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The MUGEN mouse database (MMdb) (www.mugen-noe.org/database/) is a database of murine models of immune processes and immunological diseases. Its aim is to share and publicize information on mouse strain characteristics and availability from participating institutions. MMdb's basic classification of models is based on three major research application categories: Models of Human Disease, Models of Immune Processes and Transgenic Tools. Data on mutant strains includes detailed information on affected gene(s), mutant allele(s) and genetic background (DNA origin, gene targeted, host and backcross strain background). Each gene/transgene index also includes IDs and direct links to Ensembl, ArrayExpress, EURExpress and NCBI's Entrez Gene database. Phenotypic description is standardized and hierarchically structured, based on MGI's mammalian phenotypic ontology terms. Availability (e.g. live mice, cryopreserved embryos, sperm and ES cells) is clearly indicated, along with handling and genotyping details (in the form of documents or hyperlinks) and all relevant contact information (including EMMA and Jax/IMSR hyperlinks where available). MMdb's design offers a user-friendly query interface and provides instant access to the list of mutant strains and genes. Database access is free of charge and there are no registration requirements for data querying.
Development of new vaccine platforms against viral diseases is considered urgent. In recent years, mRNA constructs have attracted great interest in this field due to unique advantages over conventional gene transfer platforms. In the present study, we developed a new naked conventional mRNA vaccine expressing the non-optimized small (S) segment of the Ank-2 strain of Crimean-Congo Hemorrhagic Fever virus (CCHFV). We then analyzed its single and booster dose immunogenicity and protection potential in the challenge assay in two mice models, including IFNα/β/γR-/- and C57BL/6. The results obtained from the immunological assays, namely IL-4 and IFN-gamma ELISPOT, intracellular IFN-gamma staining, in-house sandwich ELISA, and survival data, demonstrated that our construct elicited the production of anti-nucleocapsid (N) specific immune responses in both mice models. A 100% protection rate was only obtained in the booster dose group of IFNα/β/γR-/- mice, indicating that this platform needs further optimization in future studies. In conclusion, we assessed a novel approach in CCHFV vaccination by introducing a conventional mRNA platform which can be considered in future experiments as an efficient and safe way to battle this disease.
Endometriosis is an estrogen-dependent gynecological disease with chronic pelvic inflammation. In order to study the pathophysiology of endometriosis and examine the therapeutic effects of new pharmaceuticals for endometriosis treatment, different animal models had been developed in the last two decades, especially mouse models. However, no study evaluated the effects of various modeling approaches on pathology and immunology in endometriosis. This study aimed to compare endometriotic lesion development and immune profiles under different methods of establishing endometriosis models in mice, including estrus synchronization (ovariectomy with estrogen supplement versus male urine-soaked transfer bedding), endometrium preparations (whole uterus including endometrium and myometrium fragments versus solely endometrium fragments), and surgical transplantation (subcutaneous transplantation versus intraperitoneal injection). Our results showed that lesion growth under estrus synchronization by ovariectomy with estrogen supplement had a higher success rate and more proliferative endometrium, apart from higher body weight gain. Immune responses in peripheral blood were similar in the whole uterus and solely endometrium fragments and in intraperitoneal injection and subcutaneous transplantation, but a more innate immune response in the peritoneal microenvironment was found in solely endometrium fragments and intraperitoneal injection than counterparts. In conclusion, different endometriosis modeling methods result in different pathological and immunological features. Ovariectomy with estrogen supplement, solely endometrium fragments, and intraperitoneal injection are more suitable for both pathological and immunological studies of endometriosis in mice, which are important for mechanistic studies and immunotherapy development.
Alzheimer's disease (AD) is the most prevalent form of dementia, and it displays both clinical and molecular variability. RNA N6-methyladenosine (m6A) regulators are involved in a wide range of essential cellular processes. In this study, we aimed to identify molecular signatures associated with m6A in Alzheimer's disease and use those signatures to develop a predictive model. We examined the expression patterns of m6A regulators and immune features in Alzheimer's disease using the GSE33000 dataset. We examined the immune cell infiltration and molecular groups based on m6A-related genes in 310 Alzheimer's disease samples. The WGCNA algorithm was utilized to determine differently expressed genes within each cluster. After evaluating the strengths and weaknesses of the random forest model, the support vector machine model, the generalized linear model, and eXtreme Gradient Boosting, the best machine model was selected. Methods such as nomograms, calibration curves, judgment curve analysis, and the use of independent data sets were used to verify the accuracy of the predictions made. Alzheimer's disease and non-disease Alzheimer's groups were compared to identify dysregulated m6A-related genes and activated immune responses. In Alzheimer's disease, two molecular clusters linked to m6A were identified. Immune infiltration analysis indicated substantial variation in protection between groups. Cluster 1 included processes like the Toll-like receptor signaling cascade, positive regulation of chromatin binding, and numerous malignancies; cluster 2 included processes like the cell cycle, mRNA transport, and ubiquitin-mediated proteolysis. With a lower residual and root mean square error and a larger area under the curve (AUC = 0.951), the Random forest machine model showed the greatest discriminative performance. The resulting random forest model was based on five genes, and it performed well (AUC = 0.894) on external validation datasets. Accuracy in predicting Alzheimer's disease subgroups was also shown by analyses of nomograms, calibration curves, and decision curves. In this research, we methodically outlined the tangled web of connections between m6A and AD and created a promising prediction model for gauging the correlation between m6A subtype risk and AD pathology.
