A mouse model for ulcerative colitis based on NOD-<i>scid</i> IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals

Palamides, Pia; Jodeleit, Henrika; Föhlinger, Michael; Beigel, Florian; Herbach, Nadja; Mueller, Thomas D.; Wolf, Eckhard; Siebeck, Matthias; Gropp, Roswitha

doi:10.1242/dmm.025452

Cited by 19 publications

(33 citation statements)

References 28 publications

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“…The current study also demonstrates that humanized NSG mice engraft human monocytes and DCs. Previous studies have shown that NSG mice engraft human monocytes and DCs when injected with human cord blood, and engraft human monocytes when injected with hPBMCs . Similarly, SCID mice injected with hPBMCs engraft human DCs, but the current study is the first to demonstrate DC engraftment in NSG mice injected with hPBMCs.…”

Section: Discussionmentioning

confidence: 51%

“…Previous studies have shown that NSG mice engraft human monocytes and DCs when injected with human cord blood, 38 and engraft human monocytes when injected with hPBMCs. 39,40 Similarly, SCID mice injected with hPBMCs engraft human DCs, 41 but the current study is the first to demonstrate DC engraftment in NSG mice injected with hPBMCs. Human T cells recognize murine major histocompatibility complex I and II molecules in NSG mice to cause GVHD, 27 but the identity of the APCs involved remains to be determined.…”

Section: Discussionmentioning

confidence: 69%

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Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

2019

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Allogeneic hematopoietic stem cell transplantation is a curative therapy for a number of hematological malignancies, but is limited by the development of graft‐versus‐host disease (GVHD). CD39 and CD73 form an ectoenzymatic pathway that hydrolyzes extracellular adenosine 5′‐triphosphate (ATP) to adenosine, which respectively exacerbate or alleviate disease in allogeneic mouse models of GVHD. The current study aimed to explore the role of the CD39/CD73 pathway and adenosine receptor (AR) blockade in a humanized mouse model of GVHD. Immunodeficient nonobese diabetic‐severe combined immunodeficiency‐IL‐2 receptor γnull mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the CD39/CD73 antagonist αβ‐methylene‐ADP (APCP) (50 mg kg−1) or saline for 7 days, or the AR antagonist caffeine (10 mg kg−1) or saline for 14 days. Mice predominantly engrafted human CD4+ and CD8+ T cells, with smaller proportions of human regulatory T cells, invariant natural killer T cells, monocytes and dendritic cells. Neither APCP nor caffeine altered engraftment of these human leukocyte subsets. APCP (CD39/CD73 blockade) augmented GVHD as shown through increased weight loss and worsened liver histology, including increased leukocyte and human T‐cell infiltration, and increased apoptosis. This treatment also increased serum human IL‐2 concentrations and decreased the frequency of human CD39− CD73− CD4+ T cells. In contrast, caffeine (AR blockade) did not alter GVHD severity or human serum cytokine concentrations (IL‐2, IL‐6, IL‐10 or tumor necrosis factor‐α). In conclusion, blockade of CD39/CD73 but not ARs augments disease in a humanized mouse model of GVHD. These results indicate that CD39/CD73 blockade maintains sufficient extracellular ATP concentrations to promote GVHD in this model.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 69%

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

2019

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“…To examine the role of autoantigens in an inflammatory environment in vivo, the effect of CD99 was analyzed in NSG-UC model [7,9,23]. NSG mice were reconstituted with PBMC from donors with UC and additionally challenged with CD99.…”

Section: Additional Challenge With Cd99 Aggravates Disease Symptoms Amentioning

confidence: 99%

“…In order to gain a better understanding of the inflammatory processes an animal model was developed which is based on NOD-scid IL2Rγ null (NSG) mice reconstituted with PBMC from diseased UC-individuals (NSG-UC model) [7,8]. Challenge of mice with ethanol evoked symptoms and phenotype similar to the human disease and treatment with infliximab promoted a remodeling condition characterized by increased fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies as diagnostic markers and potential drivers of inflammation in ulcerative colitis

