Name: induction of intestinal graft-versus-host disease and its mini-endoscopic assessment in live mice
Uploaded: 2019-02-11T13:00:00
Description: Watch this Scientific Journal Video about Induction of Intestinal Graft-versus-host Disease and Its Mini-endoscopic Assessment in Live Mice at JoVE.com

This study was supported by the Collaborative Research Centers (CRC) 221 (CRC/TR221-DFG, #324392634; project B03) (to K.H.) and CRC 1181 (CRC-DFG, project B05) (to K.H.), both funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).

The experimental methods described here have been approved by the government of Mittelfranken, Bavaria, Germany.
1. GvHD induction
<ol>
	<li>Day 0: Total body irradiation of the recipient mice
	<ol>
		<li>Use female CD45.2+ H2kd+ BALB/c mice that are at least 10 weeks old as recipients.</li>
		<li>Weigh and record the weight of the recipient mice prior to GvHD induction. 
		NOTE: Ensure that the recipient has a minimal body weight ...

<ol>
	<li>Ferrara, J. L., Levine, J. E., Reddy, P., Holler, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Graft-versus-host+disease.">Graft-versus-host disease.</a> The Lancet. 373, 1550-1561 (2009).</li><li>Magenau, J., Runaas, L., Reddy, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advances+in+understanding+the+pathogenesis+of+graft-versus-host+disease.">Advances in understanding the pathogenesis of graft-versus-host disease.</a> British Journal of Haematology. 173, 190-205 (2016).</li><li>Ball, L. M., Egeler, R. M., Party, E. P. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Acute+GvHD:+pathogenesis+and+classification.">Acute GvHD: pathogenesis and classification.</a> Bone Marrow Transplantation. 41, 58-64 (2008).</li><li>Naymagon, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Acute+graft-versus-host+disease+of+the+gut:+considerations+for+the+gastroenterologist.">Acute graft-versus-host disease of the gut: considerations for the gastroenterologist.</a> Nature Reviews. Gastroenterology &amp; Hepatology. 14, 711-726 (2017).</li><li>Zeiser, R., Blazar, B. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preclinical+models+of+acute+and+chronic+graft-versus-host+disease:+how+predictive+are+they+for+a+successful+clinical+translation.">Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation.</a> Blood. 127, 3117-3126 (2016).</li><li>Cooke, K. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+experimental+model+of+idiopathic+pneumonia+syndrome+after+bone+marrow+transplantation:+I.+The+roles+of+minor+H+antigens+and+endotoxin.">An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin.</a> Blood. 88, 3230-3239 (1996).</li><li>Anthony, B. A., Hadley, G. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Induction+of+graft-versus-host+disease+and+in+vivo+T+cell+monitoring+using+an+MHC-matched+murine+model.">Induction of graft-versus-host disease and in vivo T cell monitoring using an MHC-matched murine model.</a> Journal of Visualized Experiments. (66), e3697 (2012).</li><li>Beilhack, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prevention+of+acute+graft-versus-host+disease+by+blocking+T-cell+entry+to+secondary+lymphoid+organs.">Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs.</a> Blood. 111, 2919-2928 (2008).</li><li>Becker, C., Fantini, M. C., Neurath, M. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High+resolution+colonoscopy+in+live+mice.">High resolution colonoscopy in live mice.</a> Nature Protocols. 1, 2900-2904 (2006).</li><li>Buchele, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Targeting+Inflammatory+T+Helper+Cells+via+Retinoic+Acid-Related+Orphan+Receptor+Gamma+t+Is+Ineffective+to+Prevent+Allo-Response-Driven+Colitis.">Targeting Inflammatory T Helper Cells via Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis.</a> Frontiers in Immunology. 9, 1138 (2018).</li><li>Ullrich, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=BATF-dependent+IL-7RhiGM-CSF++T+cells+control+intestinal+graft-versus-host+disease.">BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease.</a> The Journal of Clinical Investigation. 128 (3), 916-930 (2018).</li><li>Kaplan, D. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Target+antigens+determine+graft-versus-host+disease+phenotype.">Target antigens determine graft-versus-host disease phenotype.</a> Journal of Immunology. 173, 5467-5475 (2004).</li></ol>

