Unimpaired Responses to Vaccination With Protein Antigen Plus Adjuvant in Mice With Kit-Independent Mast Cell Deficiency

Innate inflammatory responses are crucial for induction and regulation of T cell and antibody responses. Mast cell (MC)-deficient Kit mutant mice showed impaired adaptive immunity, suggesting that MCs provide essential adjuvant activities, and pharmacological MC activation was proposed as a new adjuvant principle. However, the Kit mutations result in complex alterations of the immune system in addition to MC deficiency. We revisited the role of MCs in vaccination responses using Mcpt5-Cre R26DTA/DTA and Cpa3Cre/+ mice that lack connective tissue MCs or all MCs, respectively, but feature an otherwise normal immune system. These animals showed no impairment of T and B cell responses to intradermal vaccination with protein antigen plus complete Freund’s adjuvant. Moreover, we demonstrate that the adjuvant effects of the MC secretagogue c48/80 in intradermal or mucosal immunization are independent of the presence of MCs. We hence find no evidence for a regulation by MCs of adaptive immune responses to protein antigens. The finding that immunological MC functions differ from those suggested by experiments in Kit mutants, emphasizes the importance of rigorous tests in Kit-independent MC-deficiency models

Three-Dimensional Light Sheet Fluorescence Microscopy of Lungs To Dissect Local Host Immune-Aspergillus fumigatus Interactions

The use of animal models of infection is essential to advance our understanding of the complex host-pathogen interactions that take place during Aspergillus fumigatus lung infections. As in the case of humans, mice need to suffer an immune imbalance in order to become susceptible to invasive pulmonary aspergillosis (IPA), the most serious infection caused by A. fumigatus. There are several immunosuppressive regimens that are routinely used to investigate fungal growth and/or immune responses in murine models of invasive pulmonary aspergillosis. However, the precise consequences of the use of each immunosuppressive model for the local immune populations and for fungal growth are not completely understood. Here, to pin down the scenarios involving commonly used IPA models, we employed light sheet fluorescence microscopy (LSFM) to analyze whole lungs at cellular resolution. Our results will be valuable to optimize and refine animal models to maximize their use in future research.Aspergillus fumigatus is an opportunistic fungal pathogen that can cause life-threatening invasive lung infections in immunodeficient patients. The cellular and molecular processes of infection during onset, establishment, and progression of A. fumigatus infections are highly complex and depend on both fungal attributes and the immune status of the host. Therefore, preclinical animal models are of paramount importance to investigate and gain better insight into the infection process. Yet, despite their extensive use, commonly employed murine models of invasive pulmonary aspergillosis are not well understood due to analytical limitations. Here, we present quantitative light sheet fluorescence microscopy (LSFM) to describe fungal growth and the local immune response in whole lungs at cellular resolution within its anatomical context. We analyzed three very common murine models of pulmonary aspergillosis based on immunosuppression with corticosteroids, chemotherapy-induced leukopenia, or myeloablative irradiation. LSFM uncovered distinct architectures of fungal growth and degrees of tissue invasion in each model. Furthermore, LSFM revealed the spatial distribution, interaction, and activation of two key immune cell populations in antifungal defense: alveolar macrophages and polymorphonuclear neutrophils. Interestingly, the patterns of fungal growth correlated with the detected effects of the immunosuppressive regimens on the local immune cell populations. Moreover, LSFM demonstrates that the commonly used intranasal route of spore administration did not result in complete intra-alveolar deposition, as about 80% of fungal growth occurred outside the alveolar space. Hence, characterization by LSFM is more rigorous than by previously used methods employing murine models of invasive pulmonary aspergillosis and pinpoints their strengths and limitations

Impact of web application support versus standard management on adherence with adjuvant hormone therapy in patients treated for breast cancer: the WEBAPPAC study

Abstract Background Non-metastatic breast cancer treatment is mainly based on surgery, with or without chemotherapy, radiotherapy and/or hormone therapy. To reduce the risk of hormone receptor positive (HR+) disease recurrence, hormone therapy is prescribed for at least 5 years. It may induce adverse drug reactions (ADRs) as joint pain, sexual dysfunction, weight increase, fatigue, mood disorders and vasomotor symptoms. Around 30–40% of patients withhold hormone therapy within 5 years after initiation. Based on encouraging results of mobile health in patient follow-up, we developed a web-application addressed for breast cancer patients initiating adjuvant hormonal therapy and aimed to assess its impact on hormone therapy adherence, ADRs management, and health-related quality of life. Methods The WEBAPPAC trial is a randomized, open-label, prospective, single-center phase 3 study aiming to assess the interest of a web-application support as compared to standard management among breast cancer patients initiating hormone therapy. The main endpoint is the proportion of patients with hormone therapy adherence failure within 18 months after treatment start, in each arm. Eligible patients will be 1:1 randomized between the WEBAPPAC web-application support (experimental arm,) or standard support (control arm), with stratification on type of hormone therapy (Aromatase inhibitor or Tamoxifen). We plan to enroll 438 patients overall. Failure to hormone therapy will be assessed using the Morisky 8-item self-questionnaire (MMSA8), patient adherence logbook, and medical consultations. Secondary outcomes include hormone therapy adherence at 6 months, pain (Visual Analogue Scale and Brief Pain Inventory), quality of life (EORTC QLQ-C30 and BR23 self-questionnaires), anxiety and depression (Hospital and Depression Scale), and return to work and/or daily activities. The user experience with the WEBAPPAC web-application will be assessed using the System Usability Scale (SUS) questionnaire. Discussion Hormone therapy discontinuation or adherence failure in breast cancer patients may be indirectly related to an increased risk of recurrence. A better control of medication adherence, through the detection of side effects and some proposed actions trying to reduce them, appears therefore essential to limit the risk of disease recurrence. The WEBAPPAC web-application thus aims better monitoring and allowing higher level of responsiveness in case of ADRs, thus improving treatment adherence. Trial registration NCT04554927, registered September 18, 2020. Protocol version Version 2.1 dated from December 21, 2021