Humanizing the mouse immune system to study splanchnic organ inflammation

Abstract

It is well known that alterations in splanchnic organ perfusion and/or immune regulation may produce inflammatory tissue injury similar to that observed in several human disorders such as ischaemia and reperfusion injury, food allergies, diabetes, inflammatory bowel disease and graft-versus-host disease. Mouse models have been tremendously important in defining the roles of the circulation, leukocyte trafficking, inflammatory mediator generation, immune regulation and the intestinal microbiota in the pathogenesis of acute and chronic inflammation. However, few of the promising interventions or therapeutics reported in mouse models of inflammatory diseases have been translated to clinically effective treatments in patients. There is growing concern that because of the significant differences that exist between the murine and human immune systems, mouse models may not adequately recapitulate the immuno-pathogenesis of inflammatory diseases. This inconvenient reality has prompted a number of investigators to undertake a series of studies to humanize the murine immune system via adoptive transfer of human lymphoid or progenitor cells into a new generation of immuno-deficient recipients. In this review, we summarize the recent advances that have been made in the development of humanized mice and describe how these mouse models are being used to study the pathophysiology of splanchnic organ inflammation. In addition, we discuss the limitations of the different approaches and present potential solutions for the continued improvement of these important animal models.

Lung adenocarcinoma promotion by air pollutants

“…To begin exploring the mechanisms by which PM promotes EGFR mutant lung tumourigenesis, we tested if the immune system was required for PM-enhanced EGFR mutant tumourigenesis. We crossed Rosa26 LSL-tTa ;TetO-EGFR L858R mice with Rag2 -/-; Il2rg -/mice which lack T, B, NK cells and have an altered myeloid compartment 40 to generate immune-de cient EGFR mutant mice upon intratracheal delivery of adenoviral Cre (Rag2 -/-; Il2rg -/-;Rosa26 LSL-tTa/+ ; TetO-EGFR L858R ). Unlike in the ET mice (Figure 2A), 3 weeks of exposure to PM did not result in a signi cant increase in neoplastic lesions, suggesting a competent immune system is required for PM-enhanced EGFR mutant lung tumourigenesis (p=0.879; Figure 2E).…”

Biological Characteristics of Severe Combined Immunodeficient Mice Produced by CRISPR/Cas9-Mediated Rag2 and IL2rg Mutation

“…Further studies were carried out by mating NOD/shi-SCID mice or Rag2 mutation mice with interleukin-2 receptor gamma chain gene ( IL2rg ) mutation mice, which generated T, B, and NK cells combined deficiency mice, like NOG, NSG, and Rag2/IL2 - / - double knockout mice (Shultz et al, 2005; Belizário, 2009). These mouse have higher immunocompromised symptoms than the previously mentioned mice did due to the simultaneous absence of mature T-cells, B-cells, and NK cells as well as defective macrophage activity and reduced dendritic cell function (Ito et al, 2002; Shultz et al, 2007; McDaniel and Grisham, 2018). However, all of above-mentioned rodents were known as immunodeficient mice due to one or more immune response being impaired.…”

Progress, implications, and challenges in using humanized immune system mice in CAR‐T therapy—Application evaluation and improvement

“…32 35 This model is well adapted for studies on adaptive immune responses such as HIV infection, 36 inflammation in visceral organs, 37 and delayed type hypersensitivity. 38,39 Because of the better HIS simulation effect of the Hu-BLT model overcoming the disadvantages of the first two models, its application in CAR-T relevant research has also increased in recent years. CAR-T acting on the Hu-HSC B-cell acute lymphoblastic leukemia (B-ALL) disease model.…”

“…T cells mature within the human thymic epithelium of the same origin, and the maintained long‐term development in the thymus together with systemic development of T cells is conducive to the formation of an efficacious adaptive immune response 35 . This model is well adapted for studies on adaptive immune responses such as HIV infection, 36 inflammation in visceral organs, 37 and delayed type hypersensitivity 38,39 …”