The protocol describes the methodology of induction and mini-endoscopic assessment of the colonic phenotype observed in the course of intestinal GvHD. It serves the wider purpose of enabling scientists to study intestinal GvHD longitudinally and noninvasively over the entire disease course (i.e., from the onset of colonic manifestation and progression until maximal disease activity).
However, there are some critical steps and important limitations inherent to the presented methodologies the ex...

Hematopoietic malignancies directly arising from the hematopoietic stem cell compartment and uncontrolled, rapidly progressing, and severe immune-mediated disorders are often indications to perform allo-HCT1,2. However, although accounting for the occurrence of the prognostic beneficial graft-versus-tumor response, donor lymphocytes are frequently inducing and promoting an unwanted immune-mediated attack of healthy tissue components within the allo-HCT recipient, a process that is called graft-versus-host disease3. Manifestations in the gut, the so-called intestinal GvHD, represent the most dreaded complication of acute GvHD, severe forms of which are routinely associated with a high mortality1,2,4.
Overall, murine models of allo-HCT have emerged as invaluable tools to identify and study immune-mediated mechanisms underlying the pathogenesis of GvHD5. However, kinetic assessment of, for instance, beneficial effects of novel therapeutic interventions over time in live mice is routinely based on the determination of clinical GvHD scores6. While these scores are suitable to reflect, for instance, the overall disease burden (i.e., the systemic GvHD), clinical scores lack the sensitivity to reliably mirror organ-specific manifestations (e.g., in the gut). Hence, conclusions, for instance with respect to gut-protective effects of a given therapeutic intervention, that are based on these scoring systems usually fall short.
Despite major advances through the invention of novel whole-body imaging modalities in combination with the usage of either bioluminescent or fluorescent genetic mouse models7,8, methodologies to directly and specifically assess the intestinal manifestation of GvHD in live mice are lacking. Hence, the rationale behind the protocol of the endoscopic assessment of the intestinal GvHD phenotype described in the next section is to overcome this obstacle. Furthermore, the motivation is also to reduce experimental mice numbers since, so far, a detailed assessment of the cellular, morphological, and molecular characteristics (e.g., by histopathology or molecular biology) of intestinal GvHD manifestation has ultimately required the sacrifice of the experimental mouse.
Our institution has previously reported on the methodology of a mini-endoscopic assessment of colonic manifestations in the course of syngeneic colitis models9. In the protocol presented here, we have refined and adapted the colonoscopic scoring matrix for alloresponse-driven colitis in live mice with intestinal GvHD upon transplantation of alloreactive HCT and donor lymphocytes in an MHC class I fully mismatched setting. We identified four parameters suitable to reflect intestinal GvHD-related colonic lesions. Furthermore, we established a system that allows a fine-tuned grading of any single determinant, resulting in a new score that readily informs the reader about the severity of intestinal GvHD present in a given mouse at a given time point. Histopathological analyses confirmed that an endoscopic score above a certain threshold is reliably predicting moderate-to-high grade tissue inflammation. Hence, mini-endoscopic evaluation appears to represent a working substitute for the gold standard histopathology that routinely requires the sacrifice of the experimental mice. Importantly, this protocol can be applied at virtually any given time point and can be repeatedly used during the course of the disease10,11. Furthermore, in contrast to the usage of bioluminescence-dependent approaches, no labor-intense and time-consuming measures like intercrossing genetically modified mice are required and, hence, the methodology can be applied on virtually any mouse line of interest.
Taken together, given the detrimental clinical perspective of allo-HCT patients with severe intestinal GvHD, rapid scientific progress and more insight into the molecular mechanisms underlying the immune pathogenesis are urgently needed. Similarly, important, ethical considerations demand that the gain of knowledge should be achieved with the usage of the minimal number of experimental mice. Hence, both recognized claims on the research community exploring intestinal GvHD can be advanced by implementing serial mini-endoscopic evaluations of the colon in the experimental work chain to monitor and grade intestinal GvHD in live experimental mouse models, as described and validated in the protocol presented here.

