This work was supported in part by the Lupus Research Institute, NCI grant CA138617, NIDDK grant DK090978, Charlotte Schmidlapp Award (to E.M.J.), and the Albert J. Ryan Fellowship (to J.K.). We are grateful for the support and instrumentation provided by the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children&#8217;s Hospital Medical Center, supported in part by NIH AR-47363, NIH DK78392 and NIH DK90971.

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The authors have nothing to disclose.

המודל מושרה bm12 הוא דרך קלה יחסית ויעילה ללמוד את התהליכים התאיים ומולקולריים של SLE. הפעלה כרונית של תאי CD4 T הועברו adoptively המכוון נגד אנטיגנים עצמיים מובילה להצטברות של TFH, GC תאי B, ותאי פלזמה אשר ניתן למדוד על ידי cytometry זרימה, כפי שתואר כאן. מחקרים עתידיים באמצעות מודל זה ?...

זאבת אדמנתית מערכתית (לופוס) היא מחלה אוטואימונית מורכבת המאופיינת prototypically על ידי נוגדן אנטי-גרעיני ייצור (ANA) וגלומרולונפריטיס. סיבוכים רבים אחרים, כוללים עורי, לב-ריאה, ונגעים בכבד קשורים למחלה אצל אנשים מסוימים. הערכות שכיחות בארה&quot;ב משתנות במידה רבה, מ150,000-1,500,000 1,2, עם שכיחות גבוהה במיוחד בנשים ומיעוטים 3. למרות אטיולוגיה של SLE כבר קשה להבחין, הוא חשב שינבע ממשחק הגומלין של גורמים גנטיים וסביבתיים שונים, שיגיעו לשיאו באוטואימוניות המערכתית. מודלים של בעלי חיים רבים כבר מועסקים ללמוד גורמים מובילים להופעת מחלה והתקדמות. מודלים עכבר קלאסיים של SLE כוללים זני נטייה גנטית עכבר כוללים NZB x מודל NZW F1 ונגזרי NZM, המתח / LPR הקה&quot;ע, ומתח BXSB / Yaa, ומערכות מושרה, כגון pristane ודגמי מחלת שתל נגד המארח כרוני (cGVHD) 4. דיווחים מוקדמים של ייצור נוגדנים בדגמי GVHD משמשים זנים שונים עכבר או זני אוגר להורה להעברות F1 5 - 8; שיטות נפוצות יותר בשימוש ללמוד מחלה כמו זאבת-כיום כוללות הורה DBA / 2 → (DBA / 2 x C57BL / 6) F1, ומודל העברת bm12 המתואר כאן. לכל אחד יש מודל האזהרות שלה, אבל הם בדרך כלל לשתף מערך משותף של תכונות המתואמים עם מאפיינים קליניים של מחלה אנושית. הפרמטרים לרוב דיווחו במודלים של עכברים כוללים splenomegaly, בלוטות הלימפה, דלקת כליות, ייצור ANA, וברמה התאית, ההתרחבות של תאי T זקיקי עוזר (TFH), תאי B נבטי מרכז (GC), ותאי פלזמה. מודל bm12 מושרה מושגת על ידי העברת המאמצת של לימפוציטים מIA bm12 B6 (C) - H2 - עכברים (bm12) AB1 bm12 / KhEgJ, מתח אניdentical לC57BL / 6 למעט 3 החלפות חומצת אמינו בכיתת MHC II, לIA ב C57BL / 6 עכברים (B6). Alloactivation של תורם CD4 T תאים על ידי נמען נגמ&quot;שים מוביל לcGVHD עם תסמינים דומים SLE מקרוב. באופן ספציפי, אלה כוללים הרחבת TFH תורם נגזרות, התרחבות של תאי שמקורם נמען GC B ותאי פלזמה, וייצור של אנאס כולל אנטי-dsDNA, אנטי-ssDNA, אנטי-הכרומטין, ונוגדנים נגד RBC 9. לאורך זמן, עכברי נמען לפתח גלומרולונפריטיס הקשורים פיקדונות IgG בגלומרולרי, ביניים, ואזורים של כלי דם של הכליות 10. הראינו לאחרונה כי, בדומה למחלות של בני אדם, יש גם תפקיד קריטי עבור סוג אני IFN במודל זה 11. יש לציין, הקריטריונים המגדירים עבור SLE האנושי כוללים את הפיתוח של דלקת כליות תואמות עם SLE בנוכחות נוגדנים נגד dsDNA 12, שניהם מאפיינים בולטים של מודל עכבר זה. יש seיתרונות veral של מודל bm12 על המודלים ספונטניים. מודלים קלאסיים שלפתח סימנים כמו SLE-ספונטני להסתמך על שני זנים היברידיים עכבר, זנים טהורים עכבר לא על רקע B6, או לוקוסים גנטיים גדולים על רקע B6, שהופכים את מעבר לפצצה או עכברים מהונדסים גנטי אחר קשה זמן רב. עם המודל מושרה bm12, עכברים מהונדסים גנטי יכולים לשמש גם תורם או נמען, המאפשרים זיהוי מהיר יותר של התא הסלולרי שבגנים מסוימים עשויים להיות חשובים למחלה. יתר על כן, התפתחות מחלה במודל bm12 היא הרבה יותר מהר, הדורש רק 2 שבועות עד להופעת אנאס, בהשוואה למספר חודשים לדגמים ספונטניים ביותר. יתר על כן, בניגוד לדגמים ספונטניים שמתפתחים מחלה בנקודות זמן שונה, תחילת המחלה וההתקדמות במודל B6 → bm12 מסונכרנת מאוד. זה מאפשר לדור של קבוצות בגודל המתאימה שיכולות בהדואר משמש לאסטרטגיות התערבותית או טיפוליות בכל שלב של התפתחות מחלה. להלן פרוטוקול מפורט לייזום אוטואימוניות כמו SLE-ידי העברת המאמצת של לימפוציטים bm12 לעכברי C57BL / 6, או וריאנטים גנטיים על רקע B6. בנוסף, אנו מתארים פרוטוקול מכתים הזרימה cytometric לספירת TFH, GC תאי B, וסוגי תאי פלזמה תאים הקשורים למחלות אנושיות. חשוב לציין, יכולים לשמש גם פרוטוקולים אלה לאפיין מחלה ברוב דגמי עכבר של SLE ולזהות TFH, GC תאי B ותאי פלזמה בדגמי מחלה אחרים.

