Reconstitution of human microglia and resident T cells in the brain of humanized DRAGA mice.

Humanized mouse models are valuable tools for investigating the human immune system in response to infection and injury. We have previously described the human immune system (HIS)-DRAGA mice (HLA-A2.HLA-DR4.

A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19.

We report the first Human Immune System (HIS)-humanized mouse model ("DRAGA": HLA-A2.HLA-DR4.Rag1KO.

The humanized DRAGA mouse (HLA-A2. HLA-DR4. RAG1 KO. IL-2R g c KO. NOD) establishes inducible and transmissible models for influenza type A infections.

We have engineered a Human Immune System (HIS)-reconstituted mouse strain (DRAGA mouse: HLA-A2. HLA-DR4. Rag1 KO.

Humanized DRAGA mice immunized with Plasmodium falciparum sporozoites and chloroquine elicit protective pre-erythrocytic immunity.

Background: Human-immune-system humanized mouse models can bridge the gap between humans and conventional mice for testing human vaccines. The HLA-expressing humanized DRAGA (HLA-A2.HLA-DR4.

Generation and testing anti-influenza human monoclonal antibodies in a new humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO. IL-2Rγc KO. NOD).

Pandemic outbreaks of influenza type A viruses have resulted in numerous fatalities around the globe. Since the conventional influenza vaccines (CIV) provide less than 20% protection for individuals with weak immune system, it has been considered that broadly cross-neutralizing antibodies may provide a better protection. Herein, we showed that a recently generated humanized mouse (DRAGA mouse; HLA-A2.

Nonobese Diabetic (NOD) Mice Lack a Protective B-Cell Response against the "Nonlethal" 17XNL Malaria Protozoan.

. 17XNL is a nonlethal malaria strain in mice of different genetic backgrounds including the C57BL/6 mice (I-A/I-E) used in this study as a control strain. We have compared the trends of blood stage infection with the nonlethal murine strain of 17XNL malaria protozoan in immunocompetent Nonobese Diabetic (NOD) mice prone to type 1 diabetes (T1D) and C57BL/6 mice (control mice) that are not prone to T1D and -cure the 17XNL infection.

Differential effect of HLA class-I versus class-II transgenes on human T and B cell reconstitution and function in NRG mice.

Humanized mice expressing Human Leukocyte Antigen (HLA) class I or II transgenes have been generated, but the role of class I vs class II on human T and B cell reconstitution and function has not been investigated in detail. Herein we show that NRG (NOD.RagKO.

Humanized HLA-DR4.RagKO.IL2RγcKO.NOD (DRAG) mice sustain the complex vertebrate life cycle of Plasmodium falciparum malaria.

Background: Malaria is a deadly infectious disease affecting millions of people in tropical and sub-tropical countries. Among the five species of Plasmodium parasites that infect humans, Plasmodium falciparum accounts for the highest morbidity and mortality associated with malaria. Since humans are the only natural hosts for P.

Humanized HLA-DR4 mice fed with the protozoan pathogen of oysters Perkinsus marinus (Dermo) do not develop noticeable pathology but elicit systemic immunity.

Perkinsus marinus (Phylum Perkinsozoa) is a marine protozoan parasite responsible for "Dermo" disease in oysters, which has caused extensive damage to the shellfish industry and estuarine environment. The infection prevalence has been estimated in some areas to be as high as 100%, often causing death of infected oysters within 1-2 years post-infection. Human consumption of the parasites via infected oysters is thus likely to occur, but to our knowledge the effect of oral consumption of P.

Long-term silencing of autoimmune diabetes and improved life expectancy by a soluble pHLA-DR4 chimera in a newly-humanized NOD/DR4/B7 mouse.

Several human MHC class II (HLA) molecules are strongly associated with high incidence of autoimmune diseases including type 1 diabetes (T1D). The HLA-humanized mice may thus represent valuable tools to test HLA-based vaccines and therapeutics for human autoimmune diseases. Herein, we have tested the therapeutic potential of a soluble HLA-DR4-GAD65 271-280 (hu DEF-GAD65) chimera of human use in a newly-generated NOD/DR4/B7 double transgenic (dTg) mouse that develops spontaneously an accelerated T1D regardless the gender.

Differential effect of CD4+Foxp3+ T-regulatory cells on the B and T helper cell responses to influenza virus vaccination.

The T-regulatory (T-reg) cells restrict the T-cell functions in various viral infections including influenza infection. However little is known about the effect of T-regs in influenza vaccination. Herein, we found that immunization of BALB/c mice with a prototype of UV-inactivated influenza PR8/A/34 virus vaccine expanded the CD4(+)Foxp3(+) T-reg pool and fostered the development of virus-specific CD4(+)Foxp3(+) T-reg cells.

Double negative (CD3+ 4- 8-) TCR alphabeta splenic cells from young NOD mice provide long-lasting protection against type 1 diabetes.