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			<td style="width:216px;">KARL STORZ SE &#38;Co KG</td>
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			<td>AbbVie Inc.&#160;</td>
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			<td>Carl Roth GmbH &#38; Co.KG</td>
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induction of intestinal graft-versus-host disease and its mini-endoscopic assessment in live mice

Acute graft-versus-host disease (GvHD) represents the most severe complication that patients previously undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) face and is frequently associated with a poor clinical outcome. While, for instance, GvHD manifestations of the skin are usually responsive to established immune-suppressive therapies and are, hence, not taking a fatal course, the presence and the intensity of intestinal GvHD, especially of the mid-to-lower parts of the gut, strongly influence the outcome and overall survival of patients with acute GvHD. Therapeutic options are essentially limited to the classic immune-suppressive agents yielding only moderate disease-mitigating effects. Hence, detailed knowledge about the tissue-resident immune cascade, changes in the intestinal microbiota, and the stromal response prior, upon, and after intestinal GvHD onset are urgently needed to understand the events and mechanisms underlying its pathogenesis and to develop innovative therapeutic options. Murine models of GvHD are frequently employed to identify and functionally assess molecules and pathways putatively driving intestinal GvHD. However, means to specifically monitor and evaluate intestinal inflammation over time are essentially lacking since established scores to assess and grade acute GvHD are routinely comprised of various parameters which rather reflect&#160;systemic GvHD manifestations. The detailed evaluation of intestinal GvHD has been restricted to studies using euthanized mice, thereby essentially excluding longitudinal (i.e., kinetic) analyses of the colonic compartment under a given experimental condition (e.g., antibody-mediated blockade of a proinflammatory cytokine) in live mice (i.e., in vivo). The mini-endoscopic in situ assessment of the distal colon of allo-HCT-treated mice described here allows a) a detailed macroscopic evaluation of different aspects of intestinal inflammation and b) the option to collect tissue samples for downstream analyses at various time points over the course of the observation period. Overall, the mini-endoscopic approach provides a major advance in preclinical noninvasive monitoring and assessment of intestinal GvHD.

The current protocol, describing the mini-endoscopic evaluation of intestinal GvHD-associated lesions of the distal colon, has been established and validated in mice previously subjected to the systemic induction of a severe acute GvHD model. In this study, we used an MHC class I fully mismatched model system in which BALB/c mice were lethally irradiated, followed by the transplantation of T-cell-depleted allogeneic bone marrow and by the administration of GvHD-inducing alloreactive C57BL...

Watch this Scientific Journal Video about Induction of Intestinal Graft-versus-host Disease and Its Mini-endoscopic Assessment in Live Mice at JoVE.com

Induction of Intestinal Graft-versus-host Disease and Its Mini-endoscopic Assessment in Live Mice

Here, we present a protocol that describes allogeneic hematopoietic stem cell transplantation and allows repetitive mini-endoscopic evaluations of the distal colon in situ for the presence, characteristics, and severity of colonic inflammation within live mice suffering from intestinal graft-versus-host disease.

Acute graft-versus-host disease (GvHD) represents the most severe complication that patients previously undergoing allogeneic hematopoietic stem cell ...

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Acute graft-versus-host disease (GVHD) is a significant limitation for patients receiving hematopoietic stem cell transplant as therapy for hematological ...

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 ...

Bone Marrow Transplantation Platform to Investigate the Role of Dendritic Cells in Graft-versus-Host Disease

Allogeneic bone marrow transplantation (BMT) is an effective therapy for hematological malignancies due to the graft-versus-leukemia (GVL) effect to ...