<table><tbody><tr><td>B6.SJL-Ptprca Pepcb/BoyJ</td><td>The Jackson Laboratory</td><td>001162</td><td>CD45.1+ BoyJ mouse strain</td></tr><tr><td>B6(C)-H2-Ab1bm12/KhEgJ</td><td>The Jackson Laboratory</td><td>001162</td><td>Bm12 mouse strain</td></tr><tr><td>FastDigest PsuI</td><td>Life Technologies</td><td>FD1554</td><td>Restriction digest enzyme for genotyping</td></tr><tr><td>1X RBC Lysis Buffer</td><td>eBioscience</td><td>00-4333-57</td><td></td></tr><tr><td>IMDM</td><td>GE Healthcare</td><td>SH30228.01</td><td></td></tr><tr><td>Plasma Separation Tube (PST)</td><td>BD</td><td>365974</td><td>Blood collection tube with Dipotassium EDTA</td></tr><tr><td>Serum Separation Tube (SST)</td><td>BD</td><td>365967</td><td>Blood collection tube with Clot activator / SST Gel</td></tr><tr><td>Ficoll</td><td>GE Healthcare</td><td>17-1440-02&amp;nbsp;</td><td>High density cell separation solution</td></tr><tr><td>Lympholyte-M</td><td>Cedarlane</td><td>CL5030</td><td>High density cell separation solution</td></tr><tr><td>GL-7-biotin</td><td>eBioscience</td><td>13-5902-82&amp;nbsp;</td><td></td></tr><tr><td>Streptavidin-BUV395</td><td>BD</td><td>564176</td><td></td></tr><tr><td>CD138-BV421</td><td>BioLegend</td><td>142508</td><td></td></tr><tr><td>CD4-BV510</td><td>BioLegend</td><td>100559</td><td></td></tr><tr><td>TCR&amp;beta;-BV605</td><td>BD</td><td>562840</td><td></td></tr><tr><td>CD45.1-BV711</td><td>BioLegend</td><td>110739</td><td></td></tr><tr><td>CD45.2-FITC</td><td>BioLegend</td><td>109806</td><td></td></tr><tr><td>PD-1-PE</td><td>BioLegend</td><td>135206</td><td></td></tr><tr><td>CD19-PerCP</td><td>BioLegend</td><td>115532</td><td></td></tr><tr><td>Fas-PE-Cy7</td><td>BD</td><td>557653</td><td></td></tr><tr><td>CXCR5-APC</td><td>BioLegend</td><td>145506</td><td></td></tr><tr><td>Fixable Viability Dye ef780</td><td>eBioscience</td><td>65-0865-18</td><td></td></tr><tr><td>CD4-BV421</td><td>BioLegend</td><td>100443</td><td></td></tr><tr><td>1.2 ml FACS tube inserts, racked</td><td>USA Scientific</td><td>1412-1400</td><td></td></tr><tr><td>BD Falcon&amp;trade; Round-Bottom Tubes</td><td>BD</td><td>352017</td><td></td></tr></tbody></table>

