Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of 'humanized' mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, we discuss recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.
"Mouse models humanized for components of the immune system (HIS) are based on the xenotransplantation of tissues supporting longterm production of human hematopoietic cells into permissive, immuno-deficient animals. Strategies to generate HIS mice have been largely optimized over the past three decades (Shultz et al. 2012). Despite residual limitations, HIS mice are seen as attractive platforms to perform prospective in vivo analysis of human leucocyte ontogeny, function and reactivity in preclinical settings. "
"NSG mice do not express IL2rg and thus their cells cannot bind the relevant cytokines, while in NOG mice the common gamma chain receptor has a deleted cytoplasmic domain, which can bind cytokines but does not signal. BRG mice have strain-dependent disruptions in IL2rg, which are either non-expressed or incapable of intracellular signaling (Shultz et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Many important aspects of human retroviral infections cannot be fully evaluated using only in vitro systems or unmodified animal models. An alternative approach involves the use of humanized mice, which consist of immunodeficient mice that have been transplanted with human cells and/or tissues. Certain humanized mouse models can support robust infection with human retroviruses including different strains of human immunodeficiency virus (HIV) and human T cell leukemia virus (HTLV). These models have provided wide-ranging insights into retroviral biology, including detailed information on primary infection, in vivo replication and pathogenesis, latent/persistent reservoir formation, and novel therapeutic interventions. Here we describe the humanized mouse models that are most commonly utilized to study retroviral infections, and outline some of the important discoveries that these models have produced during several decades of intensive research.
"We believe that for the development of cellular therapy this is not the right approach. Even “humanized” mouse models can only mimic the human system and never completely reflect a human disease with its enormous heterogeneity and complexity (23). Animal models should be used for what they are developed for, namely, as model for mechanistic pathways and not as model for a specific disease. "
[Show abstract][Hide abstract] ABSTRACT: Clinical translation of tolerance-inducing cell therapies requires a novel approach focused on innovative networks, patient involvement, and, foremost, a fundamental paradigm shift in thinking from both Academia, and Industry and Regulatory Agencies. Tolerance-inducing cell products differ essentially from conventional drugs. They are personalized and target interactive immunological networks to shift the balance toward tolerance. The human cell products are often absent or fundamentally different in animals. This creates important limitations of pre-clinical animal testing for safety and efficacy of these products and calls for novel translational approaches, which require the combined efforts of the different parties involved. Dedicated international and multidisciplinary consortia that focus on clinical translation are of utmost importance. They can help in informing and educating regulatory policy makers on the unique requirements for these cell products, ranging from pre-clinical studies in animals to in vitro human studies. In addition, they can promote reliable immunomonitoring tools. The development of tolerance-inducing cell products requires not only bench-to-bedside but also reverse translation, from bedside back to the bench.
Frontiers in Immunology 08/2014; 5:392. DOI:10.3389/fimmu.2014.00392
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