Generation of improved humanized mouse models for human infectious diseases

Brehm, Michael A.; Wiles, Michael V.; Greiner, Dale L.; Shultz, Leonard D.

doi:10.1016/j.jim.2014.02.011

Cited by 122 publications

(105 citation statements)

References 152 publications

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“…This indicates that specific host-pathogen interactions drive pneumonia development and illustrates the importance of humanized animal models to study HAP. Additionally, an adult, immunocompetent humanized HAP animal model that mimics "human" host cytokine response would generate data and mechanisms with more translational value in directly investigating more clinically relevant infectious processes of human pneumonia (114). Besides these potential major advantages of utilizing a humanized immune system to study bacterial pneumonia, the commonly used wild-type animal models described above are currently easier to create and allow for more flexibility in the experimental setup and will therefore remain an important tool to tackle the problems surrounding hospitalacquired pneumonia.…”

Section: Humanized Modelsmentioning

confidence: 99%

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Bielen¹,

Jongers²,

Malhotra-Kumar³

et al. 2017

Ann. Transl. Med.

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Lower respiratory tract infections are amongst the leading causes of mortality and morbidity worldwide. Especially in hospital settings and more particularly in critically ill ventilated patients, nosocomial pneumonia is one of the most serious infectious complications frequently caused by opportunistic pathogens.Pseudomonas aeruginosa is one of the most important causes of ventilator-associated pneumonia as well as the major cause of chronic pneumonia in cystic fibrosis patients. Animal models of pneumonia allow us to investigate distinct types of pneumonia at various disease stages, studies that are not possible in patients.Different animal models of pneumonia such as one-hit acute pneumonia models, ventilator-associated pneumonia models and biofilm pneumonia models associated with cystic fibrosis have been extensively studied and have considerably aided our understanding of disease pathogenesis and testing and developing new treatment strategies. The present review aims to guide investigators in choosing appropriate animal pneumonia models by describing and comparing the relevant characteristics of each model using P. aeruginosa as a model etiology for hospital-acquired pneumonia. Key to establishing and studying these animal models of infection are well-defined end-points that allow precise monitoring and characterization of disease development that could ultimately aid in translating these findings to patient populations in order to guide therapy. In this respect, and discussed here, is the development of humanized animal models of bacterial pneumonia that could offer unique advantages to study bacterial virulence factor expression and host cytokine production for translational purposes.

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Section: Humanized Modelsmentioning

confidence: 99%

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Bielen¹,

Jongers²,

Malhotra-Kumar³

et al. 2017

Ann. Transl. Med.

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“…Therefore, a humanized mouse model with functional human CD4 ϩ T and B cells would be useful to assess the contributions of these immune cells to the lung disease induced by RSV infection. Murine models consisting of mice with a human immune system (HIS mice) have been developed to study the mechanisms of infection and human immune responses against human pathogens and to test the efficacy of vaccines (11)(12)(13)(14). We recently established HIS mice that possess functional human CD8 ϩ or CD4 ϩ T and B cells.…”

mentioning

confidence: 99%

Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology

Sharma

Sung

et al. 2016

J Virol

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Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease, which causes high rates of morbidity and mortality in infants and the elderly. Models of human RSV pulmonary disease are needed to better understand RSV pathogenesis and to assess the efficacy of RSV vaccines. We assessed the RSV-specific human innate, humoral, and cellular immune responses in humanized mice (mice with a human immune system [HIS mice]) with functional human CD4 ؉ T and B cells. These mice were generated by introduction of HLA class II genes, various human cytokines, and human B cell activation factor into immunodeficient NOD scid gamma (NSG) mice by the use of an adeno-associated virus vector, followed by engraftment of human hematopoietic stem cells. During the first 3 days of infection, HIS mice lost more weight and cleared RSV faster than NSG mice. Human chemokine (C-C motif) ligand 3 (CCL3) and human interleukin-1␤ (IL-1␤) expression was detected in the RSV-infected HIS mice. The pathological features induced by RSV infection in HIS mice included peribronchiolar inflammation, neutrophil predominance in the bronchioalveolar lavage fluid, and enhanced airway mucus production. Human anti-RSV IgG and RSVneutralizing antibodies were detected in serum and human anti-RSV mucosal IgA was detected in bronchioalveolar lavage fluid for up to 6 weeks. RSV infection induced an RSV-specific human gamma interferon response in HIS mouse splenocytes. These results indicate that human immune cells can induce features of RSV lung disease, including mucus hyperplasia, in murine lungs and that HIS mice can be used to elicit human anti-RSV humoral and cellular immunity. Infection of the lower respiratory tract with respiratory syncytial virus (RSV) is the most common cause for hospitalization of infants and children (1) and globally causes up to 200,000 deaths in children under the age of 5 years (2). Premature infants, especially those with chronic lung disease or congenital heart disease (3), and the elderly (4) are the most susceptible to the development of severe disease. Early RSV infections are also associated with the later development of asthma (5). No efficient therapeutics or vaccines active against RSV are available. Only immunoprophylaxis with palivizumab, a monoclonal anti-RSV F antibody, provides some protection for infants at risk (6). Several animal models have been developed to model human RSV disease (7). As mouse models have limitations in mimicking human RSV disease, better models would be useful for the preclinical assessment of novel anti-RSV therapies and vaccines. Humoral immunity is essential in the prevention of RSV infections. Higher levels of maternally derived antibodies (8) and prophylactic administration of intravenous immunoglobulin enriched for high levels of RSV-neutralizing antibodies (9) or humanized monoclonal antibody against RSV (10) are associated with a reduction of disease severity in RSV-infected infants. Therefore, a humanized mouse model with functional human CD4 ϩ T and B...

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“…Utilizing the TCR retrogenic protocol described here allows for an investigator to test and screen the development and functionality of numerous newly identified MHC class I or II restricted TCRs. With the development of the "humanized mouse" model 18,19 , the TCR retrogenic could further be expanded utilizing cloned human TCRs. Additionally, the 2A linked constructs can also be used to study other multi-proteins including the CD3 chains, interleukins and chimeric antigen receptors [20][21][22][23][24] .…”

Section: Discussionmentioning

confidence: 99%

Retroviral Transduction of Bone Marrow Progenitor Cells to Generate T-cell Receptor Retrogenic Mice

Lee

Shevchenko

Sprouse

et al. 2016

JoVE

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T cell receptor (TCR) signaling is essential in the development and differentiation of T cells in the thymus and periphery, respectively. The vast array of TCRs proves studying a specific antigenic response difficult. Therefore, TCR transgenic mice were made to study positive and negative selection in the thymus as well as peripheral T cell activation, proliferation and tolerance. However, relatively few TCR transgenic mice have been generated specific to any given antigen. Thus, studies involving TCRs of varying affinities for the same antigenic peptide have been lacking. The generation of a new TCR transgenic line can take six or more months. Additionally, any specific backcrosses can take an additional six months. In order to allow faster generation and screening of multiple TCRs, a protocol for retroviral transduction of bone marrow was established with stoichiometric expression of the TCRα and TCRβ chains and the generation of retrogenic mice. Each retrogenic mouse is essentially a founder, virtually negating a founder effect, while the length of time to generate a TCR retrogenic is cut from six months to approximately six weeks. Here we present a rapid and flexible alternative to TCR transgenic mice that can be expressed on any chosen background with any particular TCR. Video LinkThe video component of this article can be found at

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Generation of improved humanized mouse models for human infectious diseases

Cited by 122 publications

References 152 publications

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology

Retroviral Transduction of Bone Marrow Progenitor Cells to Generate T-cell Receptor Retrogenic Mice

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