the bm12 inducible model of systemic lupus erythematosus (sle) in c57bl/6 mice

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical and immunological manifestations. Several spontaneous and inducible animal models mirror common components of human disease, including the bm12 transfer model. Upon transfer of bm12 splenocytes or purified CD4 T cells, C57BL/6 mice rapidly develop large frequencies of T follicular helper cells (Tfh), germinal center (GC) B cells, and plasma cells followed by high levels of circulating anti-nuclear antibodies. Since this model utilizes mice on a pure C57BL/6 background, researchers can quickly and easily study disease progression in transgenic or knockout mouse strains in a relatively short period of time. Here we describe protocols for the induction of the model and the quantitation Tfh, GC B cells, and plasma cells by multi-color flow cytometry. Importantly, these protocols can also be used to characterize disease in most mouse models of SLE and identify Tfh, GC B cells, and plasma cells in other disease models.

עכברים חולים לפתח splenomegaly קטן כמו 14 ימים, מציגים טחולים 2-3 פעמים בגודל של עכברים בריאים במונחים של מסה וcellularity (איור 2). Splenocytes הם מגודרת ברצף על פיזור אור (FSC-ידי SSC-), חיסול כפילויות (FSC-W או -H ידי FSC-A), תאי קיימא (הכתמה נמוכה של צ?...

Watch this Scientific Journal Video about The bm12 Inducible Model of Systemic Lupus Erythematosus SLE in C57BL/6 Mice at JoVE.com

The bm12 Inducible Model of Systemic Lupus Erythematosus SLE in C57BL/6 Mice

The transfer of bm12 lymphocytes into a C57BL/6 recipient is an established model of systemic lupus erythematosus. Here we describe how to initiate disease using this model and how to characterize T follicular helper cells, germinal center B cells and plasma cells by flow cytometry.

דגם bm12 העין מתנהל של זאבת אדמנתית המערכתית (לופוס) בC57BL עכברים / 6

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical and immunological manifestations. Several spontaneous and inducible ...

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Research

JoVE Journal

Medicine

The bm12 Inducible Model of Systemic Lupus Erythematosus (SLE) in C57BL/6 Mice

17.3K Views.  Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine. The transfer of bm12 lymphocytes into a C57BL/6 recipient is an established model of systemic lupus erythematosus. Here we describe how to initiate disease using this model and how to characterize T follicular helper cells, germinal center B cells and plasma cells by flow cytometry.

Video: The bm12 Inducible Model of Systemic Lupus Erythematosus SLE in C57BL/6 Mice

Induction of Experimental Autoimmune Hypophysitis in SJL Mice

Autoimmune hypophysitis can be reproduced experimentally by the injection of pituitary proteins mixed with an adjuvant into susceptible mice1. Mouse models allow us to study how diseases unfold, often providing a good replica of the same processes occurring in humans. For some autoimmune diseases, like type 1A diabetes, there are models (the NOD mouse) that spontaneously develop a disease similar to the human counterpart. For many other autoimmune diseases, however, the model needs to be induced experimentally. A common approach in this regard is to inject the mouse with a dominant antigen derived from the organ being studied. For example, investigators interested in autoimmune thyroiditis inject mice with thyroglobulin2, and those interested in myasthenia gravis inject them with the acetylcholine receptor3. If the autoantigen for a particular autoimmune disease is not known, investigators inject a crude protein extract from the organ targeted by the autoimmune reaction. For autoimmune hypophysitis, the pathogenic autoantigen(s) remain to be identified4, and thus a crude pituitary protein preparation is used. In this video article we demonstrate how to induce experimental autoimmune hypophysitis in SJL mice.

