Comparison of gamma and x-ray irradiation for myeloablation and establishment of normal and autoimmune syngeneic bone marrow chimeras

Wittenborn, Thomas; Hagert, Cecilia; Ferapontov, Alexey; Fonager, Sofie Vestergaard; Jensen, Lisbeth; Winther, Gudrun; Degn, Søren E.

doi:10.1371/journal.pone.0247501

Cited by 17 publications

(10 citation statements)

References 21 publications

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“…Thus, even at significantly reduced frequencies of autoreactive T cells, T cell tolerance fails in a subset of animals. As irradiation itself can promote autoimmunity ( 44 ), all additional studies have utilized the HODxOTII F1 animals as the preferable murine model of idiopathic AIHA.…”

Section: Discussionmentioning

confidence: 99%

A New Murine Model of Primary Autoimmune Hemolytic Anemia (AIHA)

et al. 2021

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Loss of humoral tolerance to red blood cells (RBCs) can lead to autoimmune hemolytic anemia (AIHA), a severe, and sometimes fatal disease. Patients with AIHA present with pallor, fatigue, decreased hematocrit, and splenomegaly. While secondary AIHA is associated with lymphoproliferative disorders, infections, and more recently, as an adverse event secondary to cancer immunotherapy, the etiology of primary AIHA is unknown. Several therapeutic strategies are available; however, there are currently no licensed treatments for AIHA and few therapeutics offer treatment-free durable remission. Moreover, supportive care with RBC transfusions can be challenging as most autoantibodies are directed against ubiquitous RBC antigens; thus, virtually all RBC donor units are incompatible. Given the severity of AIHA and the lack of treatment options, understanding the cellular and molecular mechanisms that facilitate the breakdown in tolerance would provide insight into new therapeutics. Herein, we report a new murine model of primary AIHA that reflects the biology observed in patients with primary AIHA. Production of anti-erythrocyte autoantibodies correlated with sex and age, and led to RBC antigen modulation, complement fixation, and anemia, as determined by decreased hematocrit and hemoglobin values and increased reticulocytes in peripheral blood. Moreover, autoantibody-producing animals developed splenomegaly, with altered splenic architecture characterized by expanded white pulp areas and nearly diminished red pulp areas. Additional analysis suggested that compensatory extramedullary erythropoiesis occurred as there were increased frequencies of RBC progenitors detectable in the spleen. No significant correlations between AIHA onset and inflammatory status or microbiome were observed. To our knowledge, this is the first report of a murine model that replicates observations made in humans with idiopathic AIHA. Thus, this is a tractable murine model of AIHA that can serve as a platform to identify key cellular and molecular pathways that are compromised, thereby leading to autoantibody formation, as well as testing new therapeutics and management strategies.

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Section: Discussionmentioning

confidence: 99%

A New Murine Model of Primary Autoimmune Hemolytic Anemia (AIHA)

et al. 2021

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“…Mixed bone marrow chimeras were set up as previously described ( 32 ). Recipient mice were irradiated with 9 Gy in a MultiRad 350 (Faxitron), with 350 kV, 11.4 mA, a Thoraeus filter [0.75 mm Tin (Sn), 0.25 mm Copper (Cu), and 1.5 mm Aluminium (Al)], and with a beam-distance of 37 cm.…”

Section: Methodsmentioning

confidence: 99%

The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

et al. 2022

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IntroductionMany autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development.MethodsWe blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras.ResultsGC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. In vitro, loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output.DiscussionWe identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection.

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“…Wittenborn et al. showed an autoimmune phenotype achieved in mixed chimaera models after ionizing X-ray radiation and Cesium-137 treatment ( 190 ). Finally, Tandl et al.…”

Section: Physical Methods and Their Mechanismsmentioning

confidence: 99%

Chemotherapy and Physical Therapeutics Modulate Antigens on Cancer Cells

et al. 2022

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Cancer cells possess specific properties, such as multidrug resistance or unlimited proliferation potential, due to the presence of specific proteins on their cell membranes. The release of proliferation-related proteins from the membrane can evoke a loss of adaptive ability in cancer cells and thus enhance the effects of anticancer therapy. The upregulation of cancer-specific membrane antigens results in a better outcome of immunotherapy. Moreover, cytotoxic T-cells may also become more effective when stimulated ex-vivo toward the anticancer response. Therefore, the modulation of membrane proteins may serve as an interesting attempt in anticancer therapy. The presence of membrane antigens relies on various physical factors such as temperature, exposure to radiation, or drugs. Therefore, changing the tumor microenvironment conditions may lead to cancer cells becoming sensitized to subsequent therapy. This paper focuses on the therapeutic approaches modulating membrane antigens and enzymes in anticancer therapy. It aims to analyze the possible methods for modulating the antigens, such as pharmacological treatment, electric field treatment, photodynamic reaction, treatment with magnetic field or X-ray radiation. Besides, an overview of the effects of chemotherapy and immunotherapy on the immunophenotype of cancer cells is presented. Finally, the authors review the clinical trials that involved the modulation of cell immunophenotype in anticancer therapy.

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Comparison of gamma and x-ray irradiation for myeloablation and establishment of normal and autoimmune syngeneic bone marrow chimeras

Cited by 17 publications

References 21 publications

A New Murine Model of Primary Autoimmune Hemolytic Anemia (AIHA)

A New Murine Model of Primary Autoimmune Hemolytic Anemia (AIHA)

The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

Chemotherapy and Physical Therapeutics Modulate Antigens on Cancer Cells

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