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关键词： Asthma   benralizumab   IL-5   mepolizumab   mast cells   mast cell progenitors  

摘要： Background: Therapies targeting IL-5 or its receptor (IL-5Ra) are currently used to treat patients with severe eosinophilic asthma. Objective: We sought to investigate the impact of anti-IL-5 and anti-IL-5Ra biological therapies on mast cells (MCs) and their progenitors. Methods: Surface IL-5Ra expression was investigated on MCs and their progenitors in mouse lungs and bone marrow and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma before and after anti-IL-5 (mepolizumab) or anti-IL-5Ra (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Ra therapy. Results: Approximately 50% of the human primary lung MCs and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Ra. In patients with mild to moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Ra1 MC progenitors was elevated. In addition, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Furthermore, patients with severe asthma from 2 independent cohorts demonstrated a reduction in blood MC progenitors after anti-IL-5 or anti-IL-5Ra treatment. This was associated with improved asthma control as well as a decline in both blood eosinophils and TH2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Ra (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. Conclusions: This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Ra in severe asthma may also involve reduction of MC populations. (J Allergy Clin Immunol 2025;155:1310-20.)

关键词： Cytomegalovirus   UL54 mutation   Letermovir   Hematopoietic stem cell transplant   Inborn error of immunity  

摘要： Cytomegalovirus (CMV) infection remains one of the most common and challenging post-transplant infections. Children with inborn errors of immunity (IEI) and T-cell dysfunction are at high risk for CMV infection, which can be complicated by refractory and/or resistant cases. This case describes a Nepalese girl with MHC class II deficiency, who presented at 3 months of age with CMV and Pneumocystis jirovecii pneumonia. Hematopoietic stem cell transplantation (HSCT) was planned as a curative treatment for IEI. Initial antiviral therapy with ganciclovir, followed by foscarnet, achieved undetectable CMV viral loads. However, the viral load rebounded during foscarnet therapy. HSCT was performed at 7 months of age using peripheral blood stem cells from her CMV-seropositive father, despite the recipient's high CMV viral load. Empiric combination therapy with cidofovir (an unapproved drug in Japan), foscarnet, leflunomide, and artesunate was initiated. CMV genetic testing revealed UL54 mutations conferring high-level resistance to foscarnet and moderate-level resistance to ganciclovir. The regimen was adjusted to letermovir, ganciclovir, leflunomide, and artesunate, which successfully suppressed the viral load following engraftment. At three months post-HSCT, combination therapy was discontinued after sustained undetectable CMV viral loads. Although CMV infection was controlled, the patient died from idiopathic pulmonary hemorrhage at five months post-HSCT. This case highlights the potential efficacy of a letermovir-inclusive therapy regimen in managing drug-resistant CMV with UL54 mutations in a pediatric HSCT recipient.

关键词： COVID-19   acute respiratory distress syndrome   dexamethasone   IL-6 inhibitor   tocilizumab  

摘要： Background During the COVID-19 pandemic, treatment strategies evolved rapidly. The RECOVERY trial established corticosteroids as the standard care for reducing mortality in COVID-19 patients. However, some critical care clinicians began using doses higher than those recommended in *** To characterize the use of high-dose corticosteroids and IL-6 inhibitors in critically ill COVID-19 patients and examine their association with adverse drug events (ADEs).Methods A retrospective cohort study of 320 electronic health records (January 1, 2020 - June 30, 2022) was conducted on COVID-19 patients requiring high-flow oxygen or mechanical ventilation. Patients were categorized based on corticosteroid dose: "high dose dexamethasone" (daily dose greater than 12 mg and/or for longer than 10 days), "low dose dexamethasone" (daily dose 12 mg or less for 10 days or less), and "no dexamethasone" (no corticosteroid therapy). Subgroups were created based on IL-6 inhibitor *** High-dose dexamethasone was associated with increased odds of ADEs compared to low dose (OR 2.55, 95% CI 1.45 to 4.49) and no dexamethasone (OR 6.29, 95% CI 2.08 to 19.03). No additional efficacy benefit was observed in patients receiving high dose corticosteroids when compared to low dose corticosteroids. Patients receiving both an IL-6 inhibitor and high-dose dexamethasone had further increased odds of ADEs. High-dose dexamethasone was also associated with increased mortality compared to low dose (OR 3.78, 95% CI 1.97-7.25) and no dexamethasone (OR 15.22, 95% CI 3.27-70.74).Conclusions Acknowledging the risk for residual confounding, higher doses of dexamethasone were associated with increased ADEs and mortality. These findings highlight the need for careful consideration of the use of high-dose dexamethasone.

摘要： Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.

关键词： endometritis   alloferon   NLRP3   CASP1   IL-1 beta  

摘要： Endometritis is an inflammatory reaction of the uterine lining that can lead to infertility. Alloferon, a linear non-glycosylated oligopeptide, has been recognized for its potent anti-inflammatory and immunomodulatory effects. In light of these attributes, this study aims to explore the potential therapeutic effects of alloferon in alleviating endometrial inflammation induced by lipopolysaccharide (LPS), while elucidating the underlying protective mechanisms. Two conditions representing pre- and post-menopause states were simulated using an ovariectomized (Ovx) murine model. The findings underscore alloferon's remarkable capacity to alleviate cardinal signs of endometritis, including redness, swelling, and congestion, while concurrently restoring the structural integrity of the endometrial tissue. Moreover, alloferon effectively modulates the expression of key inflammatory mediators, such as nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), cysteine aspartate-specific protease 1 (CASP1), interleukin-1 beta (IL-1 beta), and interleukin-18 (IL-18). In vitro experiments were conducted to further corroborate and validate these findings. In conclusion, alloferon shows promising potential in mitigating LPS-induced inflammation by attenuating the NLRP3/CASP1/IL-1 beta/IL-18 signaling cascade.

关键词： HLA-C*15:292   HLA-C*15:02:01   next-generation sequencing  

摘要： HLA-C*15:292 differs from HLA-C*15:02:01 by a G>A substitution in exon 2.

摘要： Anti-interleukin 17 use has been associated with a higher risk of candidiasis, as this cytokine is involved in maintaining mucosal barriers and orchestrating immune responses to fungal pathogens. We performed a real-life retrospective multicentre study aiming to assess the risk of candidiasis in patients undergoing treatment with bimekizumab at labelled dosage for psoriasis, for at least 16 weeks.