This video shows how to induce autoimmune hypophysitis in SJL mice and how to assess its severity by histopathology.

אינדוקציה של Hypophysitis אוטואימוניות הניסויי עכברים SJL

Autoimmune hypophysitis can be reproduced experimentally by the injection of pituitary proteins mixed with an adjuvant into susceptible mice1. Mouse ...

Immunology and Infection

The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice

Autoimmune hepatitis is a rare but life threatening autoimmune disease of the liver of unknown etiology1,2. In the past many attempts have been made to generate an animal model that reflects the characteristics of the human disease 3-5. However, in various models the induction of disease was rather complex and often hepatitis was only transient3-5. Therefore, we have developed a straightforward mouse model that uses the major human autoantigen in type 2 autoimmune hepatitis (AIH-2), namely hCYP2D6, as a trigger6. Type 1 liver-kidney microsomal antibodies (LKM-1) antibodies recognizing hCYP2D6 are the hallmark of AIH-27,8. Delivery of hCYP2D6 into wildtype FVB or C57BL/6 mice was by an Adenovirus construct (Ad-2D6) that ensures a direct delivery of the triggering antigen to the liver. Thus, the ensuing local inflammation generates a fertile field9 for the subsequent development of autoimmunity. A combination of intravenous and intraperitoneal injection of Ad-2D6 is the most effective route to induce a long-lasting autoimmune damage to the liver (section 1). Here we provide a detailed protocol on how autoimmune liver disease is induced in the CYP2D6 model and how the different aspects of liver damage can be assessed. First, the serum levels of markers indicating hepatocyte destruction, such as aminotransferases, as well as the titers of hCYP2D6 antibodies are determined by sampling blood retroorbitaly (section 2). Second, the hCYP2D6-specific T cell response is characterized by collecting lymphocytes from the spleen and the liver. In order to obtain pure liver lymphocytes, the livers are perfused by PBS via the portal vein (section 3), digested in collagen and purified over a Percoll gradient (section 4). The frequency of hCYP2D6-specific T cells is analyzed by stimulation with hCYP2D6 peptides and identification of IFN&gamma;-producing cells by flow cytometry (section 5). Third, cellular infiltration and fibrosis is determined by immunohistochemistry of liver sections (section 6). Such analysis regimen has to be conducted at several times after initiation of the disease in order to prove the chronic nature of the model. The magnitude of the immune response characterized by the frequency and activity of hCYP2D6-specific T and/or B cells and the degree of the liver damage and fibrosis have to be assessed for a subsequent evaluation of possible treatments to prevent, delay or abrogate the autodestructive process of the liver.

Infection of mice with an Adenovirus expressing the major human autoantigen cytochrome P450 2D6 (hCYP2D6) recognized by sera of patients suffering from type 2 autoimmune hepatitis results in a persistent form of autoimmune-mediated liver disease characterized by extensive hepatitis, fibrosis and generation of a CYP2D6-specific immune response.

CYP2D6 מודל החיה: כיצד לגרום דלקת כבד אוטואימונית עכברים

Autoimmune hepatitis is a rare but life threatening autoimmune disease of the liver of unknown etiology1,2. In the past many attempts have been made to ...

Myelin Oligodendrocyte Glycoprotein (MOG35-55) Induced Experimental Autoimmune Encephalomyelitis (EAE) in C57BL/6 Mice

