Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells.

In vivo models that recapitulate human erythropoiesis with persistence of circulating red blood cells (RBCs) have remained elusive. We report an immunodeficient murine model in which combined human liver and cytokine humanization confer enhanced human erythropoiesis and RBC survival in the circulation. We deleted the fumarylacetoacetate hydrolase () gene in MISTRG mice expressing several human cytokines in place of their murine counterparts.

A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production.

Humanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen-specific antibody responses. Here we describe a new mouse strain, in which human interleukin 6 (IL-6) gene encoding the cytokine that is important for B- and T-cell differentiation was knocked into its respective mouse locus.

Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice.

Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo.

AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites.

Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms including the house dust mite (HDM). Here we show that knockin mice expressing an enzymatically inactive acidic mammalian chitinase (AMCase), the dominant true chitinase in mouse lung, showed enhanced type 2 immune responses to inhaled HDM. We found that uncleaved chitin promoted the release of IL-33, whereas cleaved chitin could be phagocytosed and could induce the activation of caspase-1 and subsequent activation of caspase-7; this results in the resolution of type 2 immune responses, probably by promoting the inactivation of IL-33.

Human hemato-lymphoid system mice: current use and future potential for medicine.

To directly study complex human hemato-lymphoid system physiology and respective system-associated diseases in vivo, human-to-mouse xenotransplantation models for human blood and blood-forming cells and organs have been developed over the past three decades. We here review the fundamental requirements and the remarkable progress made over the past few years in improving these systems, the current major achievements reached by use of these models, and the future challenges to more closely model and study human health and disease and to achieve predictive preclinical testing of both prevention measures and potential new therapies.

Efficient differentiation and function of human macrophages in humanized CSF-1 mice.

Humanized mouse models are useful tools to understand pathophysiology and to develop therapies for human diseases. While significant progress has been made in generating immunocompromised mice with a human hematopoietic system, there are still several shortcomings, one of which is poor human myelopoiesis. Here, we report that human CSF-1 knockin mice show augmented frequencies and functions of human myeloid cells.

Transgenic expression of human signal regulatory protein alpha in Rag2-/-gamma(c)-/- mice improves engraftment of human hematopoietic cells in humanized mice.

Transplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/γ(c)(-/-) (NSG) and BALB/c Rag2(-/-)γ(c)(-/-) mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo.

In vivo diabetogenic action of CD4+ T lymphocytes requires Fas expression and is independent of IL-1 and IL-18.

CD4(+) T lymphocytes are required to induce spontaneous autoimmune diabetes in the NOD mouse. Since pancreatic β cells upregulate Fas expression upon exposure to pro-inflammatory cytokines, we studied whether the diabetogenic action of CD4(+) T lymphocytes depends on Fas expression on target cells. We assayed the diabetogenic capacity of NOD spleen CD4(+) T lymphocytes when adoptively transferred into a NOD mouse model combining: (i) Fas-deficiency, (ii) FasL-deficiency, and (iii) SCID mutation.

Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo.

Hematopoietic stem cells (HSCs) both self-renew and give rise to all blood cells for the lifetime of an individual. Xenogeneic mouse models are broadly used to study human hematopoietic stem and progenitor cell biology in vivo. However, maintenance, differentiation, and function of human hematopoietic cells are suboptimal in these hosts.

Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung.

Mice with a functional human immune system have the potential to allow in vivo studies of human infectious diseases and to enable vaccine testing. To this end, mice need to fully support the development of human immune cells, allow infection with human pathogens, and be capable of mounting effective human immune responses. A major limitation of humanized mice is the poor development and function of human myeloid cells and the absence of human immune responses at mucosal surfaces, such as the lung.

A mouse model for the human pathogen Salmonella typhi.

Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a life-threatening human disease. The lack of animal models due to S.

The transcription cofactor Hopx is required for regulatory T cell function in dendritic cell-mediated peripheral T cell unresponsiveness.

Induced regulatory T cells (iT(reg) cells) can be generated by peripheral dendritic cells (DCs) that mediate T cell unresponsiveness to rechallenge with antigen. The molecular factors required for the function of such iT(reg) cells remain unknown. We report a critical role for the transcription cofactor homeodomain-only protein (Hop; also known as Hopx) in iT(reg) cells to mediate T cell unresponsiveness in vivo.

Regulating human Th17 cells via differential expression of IL-1 receptor.

In humans, interleukin-1beta (IL-1beta) has been suggested as an essential cytokine for developing IL-17- or IL-17A-producing CD4(+) T helper 17 (Th17) cells. However, little is known about the relationship of IL-1 receptor expression and Th17 cell differentiation. We report here the presence of 2 distinct CD4(+) T-cell populations with and without expression of IL-1RI that correlates with the capacity to produce IL-17 in naive and memory CD4(+) T cells of human peripheral blood.

Humanized mice for modeling human infectious disease: challenges, progress, and outlook.

Over 800 million people worldwide are infected with hepatitis viruses, human immunodeficiency virus (HIV), and malaria, resulting in more than 5 million deaths annually. Here we discuss the potential and challenges of humanized mouse models for developing effective and affordable therapies and vaccines, which are desperately needed to combat these diseases.

Amino acid polymorphisms altering the glycosylation of IL-2 do not protect from type 1 diabetes in the NOD mouse.

Idd3 is one of many gene regions that affect the development of type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse. Idd3 has been localized to a 650-kb region on chromosome 3 containing the IL-2 gene. Exon 1 of the IL-2 gene is polymorphic between the susceptible NOD and the protective C57BL/6 (B6) alleles, causing multiple amino acid changes that have been proposed to be responsible for the differing glycosylation status.

IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells.

Constitutive expression of IL9 in the lungs of transgenic (Tg) mice resulted in an asthma-like phenotype consisting of lymphocytic and eosinophilic lung inflammation, mucus hypersecretion and mast cell hyperplasia. Several T(h)2 cytokines including IL4, IL5 and IL13 were expressed in the lung in response to Tg IL9. IL13 was absolutely necessary for the development of lung pathology.

FAT10/diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences.

The FAT10 gene encodes a diubiquitin-like protein containing two tandem head-to-tail ubiquitin-like domains. There is a high degree of similarity between murine and human FAT10 sequences at both the mRNA and protein levels. In various cell lines, FAT10 expression was shown to be induced by gamma interferon or by tumor necrosis factor alpha.

Sugar-coated regulation of T cells.

The human gut is host to hundreds of different species of commensal bacteria that live in peaceful partnership with the host immune system. These commensal bacteria are far from neutral bystanders as they are intimately involved in the development of the immune system. Reporting in this issue of Cell, Kasper and colleagues (Mazmanian et al.

A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen.

Antibodies against a conserved RNA-binding protein, the Ro 60-kDa autoantigen, occur in 24-60% of all patients with systemic lupus erythematosus. Anti-Ro antibodies are correlated with photosensitivity and cutaneous lesions in these patients and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with complete congenital heart block and photosensitive skin lesions. In higher eukaryotes, the Ro protein binds small RNAs of unknown function known as Y RNAs.