Neutrophil-depleting antibodies, such as anti-GR1 (RB6-8C5) and anti-Ly6G (1A8), are commonly used to study the in vivo function of neutrophils in murine disease models. Anti-Ly6G antibodies became the standard, because in contrast to anti-GR1, these do not bind Ly6C. The efficiency of the depletion needs to be carefully analysed as flow cytometry plots may be misinterpreted. For example, the staining intensity of GR1 on neutrophils (CD11b+ GR1hi) drops upon anti-Ly6G administration. We show that this drop is due to competition between anti-GR1 and anti-Ly6G antibodies. Neutrophil depletion with anti-Ly6G in naive mice was organ- and strain-specific. Furthermore, an incomplete anti-Ly6G-dependent neutrophil depletion was obtained in two immune-mediated mouse models, i.e. in malaria-infected C57BL/6 mice and in complete Freund's adjuvant (CFA)-challenged BALB/c mice. BrdU-incorporation studies show a slight increase in proliferating bone marrow neutrophils upon depletion in naive mice. Strikingly, depletion with anti-Ly6G in CFA-challenged BALB/c mice resulted in a significant increase in proliferating splenic neutrophils, causing a fast rebound of new immature neutrophils. In conclusion, our results emphasize the importance of careful panel design, gating strategies and duration of neutrophil depletion and highlight the context-dependent Ly6G depletion efficiency. It furthermore underlines the need for new tools to understand the in vivo role of neutrophils in immunological models.
Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, (44)AANA(47)-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS) is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.
Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets. Lieber-DeCarli diet (LD) and Meadows-Cook diet (MC) are the most accepted models of chronic alcohol consumption. It is unclear how similar these models are at the cellular, immunologic, and transcriptome levels. We investigated the common and specific pathways of LD and MC models. Livers from LD and MC mice were subjected to histologic changes, hepatic leukocyte population, hepatic transcripts level related to leukocyte recruitment, and hepatic RNA-seq analysis. Cross-species comparison was performed using the alcoholic liver disease (ALD) transcriptomic public dataset. Despite LD mice have increased liver injury and steatosis by alcohol exposure, the number of CD45+ cells were reduced. Opposite, MC mice have an increased number of monocytes/liver by alcohol. The pattern of chemokine gradient, adhesion molecules, and cytokine transcripts is highly specific for each model, not shared with advanced human alcoholic liver disease. Moreover, hepatic RNA-seq revealed a limited and restricted number of shared genes differentially changed by alcohol exposure in these 2 models. Thus, mechanisms involved in alcohol tissue injury are model-dependent at multiple levels and raise the consideration of significant pathophysiological diversity of human alcoholic liver injury.
The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.
For decades, tumor-bearing murine models established using tumor cell lines have been the most commonly used models to study human cancers. Even though there are several studies reported that implant sites caused disparities in tumor behaviors, few of them illuminated the positional effect on immunotherapy. Herein, we describe surgical techniques for a novel orthotopic implantation of syngeneic pancreatic ductal adenocarcinoma (PDAC) tissue slices. This method has a high success modeling rate and stable growth kinetics, which makes it useful for testing novel therapeutics. Pathological examination indicated that the orthotopic tumor displayed poor vascularization, desmoplastic stromal reaction, and a highly immunosuppressive tumor microenvironment. This unique microenvironment resulted in limited response to PD1/CTLA4 blockade therapy and anti-MUC1 (αMUC1) CAR-T transfer treatment. To reverse the suppressive tumor microenvironment, we developed gene modified T-cells bearing a chimeric receptor in which activating receptor NKG2D fused to intracellular domains of 4-1BB and CD3ζ (NKG2D CAR). The NKG2D CAR-T cells target myeloid-derived suppressor cells (MDSCs), which overexpress Rae1 (NKG2D ligands) within the TME. Results indicated that NKG2D CAR-T cells eliminated MDSCs and improved antitumor activity of subsequently infused CAR-T cells. Moreover, we generated a bicistronic CAR-T, including αMUC1 CAR and NKG2D CAR separated by a P2A element. Treatment with the dual targeted bicistronic CAR-T cells also resulted in prolonged survival of orthotopic model mice. In summary, this study describes construction of a novel orthotopic PDAC model through implantation of tissue slices and discusses resistance to immunotherapy from the perspective of a PDAC microenvironment. Based on the obtained results, it is evident that elimination MDSCs by NKG2D CAR could rescue the impaired CAR-T cell activity.