Multiple sclerosis is a chronic neuroinflammatory demyelinating disorder of the central nervous system with a strong neurodegenerative component. While the exact etiology of the disease is yet unclear, autoreactive T lymphocytes are thought to play a central role in its pathophysiology. MS therapy is only partially effective so far and research efforts continue to expand our knowledge on the pathophysiology of the disease and to develop novel treatment strategies. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model for MS sharing many clinical and pathophysiological features. There is a broad diversity of EAE models which reflect different clinical, immunological and histological aspects of human MS. Actively-induced EAE in mice is the easiest inducible model with robust and replicable results. It is especially suited for investigating the effects of drugs or of particular genes by using transgenic mice challenged by autoimmune neuroinflammation. Therefore, mice are immunized with CNS homogenates or peptides of myelin proteins. Due to the low immunogenic potential of these peptides, strong adjuvants are used. EAE susceptibility and phenotype depends on the chosen antigen and rodent strain. C57BL/6 mice are the commonly used strain for transgenic mouse construction and respond among others to myelin oligodendrocyte glycoprotein (MOG). The immunogenic epitope MOG35-55 is suspended in complete Freund's adjuvant (CFA) prior to immunization and pertussis toxin is applied on the day of immunization and two days later. Mice develop a "classic" self-limited monophasic EAE with ascending flaccid paralysis within 9-14 days after immunization. Mice are evaluated daily using a clinical scoring system for 25-50 days. Special considerations for care taking of animals with EAE as well as potential applications and limitations of this model are discussed.

Myelin Oligodendrocyte Glycoprotein MOG35-55 Induced Experimental Autoimmune Encephalomyelitis EAE in C57BL/6 Mice

Experimental autoimmune encephalomyelitis (EAE) is an established animal model of multiple sclerosis. C57BL/6 mice are immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (MOG35-55), resulting in an ascending flaccid paralysis caused by autoreactive immune cells in the central nervous system. Protocols for disease induction and monitoring will be discussed.

המיאלין oligodendrocyte גליקופרוטאין (MOG<sub&gt; 35-55</sub&gt;) מושרה ניסויי אוטואימוניות Encephalomyelitis (EAE) בעכברים C57BL / 6

Multiple sclerosis is a chronic neuroinflammatory demyelinating disorder of the central nervous system with a strong neurodegenerative component. While ...

Induction of Experimental Autoimmune Encephalomyelitis in Mice and Evaluation of the Disease-dependent Distribution of Immune Cells in Various Tissues

Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) resulting in cognitive and motor impairment. Experimental autoimmune encephalomyelitis (EAE) is a useful animal model of MS, because it is also characterized by lesion formation in the CNS, motor impairment and is also driven by autoimmune and inflammatory reactions. One of the EAE models is induced with a peptide derived from the myelin oligodendrocyte protein (MOG)35-55 in mice. The EAE mice develop a progressive disease course. This course is divided into three phases: the preclinical phase (day 0 - 9), the disease onset (day 10 - 11) and the acute phase (day 12 - 14). MS and EAE are induced by autoreactive T cells that infiltrate the CNS. These T cells secrete chemokines and cytokines which lead to the recruitment of further immune cells. Therefore, the immune cell distribution in the spinal cord during the three disease phases was investigated. To highlight the time point of the disease at which the activation/proliferation/accumulation of T cells, B cells and monocytes starts, the immune cell distribution in lymph nodes, spleen and blood was also assessed. Furthermore, the levels of several cytokines (IL-1&#946;, IL-6, IL-23, TNF&#945;, IFN&#947;) in the three disease phases were determined, to gain insight into the inflammatory processes of the disease. In conclusion, the data provide an overview of the functional profile of immune cells during EAE pathology.

This manuscript describes the methods for induction and scoring of the experimental autoimmune encephalomyelitis (EAE) model, together with the assessment of immune cell distribution and mRNA cytokine levels in lymph nodes, spleen, blood and spinal cord using flow cytometry and quantitative PCR, respectively, at various disease phases.

אינדוקציה של ניסיוני אוטואימוניות Encephalomyelitis עכברים וההערכה של הפצת מחלות התלויה של תאים חיסוניים ברקמות שונות

Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) ...

Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination

A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in myelin destruction, which not only slows conduction of nerve impulses, but causes axonal injury resulting in motor and cognitive decline. Current treatments for MS focus on attenuating immune cell infiltration into the central nervous system (CNS). These treatments decrease the number of relapses, improving quality of life, but do not completely eliminate relapses so long-term disability is not improved. Therefore, therapeutic agents that protect the CNS are warranted. In both animal models as well as human patients with MS, T cell entry into the CNS is generally considered the initiating inflammatory event. In order to assess if a drug protects the CNS, any potential effects on immune cell infiltration or proliferation in the periphery must be ruled out. This protocol describes how to determine whether CNS protection observed after drug intervention is a consequence of attenuating CNS-infiltrating immune cells or blocking death of CNS cells during inflammatory insults. The ability to examine MS treatments that are protective to the CNS during inflammatory insults is highly critical for the advancement of therapeutic strategies since current treatments reduce, but do not completely eliminate, relapses (i.e., immune cell infiltration), leaving the CNS vulnerable to degeneration.

