Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice

Khosravi‐Maharlooei, Mohsen; Li, Haowei; Hoelzl, Markus; Zhao, Genshi; Ruiz, Amanda; Misra, Aalok; Li, Yang; Teteloshvili, Nato; Nauman, Grace; Danzl, Nichole; Ding, Xiaolan; Pinker, Elisha Y.; Obradovic, Aleksandar Z.; Yang, Yong‐Guang; Iuga, Alina; Creusot, Rémi J.; Winchester, Robert; Sykes, Megan

doi:10.1016/j.jaut.2021.102612

Cited by 7 publications

(35 citation statements)

References 36 publications

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“…HuHSC mice have long-lasting engraftment, but human T cells develop in the murine thymus and are thus restricted to murine rather than human major histocompatibility complex (MHC) molecules. These mouse-restricted human T cells have been implicated in the development of GvHD and wasting syndrome (11)(12)(13), and are, in principle, incapable of TCR : MHC-mediated cross-talk with human antigen-presenting cells such as monocytes, macrophages, dendritic cells, and B cells.…”

Section: Introductionmentioning

confidence: 99%

Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection

et al. 2021

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Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1–specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRβ sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution.

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Section: Introductionmentioning

confidence: 99%

Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection

et al. 2021

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“…scid mice (but not NSG mice) develop thymic lymphoma [ 143 ], which limits the experimental window. While the NSG mouse has its own drawbacks (most of them discussed further below), including the eventual development of xGvHD at later times [ 144 ], it remains the preferred recipient to date for engrafting human fetal tissues and cells.…”

Section: Models Supporting Human Immune Systems In Vivomentioning

confidence: 99%

“…As a major drawback, unlike fetal HSCs, these HSCs do not come with autologous thymic tissue. Of note, when mice are reconstituted with HSCs, regardless of the source (fetal, cord-blood, adult, iPSC), human thymopoiesis may be supported to a very limited extent by the NSG and NOG mouse thymus, despite its primitive and unorganized structure [ 144 , 156 , 161 ], and the resulting T cells are primarily restricted to mouse MHC [ 156 ]. The NeoThy model uses thymic tissue retrieved from neonatal cardiac surgeries, combined with cord blood from the same or unrelated (matched) donors [ 162 ].…”

Section: Models Supporting Human Immune Systems In Vivomentioning

confidence: 99%

“…HIS mouse models without a human thymic graft but instead with HLA transgenes to facilitate positive selection in the mouse thymus can be used to produce TCR-transgenic T cells. However, the NSG mouse thymus structure remains abnormal, even if human HSCs are given early in life [ 144 ], making murine thymi unsuitable for the analysis of normal human T-cell negative selection.…”

Section: Applications Of His Models To Study Immune Tolerance and Autoimmune Processesmentioning

confidence: 99%

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Modeling human T1D-associated autoimmune processes

Khosravi‐Maharlooei

Madley

Borsotti

et al. 2022

Molecular Metabolism

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Background Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to β-cell antigens and progressive destruction of insulin-producing β-cells. Animal models have provided valuable insights for understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics. Scope of review Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system (HIS) in a xenogeneic recipient, and what remains to be done to improve their physiological relevance. Major conclusions To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, HIS mice enable more extensive analyses using in vivo systems.

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“…It appears that disease developed in an indirectly and without recognition of antigens on recipient mouse MHC. Even if human thymus grafts have normal structure and negative selection, failure in tolerating human T cells that recognize mouse antigens being presented on HLA molecules may explain the development of autoimmunity 75 . This suggests generating methodologies that bypass human autoimmunity in the next generation of HIS mice.…”

Section: Improving Humanized Mice By Overcoming Current Limitationsmentioning

confidence: 99%

Development of humanized mouse with patient‐derived xenografts for cancer immunotherapy studies: A comprehensive review

Jin

Lan

et al. 2021

Cancer Science

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Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre‐clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient‐derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre‐clinical evaluation of onco‐immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.

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Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice

Cited by 7 publications

References 36 publications

Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection

Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection

Modeling human T1D-associated autoimmune processes

Development of humanized mouse with patient‐derived xenografts for cancer immunotherapy studies: A comprehensive review

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