Induction of acute graft vs. host disease in lymphopenic mice

Mims, Brianyell McDaniel; Jones-Hall, Yava L.; Santos, Andrea Pires dos; Furr, Kathryn L.; Enriquez, Josue; Grisham, Matthew B.

doi:10.1016/j.pathophys.2019.06.002

Cited by 4 publications

(17 citation statements)

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“…Xenotransplantation models using immunodeficient mice provide an opportunity to address these gaps in our understanding of the posttransplant behavior of different sources of human graft tissues. However, possibly as a result of inefficient competition for murine hematopoietic factors, pretransplant irradiation is required for human cells to successfully engraft most strains of immunodeficient mice (9)(10)(11). Because irradiation causes damage that promotes GVHD by activating host responses, we sought an approach that would allow us to investigate the inherent propensity of human T cells to cause pathology in a host environment lacking radiation-associated damage.…”

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confidence: 99%

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

Hess

Hudson

Hematti

et al. 2020

The Journal of Immunology

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Acute graft-versus-host disease (GVHD) is a frequent complication of hematopoietic transplantation, yet patient risk stratification remains difficult, and prognostic biomarkers to guide early clinical interventions are lacking. We developed an approach to evaluate the potential of human T cells from hematopoietic grafts to produce GVHD. Nonconditioned NBSGW mice transplanted with titrated doses of human bone marrow developed GVHD that was characterized by widespread lymphocyte infiltration and organ pathology. Interestingly, GVHD was not an inevitable outcome in our system and was influenced by transplant dose, inflammatory status of the host, and type of graft. Mice that went on to develop GVHD showed signs of rapid proliferation in the human T cell population during the first 1-3 wk posttransplant and had elevated human IFN-g in plasma that correlated negatively with the expansion of the human hematopoietic compartment. Furthermore, these early T cell activation metrics were predictive of GVHD onset 3-6 wk before phenotypic pathology. These results reveal an early window of susceptibility for pathological T cell activation following hematopoietic transplantation that is not simply determined by transient inflammation resulting from conditioning-associated damage and show that T cell parameters during this window can serve as prognostic biomarkers for risk of later GVHD development.

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confidence: 99%

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

Hess

Hudson

Hematti

et al. 2020

The Journal of Immunology

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“…During the 7-day pretreatment, all mice were injected (i.p) with NK1.1 mAb (250 μg in 0.5ml PBS; clone PK136) at 48 and 24 hours prior to T cell transfer to deplete NK cells. We have found that this treatment protocol reduces CD335-expressing NK cells by~90% when assessed at 24 hrs following the second injection (21). NK cell depleted RAG1 -/-(-NK/RAG) mice were then injected (i.p.)…”

Section: Abx Treatment and Induction Of Agvhdmentioning

confidence: 99%

“…Representative sections of colon, lung, liver, spleen and skin were scored in a blinded fashion by our collaborator Dr. Yava Jones-Hall as previously described [21]. Briefly, the severity and distribution of inflammation in the colonic mucosa was quantified as mild to severe using a score of 0-3.…”

Section: Blinded Histological Evaluationmentioning

confidence: 99%

“…Total disease score ranged from 0 to a maximum of 7 points based upon summation of each assigned criterion. Both spleens and bone marrow were scored in a blinded fashion by our collaborator Dr. Andrea Pires dos Santos as previously described [21]. Briefly, spleen scores were based on different aspects of the lesions including the presence of the red and white pulp, T zone lymphocytes, and presence of follicles (scores 0, present in the right amount; 1, mild decrease; 2, moderate decrease; 3, marked decrease), as well as extramedullary hematopoiesis, mantle cell zone, and the red to white pulp ratio (scores 0, present in the right amount; 1, mild increase; 2, moderate increase; 3, marked increase) for a maximum organ score of 24.…”

Section: Blinded Histological Evaluationmentioning

confidence: 99%

“…We hypothesized that in the absence of intestinal mucosal barrier disruption, commensal bacteria would play little or no role in the development of aGVHD. To test this hypothesis, we used our recently described mouse model of aGVHD that does not use toxic, pre-transplant conditioning [21]. We found that treatment of NK cell-depleted recombination activating gene-1-deficient (-NK/RAG1) recipients with an Abx cocktail containing vancomycin and neomycin for 7 days prior to and 4 weeks following adoptive transfer of allogeneic CD4 + T cells exacerbated aGVHD-induced bone marrow and spleen damage when compared to untreated mice engrafted with allogeneic or syngeneic T cells.…”

Section: Introductionmentioning

confidence: 99%

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Antibiotic administration exacerbates acute graft vs. host disease-induced bone marrow and spleen damage in lymphopenic mice

et al. 2021

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Background Hematopoietic stem cell transplantation is a potential cure for certain life-threatening malignant and nonmalignant diseases. However, experimental and clinical studies have demonstrated that pre-transplant myeloablative conditioning damages the gut leading to translocation of intestinal bacteria and the development of acute graft vs. host disease (aGVHD). The overall objective of this study was to determine whether administration of broad spectrum antibiotics (Abx) affects the onset and/or severity of aGVHD in lymphopenic mice that were not subjected to toxic, pre-transplant conditioning. Results We found that treatment of NK cell-depleted recombination activating gene-1-deficient (-NK/RAG) recipients with an Abx cocktail containing vancomycin and neomycin for 7 days prior to and 4 weeks following adoptive transfer of allogeneic CD4+ T cells, exacerbated the development of aGVHD-induced BM failure and spleen damage when compared to untreated–NK/RAG recipients engrafted with syngeneic or allogeneic T cells. Abx-treated mice exhibited severe anemia and monocytopenia as well as marked reductions in BM- and spleen-residing immune cells. Blinded histopathological analysis confirmed that Abx-treated mice engrafted with allogeneic T cells suffered significantly more damage to the BM and spleen than did untreated mice engrafted with allogeneic T cells. Abx-induced exacerbation of BM and spleen damage correlated with a dramatic reduction in fecal bacterial diversity, marked loss of anaerobic bacteria and remarkable expansion of potentially pathogenic bacteria. Conclusions We conclude that continuous Abx treatment may aggravate aGVHD-induced tissue damage by reducing short chain fatty acid-producing anaerobes (e.g. Clostridium, Blautia) and/or by promoting the expansion of pathobionts (e.g. Akkermansia) and opportunistic pathogens (Cronobacter).

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Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension

et al. 2022

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People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.

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Induction of acute graft vs. host disease in lymphopenic mice

Cited by 4 publications

References 58 publications

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

Antibiotic administration exacerbates acute graft vs. host disease-induced bone marrow and spleen damage in lymphopenic mice

Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension

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