This protocol describes how to determine whether pharmacological treatments for experimental autoimmune encephalomyelitis show CNS protection as a consequence of suppressing immune cell infiltration or are neuroprotective during the onslaught of immune cell infiltration.

דיכוי מערכת החיסון קביעת לעומת להגנת CNS להתערבויות פרמקולוגיים demyelination אוטואימוניות

A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in ...

A Simple Approach to Induce Experimental Autoimmune Neuritis in C57BL/6 Mice for Functional and Neuropathological Assessments

Experimental autoimmune neuritis (EAN) is a well-appreciated experimental model of autoimmune peripheral demyelinating diseases. EAN disease is induced by immunizing mice with neurogenic peptides to direct an inflammatory attack toward components of the peripheral nervous system (PNS). Recent advances have enabled the induction of EAN in the relatively resistant C57BL/6 mouse line using myelin protein zero (P0)106-125 or P0180-199 peptides delivered in adjuvant combined with the injection of pertussis toxin. The ability to induce EAN in the C57BL/6 strain allows for the use of the numerous genetic tools that exist on this mouse background, and thus allows the sophisticated study of disease pathogenesis and interrogation of the mechanistic action of novel therapeutics in combination with transgenic approaches. In this study, we demonstrate a simple approach to successfully induce EAN using the P0180-199 peptide in C57BL/6 mice. We also outline a protocol for the assessment of functional deficits that occur in this model, accompanied by an array of neuropathological features. Thus, this model is a powerful experimental model to study the pathogenesis of human peripheral demyelinating neuropathies, and to determine the efficacy of potential therapies that aim to promote myelin repair and protect against nerve damage in autoimmune neuritis.

This report outlines a simple approach to successfully induce experimental autoimmune neuritis (EAN) using the myelin protein zero (P0)180-199 peptide in combination with Freund&#39;s complete adjuvant and pertussis toxin. We present a sophisticated paradigm capable of accurately assessing the extent of functional deficits and neuropathology that occur in this EAN.

גישה פשוטה כדי לגרום לדלקת בעצה חיסון ניסיוני בעכברים C57BL/6 עבור הערכות Neuropathological פונקציונלי

Experimental autoimmune neuritis (EAN) is a well-appreciated experimental model of autoimmune peripheral demyelinating diseases. EAN disease is induced by ...

Neuroscience

Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms

Drug-induced autoimmune hepatitis (DIH) is the most common hepatic drug-induced hypersensitization process observed in approximately 9 to 12% of patients with autoimmune hepatitis. The overwhelming majority of patients with DIH are women. The underlying mechanisms of these sex differences in prevalence are unclear because of the paucity of animal models that mimic human disease. Even so, underlying mechanisms are widely believed to be associated with human leukocyte antigen haplotypes and sex hormones. In contrast, using a DIH mouse model, we have uncovered that IL-4 initiated&#160;CD4+ T cells directed against an epitope of cytochrome P450 2E1 induces influx of neutrophils, macrophages and mast cells into the livers of female BALB/c mice. Using this model, we have also shown that IL-33-induced FoxP3+regulatory T cells confer protection against DIH in female and male mice. This DIH model is induced by immunizing mice with an epitope of CYP2E1 that has been covalently altered with a drug metabolite that has been associated with DIH. This epitope is recognized by patients with DIH. Our method induces robust and reproducible hepatitis and autoantibodies that can be utilized to study the pathogenesis of DIH. While in vivo studies can cause undue pain and distress in mice when done improperly, the advantage of an in vivo model is the ability to evaluate the pathogenesis of disease in a large number of mice. Additionally, biological effects of the altered liver proteins can be studied using invasive procedures. The addition of in vitro studies to the experimental design allows rapid repetition and mechanistic analysis at a cellular level. Thus, we will demonstrate our model protocol and how it can be utilized to study in vivo and in vitro mechanisms of DIH.