Extracellular vesicles (EVs) are promising drug carriers of photosensitizers for photodynamic therapy (PDT) in cancer treatment, due to their ability to circulate in blood and enter cells efficiently. The therapeutic potential of EVs has been suggested to depend on the type and physiological state of their cell of origin. However, the effects of deriving EVs from various cells in different physiological states on their antitumor capacity are rarely evaluated. In the present study, we compared the antitumor efficacy of EV-mediated PDT by incorporating the photosensitizer Zinc Phthalocyanine (ZnPc) into EVs from multiple cells sources. ZnPc was incorporated by a direct incubation strategy into EVs derived from immune cells (M1-like macrophages and M2-like macrophages), cancer cells (B16F10 melanoma cancer cells) and external sources (milk). Our data show that all EVs are suitable carriers for ZnPc and enable efficient PDT in vitro in co-culture models and in vivo. We observed that EV-mediated PDT initiates immunogenic cell death through the release and exposure of damage associated molecular patterns (DAMPs) on cancer cells, which subsequently induced dendritic cell (DC) maturation. Importantly, of all ZnPc-EVs tested, in absence of light only M1-ZnPc displayed toxicity to MC38, but not to DC, in monoculture and in co-culture, indicating specificity for cancer over immune cells. In MC38 tumor-bearing mice, only M1-ZnPc induced a tumor growth delay compared to control in absence of light. Interestingly, M1- but not M2-mediated PDT, induced complete responses against MC38 tumors in murine models (100% versus 38% of cases, respectively), with survival of all animals up to at least 60 days post inoculation. Finally, we show that all cured animals are protected from a rechallenge with MC38 cells, suggesting the induction of immunological memory after EV-mediated PDT. Together, our data show the importance of the cell type from which the EVs are obtained and highlight the impact of the immunological state of these cells on the antitumor efficacy of EV-mediated PDT.
The Vk*MYC transgenic and transplant mouse models of multiple myeloma (MM) are well established as a research tool for anti-myeloma drug discovery. However, little is known of the immune response in these models. Understanding the immunological relevance of these models is of increasing importance as immunotherapeutic drugs are developed against MM.
Gene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). However, current gRV have significant potential for insertional mutagenesis as reported in clinical trials for other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy (GT), we generated a self-inactivating lentiviral vector (LV) with a codon-optimized human cADA gene under the control of the short form elongation factor-1α promoter (LV EFS ADA). In ADA(-/-) mice, LV EFS ADA displayed high-efficiency gene transfer and sufficient ADA expression to rescue ADA(-/-) mice from their lethal phenotype with good thymic and peripheral T- and B-cell reconstitution. Human ADA-deficient CD34(+) cells transduced with 1-5 × 10(7) TU/ml had 1-3 vector copies/cell and expressed 1-2x of normal endogenous levels of ADA, as assayed in vitro and by transplantation into immune-deficient mice. Importantly, in vitro immortalization assays demonstrated that LV EFS ADA had significantly less transformation potential compared to gRV vectors, and vector integration-site analysis by nrLAM-PCR of transduced human cells grown in immune-deficient mice showed no evidence of clonal skewing. These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, while reducing the potential for vector-mediated insertional mutagenesis.
In Sub-Saharan African (SSA) resource limited settings, Cluster of Differentiation 4 (CD4) counts continue to be used for clinical decision making in antiretroviral therapy (ART). Here, HIV-infected people often remain with CD4 counts <350 cells/μL even after 5 years of viral load suppression. Ongoing immunological monitoring is necessary. Due to varying statistical modeling methods comparing immune response to ART across different cohorts is difficult. We systematically review such models and detail the similarities, differences and problems.
Anti-proinflammatory cytokine therapies against interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), a simple monosaccharide, attenuated cellular responses to IL-6 by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglycoforms of gp130 did not bind to IL-6 or activate downstream intracellular signals that included Janus kinases. 2-DG completely inhibited dextran sodium sulfate-induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin-induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL-6. We also found that 2-DG inhibited signals for other proinflammatory cytokines such as TNF-α, IL-1β, and interferon -γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2-DG prevented LPS shock, a model for a cytokine storm, and LPS-induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID-19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases.