et al. 2020

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To date, no comprehensive analysis of autoantibodies in sera of patients with ulcerative colitis has been conducted. To analyze the spectrum of autoantibodies and to elucidate their role serum-IgG from UC patients (n = 49) and non-UC donors (n = 23) were screened by using a human protein microarray. Screening yielded a remarkable number of 697 differentially-reactive at the nominal 0�01 significance level (FDR<0�1) of the univariate test between the UC and the non-UC group. CD99 emerged as a biomarker to discriminate between both groups (p = 1e-04, AUC = 0�8). In addition, cytokines, chemokines and growth factors were analyzed by Olink's Proseek® Multiplex Inflammation-I 96×96 immuno-qPCR assay and 31 genes were significant at the nominal 0.05 level of the univariate test to discriminate between UC and non-UC donors. MCP-3, HGF and CXCL-9 were identified as the most significant markers to discriminate between UC patients with clinically active and inactive disease. Levels of CXCL10 (cor = 0.3; p = 0.02), CCL25 (cor = 0.25; p = 0.04) and CCL28 (cor = 0.3; p = 0.02) correlated positively with levels of anti CD99. To assess whether autoantibodies are detectable prior to diagnosis with UC, sera from nine donors at two different time points (T-early, median 21 months and T-late, median 6 months) were analyzed. 1201 features were identified with higher reactivity in samples at time points closer to clinical UC presentation. In vitro, additional challenge of peripheral mononuclear cells with CD99 did not activate CD4+ T cells but induced the secretion of IL-10 (-CD99: 20.21±20.25; +CD99: 130.20±89.55; mean ±sd; p = 0.015). To examine the effect of CD99 in vivo, inflammation and autoantibody levels were examined in NOD/ScidIL2Rγ null mice reconstituted with PBMC from UC donors (NSG-UC). Additional challenge with CD99 aggravated disease symptoms and pathological phenotype as indicated by the elevated clinical score (-CD99: 1�85 ± 1�94; +CD99: 4�25 ± 1�48) and histological score (-CD99: 2�16 ± 0�83; +CD99: 3�15 ± 1�16, p = 0�01). Furthermore, levels of anti-CD99 antibodies increased (Control: 398 ± 323; mean MFI ± sd; Ethanol + PBS: 358 ±316; Ethanol + CD99: 1363 ± 1336; Control versus PLOS ONE | https://doi.Ethanol + CD99: p = 0.03). In a highly inflammatory environment, frequencies of pro-inflammatory M1 monocytes (CD14+ CD64+: unchallenged 8.09±4.72; challenged 14.2±8.62; p = 0.07; CD14+ CD1a+: unchallenged 16.29 ±6.97; challenged 43.81±14.4, p = 0.0003) increased and levels of autoantibodies in serum decreased in the NSG-UC mouse model. These results suggest that autoantibodies are potent biomarkers to discriminate between UC and non-UC and indicate risk to develop UC. In an inflammatory environment, auto-antibodies may promote the pathological phenotype by activating M1 monocytes in the NSG-UC animal model and also in patients with UC.

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“…Therefore, preclinical models with better reflection of human disease are needed. Recently, a humanized mouse model that mimics disease patterns of patients with UC has been successfully established [50]. Peripheral blood mononuclear cells of stratified patients with UC are injected in immunodeficient NOD/scid IL2R-γnull mice.…”

Section: New Therapeutic Approachesmentioning

confidence: 99%

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis

Kuehn

Hodin

2018

Visc Med

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Background: The primary treatment of ulcerative colitis (UC) is conservative, and substantial therapeutic progress has been made in the past few decades. Meanwhile, biologicals have become a mainstay in the treatment for steroid-refractory UC. Despite further development of drug therapy and an increased time span to operation, a significant proportion of patients with UC require surgical intervention. Surgical intervention needs to be carried out in medically refractory cases, imminent or malignant transformation, or complications. This article discusses the impact of modern drug therapy on surgery for UC. Methods: A selective literature search of PubMed was conducted, taking into account current studies, reviews, meta-analyses, and guidelines. Selected articles were then reviewed in detail and recommendations were drafted based on data and conclusions of the articles. Results: In recent years, modern drug therapy has changed the timing, approach, and outcomes of surgery for UC. Most of the studies showed a decrease in surgery rates over time while the rate of emergency colectomies remains unchanged. So far, no convincing surgery-sparing effect of newer medications has been established, and it remains debatable if surgery rates have decreased because of improved management for UC in general or due to the introduction of biologicals. The intensified conservative therapy with increasing use of biologics has been accompanied by a trend towards performing a three-step procedure in the last decade. There is a subset of patients with complex refractory disease who most likely benefit from elective surgery as an alternative to prolonged conservative therapies after failure of first-line treatment. The majority of patients after ileal pouch-anal anastomosis can avoid hospitalizations and colitis-related medications with their associated potential adverse effects. In addition, the procedure substantially reduces UC-related symptoms and the risk for dysplasia or cancer. There is a long-term pouch success rate of >90% after 10 and 20 years of follow-up. Conclusion: Conservative medical therapy in the treatment of UC will continue to develop and the number of approved therapeutics will grow. Surgery should not be considered as the negative endpoint of treatment modalities but as a good alternative to a prolonged conservative therapy for some patients. In conclusion, a close cooperation between the various disciplines in the pre- and postoperative management is essential in order to optimize the timing and outcome of patients with UC.

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A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals

Cited by 19 publications

References 28 publications

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

Autoantibodies as diagnostic markers and potential drivers of inflammation in ulcerative colitis

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis

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