We describe an in vivo immunization, translational hepatitis model in BALB/c mice that can be utilized to study the pathogenesis of drug-induced autoimmune hepatitis including sex differences seen in this disease. We will describe how this model demonstrates reproducible analyses using in vivo and in vitro experimental techniques.

אינדוקציה של הפטיטיס אוטואימונית הנגרמת על ידי תרופות בעכברי BALB/c לחקר המנגנונים הפתוגניים שלה

Drug-induced autoimmune hepatitis (DIH) is the most common hepatic drug-induced hypersensitization process observed in approximately 9 to 12% of patients ...

Murine Distal Colostomy, A Novel Model of Diversion Colitis in C57BL/6 Mice

Diversion colitis (DC) is a frequent clinical condition occurring in patients with bowel segments excluded from the fecal stream as a result of a diverting enterostomy. The etiology of this disease remains ill-defined but appears to differ from that of classical inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Research aimed to decipher the pathophysiological mechanisms leading to the development of this disease has been severely hampered by the lack of an appropriate murine model. This protocol generates a murine model of DC that facilitates the study of the immune system's role and its interaction with the microbiome in the development of DC. In this model using C57BL/6 animals, distal parts of the colon are excluded from the fecal stream by creating a distal colostomy, triggering the development of mild to moderate inflammation in the excluded bowel segments and reproducing the hallmark lesions of human DC with a moderate systemic inflammatory response. In contrast to the rat model, a large number of genetically-modified murine models on the C57BL/6 background are available. The combination of these animals with our model allows the potential roles of individual cytokines, chemokines, or receptors of bioactive molecules (e.g., interleukin (IL)-17; IL-10, chemokine CXCL13, chemokine receptors CXCR5 and CCR7, and the sphingosine-1-phosphate receptor 4) to be assessed in the pathogenesis of DC. The availability of congenic mouse strains on the C57BL/6 background largely facilitates transfer experiments to establish the roles of distinct cell types involved in the etiology of DC. Finally, the model offers the opportunity to assess the influences of local interventions (e.g., modification of the local microbiome or local anti-inflammatory therapy) on mucosal immunity in affected and non-affected bowel segments and the on systemic immune homeostasis.

Murine distal colostomy provides a murine model for human diversion colitis, a predominantly lymphocytic colitis in colon segment excluded from the fecal stream.

מאתר למעי הגס הדיסטלי, מודל הרומן של הסחה קוליטיס בעכברים C57BL/6

Diversion colitis (DC) is a frequent clinical condition occurring in patients with bowel segments excluded from the fecal stream as a result of a ...

Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice

Systemic lupus erythematosus (SLE) is an autoimmune disorder with no known cure and is characterized by persistent inflammation in many organs, including the kidneys. Under such circumstances, the kidney loses its ability to clean waste from the blood and regulate salt and fluid concentrations, eventually leading to renal failure. Women, particularly those of childbearing age, are diagnosed nine times more often than men. Kidney disease is the leading cause of mortality in SLE patients. The present protocol describes a quick and simple method to measure excreted protein levels in collected urine, tracking lupus progression over time. In addition, an approach to isolate kidney mononuclear cells is provided based on size and density selection to investigate renal infiltration of leukocytes. Furthermore, an immunohistochemical method has been developed to characterize protein deposition in the glomeruli and leukocyte infiltration in the tubulointerstitial space. Together, these methods can help investigate the progression of chronic inflammation associated with the kidneys of lupus-prone MRL/lpr mice.

The present protocol describes a method to track lupus progression in mice. Two additional procedures are presented to characterize lupus nephritis based on cell infiltration and protein deposition in the kidneys.

ניתוחים של פרוטאינוריה, חדירה כלייתית של לויקוציטים ותצהיר כלייתי של חלבונים בעכברי MRL/lpr המועדים לזאבת

Systemic lupus erythematosus (SLE) is an autoimmune disorder with no known cure and is characterized by persistent inflammation in many organs, including ...