Background: Double negative CD3(+)4(-)8(-) TCR alphabeta splenic cells (DNCD3) can suppress the immune responses to allo and xenografts, infectious agents, tumors, and some autoimmune disorders. However, little is known about their role in autoimmune diabetes, a disease characterized by the reduction of insulin production subsequent to destruction of pancreatic beta-cells by a polyclonal population of self-reactive T-cells. Herein, we analyzed the function and phenotype of DNCD3 splenic cells in young NOD mice predisposed to several autoimmune disorders among which, the human-like autoimmune diabetes.

Reversal of type 1 diabetes by a new MHC II-peptide chimera: "Single-epitope-mediated suppression" to stabilize a polyclonal autoimmune T-cell process.

Polyclonality of self-reactive CD4(+) T cells is the hallmark of several autoimmune diseases like type 1 diabetes. We have previously reported that a soluble dimeric MHC II-peptide chimera prevents and reverses type 1 diabetes induced by a monoclonal diabetogenic T-cell population in double Tg mice [Casares, S. et al.

A peptide-major histocompatibility complex II chimera favors survival of pancreatic beta-islets grafted in type 1 diabetic mice.

Background: Transplantation of pancreatic islets showed a tremendous progress over the years as a promising, new therapeutic strategy in patients with type 1 diabetes. However, additional immunosuppressive drug therapy is required to prevent rejection of engrafted islets. The current immunosuppressive therapies showed limited success in maintaining long-term islet survival as required to achieve insulin independence in type 1 diabetes, and they induce severe adverse effects.

Differential partitioning and trafficking of GM gangliosides and cholesterol-rich lipid rafts in thymic and splenic CD4 T cells.

The GM gangliosides and cholesterol components of plasma membrane lipid rafts play an important role in the recruitment and signaling of protein receptors in eukaryotic cells. Herein, we have analyzed at the single-cell level the partitioning and intracellular trafficking of GM gangliosides and cholesterol in quiescent (CD4+CD69-) and CD3-activated (CD4+CD69+) thymic and splenic T cells. First, regardless the gender and the quiescent or activated status of T cells, the GM and cholesterol content in cytosol and plasma membrane as well as the expression levels of GM synthase, Sphingomyelin phosphodiestarase 2 and HMG Co-A reductase genes involved in GM and cholesterol synthesis were constantly lower in CD4 thymocytes than in CD4 splenocytes.

Down-regulation of autoreactive T-cells by HMG CoA reductase inhibitors.

The inhibitors of HMG CoA reductase (statins) are widely used as cholesterol-lowering drugs with excellent safety records in hypercholesterolemic patients. Statins exert pleiotropic effects on a variety of cells, and they were recently described as a new class of immune modulators. Depending on their structure, dose, and route of administration, statins regulate the function of both the antigen-presenting cells and T-cells by HMG CoA reductase-dependent and independent mechanisms.

Soluble, dimeric HLA DR4-peptide chimeras: an approach for detection and immunoregulation of human type-1 diabetes.

Still there are no effective methods to predict or cure type 1 diabetes (T1D) in humans. Soluble, dimeric MHC class II-peptide (DEF) chimeras have potential for both early diagnosis and immunospecific therapy. DEF chimeras prevent and reverse diabetes in mice by stimulating antigen-specific type 1 T regulatory cell (Tr1)-like cells.

Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes.

The self-reactive CD4 T-cells play an essential role in triggering and sustaining organ-specific autoimmune diseases. Silencing or elimination of these cells can prevent and reverse an autoimmune process. We have previously showed that a single dose-administration of a soluble dimeric MHC II-peptide chimera (DEF) in double-transgenic mice delayed the onset autoimmune diabetes, and restored the euglycemia in already diabetic mice for a period of 1 week.

Role of lipid rafts in T cells.

The plasma membrane of T cells is made up of a combination of phospholipids and proteins organized as glycolipoprotein microdomains termed lipid rafts. The structural assembly of lipid rafts was investigated by various physical and biochemical assays. Depending on the differentiation status of T cells, the lipid rafts seclude various protein receptors instrumental for the early T cell signaling, cytoskeleton reorganization, protein and membrane trafficking, and the entry of infectious organisms into the cells.

Analysis of lipid rafts in T cells.

The plasma membrane of T cells is made of a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains termed lipid rafts. The structural assembly of lipid rafts was investigated by various physical and biochemical assays. Depending on the differentiation status of T cells, the lipid rafts seclude various protein receptors involved in T cell signaling, cytoskeleton reorganization, membrane trafficking, and the entry of infectious organisms into the cells.

A model for antigen-specific T-cell anergy: displacement of CD4-p56(lck) signalosome from the lipid rafts by a soluble, dimeric peptide-MHC class II chimera.

Soluble, dimeric peptide-MHC chimeras were shown to induce Ag-specific T cell anergy in vitro and in vivo. In this study, we describe a mechanism by which a soluble, dimeric peptide MHC class II chimera (DEF) induces Ag-specific T cell anergy. The anergic cells showed a displacement of the CD4-p56(lck) signaling module from the GM1-rich plasma membrane microdomains (lipid rafts), and subsequently an increase in p59(fyn) kinase activity, a dominant expression of p21 inhibitory TCR zeta-chain, and a poor phosphorylation and recruitment of zeta-associated protein of 70 kDa kinase to the TCR's immunoreceptor tyrosine-based activation motifs.