or tissue damage were observed. In summary, hamsters exposed to 2.5% DSS for 6 days develop acute colitis resembling murine DSS-induced colitis. In addition, DSS-exposed hamster showed alterations in hepatic fatty acids metabolism resembling human IBD, suggesting that the model can potentially be used for target discovery and validation of hepatic-related metabolic alterations.

Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease.

Dextran sulfate sodium (DSS)-induced colitis is one of the most frequently used rodent models for inflammatory bowel disease (IBD). The aim of this study was to validate the murine DSS-induced colitis model using four therapeutic agents for IBD. C57BL/6 mice were exposed to 3% DSS for 5days followed by 7-9 days of water (acute inflammation) or 20-31 days of water (chronic phase). Clinical symptoms, plasma and colonic inflammatory markers and histology were assessed for the efficacy of cyclosporine A (CsA), methotrexate or anti-IL-12p40 in acute colitis and of anti-IL-12p40 or an agonistic anti-CD3 antibody in chronic colitis. Cyclosporine A and anti-IL-12p40 (in the acute phase) and anti-CD3 (in the chronic phase) treatment attenuated local cytokine levels, improved clinical symptoms (CsA and anti-IL-12p40) and histology (CsA and anti-CD3). Further, anti-IL-12p40 treatment was partly efficacious in the chronic phase, whereas methotrexate showed no efficacy in the acute colitis. Thus, three of the current tested agents showed efficacy in the disease model, arguing that DSS-induced colitis can be used as a relevant model for the translation of mice data to human disease.

Teenagers with type 1 diabetes--a phenomenological study of the transition towards autonomy in self-management.

BACKGROUND: Becoming autonomous is an important aspect of teenagers' psychosocial development, and this is especially true of teenagers with type 1 diabetes. Previous studies exploring the everyday problems of teenagers with diabetes have focused on adherence to self-care management, how self-determination affects metabolic control, and the perception of social support. OBJECTIVE: The aim of the study was to elucidate lived experiences, focusing on the transition towards autonomy in diabetes self-management among teenagers with type 1 diabetes. DESIGN AND METHOD: Data were collected using interviews, and a qualitative phenomenological approach was chosen for the analysis. PARTICIPANTS: Thirty-two teenagers (18 females and 14 males) were interviewed about their individual experiences of self-management of diabetes. FINDINGS: The lived experiences of the transition towards autonomy in self-management were characterized by the over-riding theme "hovering between individual actions and support of others". The findings indicate that individual self-reliance and confirmation of others are helpful in the transition process. Growth through individual self-reliance was viewed as a developmental process of making one's own decisions; psychological maturity enabled increased responsibility and freedom; motivation was related to wellbeing and how well the diabetes could be managed. The theme "confirmation of others" showed that parental encouragement increased the certainty of teenagers' standpoints; peers' acceptance of diabetes facilitated incorporation of daily self-management activities; support from the diabetes team strengthened teenagers' self-esteem. CONCLUSION: In striving for autonomy, teenagers needed distance from others, but still to retain the support of others. A stable foundation for self-management includes having the knowledge required to practice diabetes management and handle different situations.

Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation.

Exposure to dextran sulfate sodium (DSS) induces acute colitis, which is normally resolved after DSS removal. To study chronicity, mice are typically subjected to three to five cycles of weekly DSS exposures, each followed by a 1- to 2-wk rest period. Here, we describe a novel and convenient way of inducing chronic, progressive colitis by a single exposure to DSS. C57BL/6 mice exposed to DSS for 5 days developed acute colitis that progressed to severe chronic inflammation. The plasma haptoglobin levels remained high during the chronic phase, showing that the inflammation was active. Surprisingly, the mice regained their original weight along with the progression of colitis, and the only apparent symptom was loose feces. Histopathological changes 4 wk after DSS removal were dense infiltrates of mononuclear cells, irregular epithelial structure, and persistent deposits of collagen. A progressive production of the cytokines IL-1beta, IL-12 p70, and IL-17 correlated with the extensive cellular infiltration, whereas high IFN-gamma production was mainly found late in the chronic phase. Similar to C57BL/6 mice, BALB/c mice exposed to 5 days of DSS developed acute colitis as previously described. The acute colitis was accompanied by elevated plasma levels of haptoglobin and increased colonic levels of IL-1alpha/beta, IL-6, IL-18, and granulocyte colony-stimulating factor. However, soon after DSS removal, BALB/c mice recovered and were symptom free within 2 wk and completely recovered 4 wk after DSS removal in terms of histopathology, haptoglobin levels, and local cytokine production. In summary, these data stress the effect of genetic background on the outcome of DSS provocation. We believe that the present protocol to induce chronic colitis in C57BL/6 mice offers a robust model for validating future therapies for treatment of inflammatory bowel disease.

Shame-inducing encounters. Negative emotional aspects of sickness-absentees' interactions with rehabilitation professionals.

There is little knowledge on how sickness absentees experience encounters with rehabilitation professionals. This paper explores and describes negative emotions ("shame" in a broad sense) experienced by individuals on sick leave in their interactions with rehabilitation professionals. We performed a qualitative analysis of data from five focus-group interviews. The participants had experience of sickness absence with back diagnoses and discussed factors that facilitate or impede return to work. Reports of demeaning experiences in encounters with rehabilitation workers were frequent and could be divided into two major categories: 1) subjects perceived the behavior of rehabilitation professionals as distanced in a negative way, and felt that they were treated in an indifferent and nonchalant manner or fairly routinely; 2) subjects felt that they were disqualified, which included being discredited or belittled. This explorative study indicates the need for further, more directed investigations of emotional aspects of interactions between sickness absentees and rehabilitation professionals.