אינדוקציה והערכה של אנצפלומיאליטיס אוטואימונית ניסיונית בעכבר

Modeling Multiple Sclerosis in the Two Sexes: MOG35-55-Induced Experimental Autoimmune Encephalomyelitis

Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease affecting the central nervous system (CNS). It is characterized by different prevalence in the sexes, affecting more women than men, and different outcomes, showing more aggressive forms in men than in women. Furthermore, MS is highly heterogeneous in terms of clinical aspects, radiological, and pathological features. Thus, it is necessary to take advantage of experimental animal models that allow the investigation of as many aspects of the pathology as possible. Experimental autoimmune encephalomyelitis (EAE) represents one of the most used models of MS in mice, modeling different disease features, from the activation of the immune system to CNS damage. Here we describe a protocol for the induction of EAE in both male and female C57BL/6J mice using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) immunization, which leads to the development of a chronic form of the disease. We also report the evaluation of the daily clinical score and motor performance of these mice for 28 days post immunization (28 dpi). Lastly, we illustrate some basic histological analysis at the CNS level, focusing on the spinal cord as the primary site of disease-induced damage.

מחבר זרקור: יצירת מודל ניסיוני רב-תכליתי של אנצפלומיאליטיס אוטואימונית הרלוונטי לעכברים זכרים ונקבות כאחד 

Experimental autoimmune encephalomyelitis is one of the most widely used murine models of multiple sclerosis. In the current protocol, C57BL/6J mice of both sexes are immunized with myelin oligodendrocyte glycoprotein peptide, resulting mainly in ascending paresis of the tail and limbs. Here we discuss the protocol of EAE induction and evaluation.

דגם bm12 העין מתנהל של זאבת אדמנתית המערכתית (לופוס) בC57BL עכברים / 6

Summary

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CYP2D6 מודל החיה: כיצד לגרום דלקת כבד אוטואימונית עכברים

המיאלין oligodendrocyte גליקופרוטאין (MOG

אינדוקציה של ניסיוני אוטואימוניות Encephalomyelitis עכברים וההערכה של הפצת מחלות התלויה של תאים חיסוניים ברקמות שונות

דיכוי מערכת החיסון קביעת לעומת להגנת CNS להתערבויות פרמקולוגיים demyelination אוטואימוניות

גישה פשוטה כדי לגרום לדלקת בעצה חיסון ניסיוני בעכברים C57BL/6 עבור הערכות Neuropathological פונקציונלי

אינדוקציה של הפטיטיס אוטואימונית הנגרמת על ידי תרופות בעכברי BALB/c לחקר המנגנונים הפתוגניים שלה

מאתר למעי הגס הדיסטלי, מודל הרומן של הסחה קוליטיס בעכברים C57BL/6

ניתוחים של פרוטאינוריה, חדירה כלייתית של לויקוציטים ותצהיר כלייתי של חלבונים בעכברי MRL/lpr המועדים לזאבת

מידול טרשת נפוצה בשני המינים: MOG_35-induced ניסיוני אוטואימוני אנצפלומיאליטיס

דגם bm12 העין מתנהל של זאבת אדמנתית המערכתית (לופוס) בC57BL עכברים / 6

Summary

Explore More Videos

Chapters in this video

אינדוקציה של Hypophysitis אוטואימוניות הניסויי עכברים SJL

CYP2D6 מודל החיה: כיצד לגרום דלקת כבד אוטואימונית עכברים

המיאלין oligodendrocyte גליקופרוטאין (MOG

אינדוקציה של ניסיוני אוטואימוניות Encephalomyelitis עכברים וההערכה של הפצת מחלות התלויה של תאים חיסוניים ברקמות שונות

דיכוי מערכת החיסון קביעת לעומת להגנת CNS להתערבויות פרמקולוגיים demyelination אוטואימוניות

גישה פשוטה כדי לגרום לדלקת בעצה חיסון ניסיוני בעכברים C57BL/6 עבור הערכות Neuropathological פונקציונלי

אינדוקציה של הפטיטיס אוטואימונית הנגרמת על ידי תרופות בעכברי BALB/c לחקר המנגנונים הפתוגניים שלה

מאתר למעי הגס הדיסטלי, מודל הרומן של הסחה קוליטיס בעכברים C57BL/6

ניתוחים של פרוטאינוריה, חדירה כלייתית של לויקוציטים ותצהיר כלייתי של חלבונים בעכברי MRL/lpr המועדים לזאבת

מידול טרשת נפוצה בשני המינים: MOG35-induced ניסיוני אוטואימוני אנצפלומיאליטיס

מידול טרשת נפוצה בשני המינים: MOG_35-induced ניסיוני אוטואימוני אנצפלומיאליטיס