Henoch-Schönlein purpura (HSP) is a common systemic vasculitis in children. Animal models of HSP are needed to better understand the mechanism of HSP. Here, we investigated hematologic and immunologic profiles in HSP rat and rabbit models. Models were established with ovalbumin (OVA) based on type III hypersensitivity. During the acute phase, the models exhibited varying degrees of cutaneous purpura, joint inflammatory response, gastrointestinal bleeding, glomerular capsule protein exudation, vascular dilatation, and increased IgA expression and immune complex deposition. Twenty four hours after antigen challenge, compared with the controls, the models showed a significantly increased white blood cell count and granulocytes count and percentage, decreased number and percentage of lymphocytes, no change in platelet concentration, significantly increased serum IL-4 and TNF-α levels, and decreased CD4(+) T cell, CD4/CD8 ratio, and C3 and C4 levels. Compared with the hematologic and immunologic profiles in pediatric HSP patients, the rat and rabbit HSP models can mimic pediatric HSP characteristics. Our studies provide two useful animal models for further investigations of the pathogenesis, diagnosis, drug screening and treatment of HSP.
The intestine is the main reservoir of bacterial pathogens in most organisms. Klebsiella pneumoniae is an important opportunistic pathogen associated with nosocomial bacterial infections. Intestinal colonization with K. pneumoniae has been shown to be associated with an increased risk of subsequent infections. However, not all K. pneumoniae strains in the intestine cause further infection, and the distinction of the difference among strains that cause infection after colonization and the ones causing only asymptomatic colonization is unclear. In this study, we report a case of a hospitalized patient from the ICU. We screened out two intestine colonization strains (FK4111, FK4758) to analyze the subsequent infection conditions. We set up infection models of zebrafish and Galleria mellonella to establish the differences in the potential for causing subsequent infection and the immunological specificities after K. pneumoniae intestine colonization. Sudan Black B and neutral red staining results indicated that FK4758 was more responsive to neutrophil recruitment and phagocytosis of macrophages than FK4111. The results of the assessment of the organ bacterial load revealed that FK4111 and FK4758 both had the highest bacterial loads in the zebrafish intestine compared to those in other organs. However, in the zebrafish spleen, liver, and heart, the FK4758 load was significantly higher than that of FK4111. The ST37 strain FK4111, which does not produce carbapenemase, did not cause infection after colonization, whereas the ST11 strain FK4758, which produces carbapenemase, caused infection after intestinal colonization. Our finding demonstrated that not all intestinal colonization of K. pneumoniae subsequently caused infections, and the infections of K. pneumoniae after colonization are different. Therefore, the infection models we established provided possibility for the estimation of host-microbial interactions.
Regardless of the eventual site of disease, the point of entry for Mycobacterium tuberculosis (M.tb) is via the respiratory tract and tuberculosis (TB) remains primarily a disease of the lungs. Immunological biomarkers detected from the respiratory compartment may be of particular interest in understanding the complex immune response to M.tb infection and may more accurately reflect disease activity than those seen in peripheral samples. Studies in humans and a variety of animal models have shown that biomarkers detected in response to mycobacterial challenge are highly localized, with signals seen in respiratory samples that are absent from the peripheral blood. Increased understanding of the role of pulmonary specific biomarkers may prove particularly valuable in the field of TB vaccines. Here, development of vaccine candidates is hampered by the lack of defined correlates of protection (COPs). Assessing vaccine immunogenicity in humans has primarily focussed on detecting these potential markers of protection in peripheral blood. However, further understanding of the importance of local pulmonary immune responses suggests alternative approaches may be necessary. For example, non-circulating tissue resident memory T cells (TRM) play a key role in host mycobacterial defenses and detecting their associated biomarkers can only be achieved by interrogating respiratory samples such as bronchoalveolar lavage fluid or tissue biopsies. Here, we review what is known about pulmonary specific immunological biomarkers and discuss potential applications and further research needs.
Tumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, and regulatory T cells (Tregs).
As we explore other planetary bodies, astronauts will face unique environmental and physiological challenges. The human immune system has evolved under Earth's gravitational force. Consequently, in the microgravity environment of space, immune function is altered. This can pose problematic consequences for astronauts on deep space missions where medical intervention will be limited. Studying the unique environment of microgravity has its challenges, yet current research has uncovered immunological states that are probable during exploration missions. As microgravity-induced immune states are uncovered, novel countermeasure developments and personalized mitigation programs can be designed to improve astronaut health. This can also benefit immune-related monitoring programs for disorders on Earth. This is a comprehensive review, including gaps in knowledge, of simulated and spaceflight microgravity studies in human and rodent models.
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