المؤلفون: Larry D. Bozulic, Yiming Huang, Paula M. Chilton, Mary Jane Elliott, Suzanne T. Ildstad, Hong Xu, Thomas Miller, Isabelle Fugier-Vivier

المصدر: Diabetes

مصطلحات موضوعية: Male, CD8 Antigens, Endocrinology, Diabetes and Metabolism, Antigens, CD19, Receptors, Antigen, T-Cell, Nod, CD19, Immunophenotyping, Mice, 03 medical and health sciences, 0302 clinical medicine, Adjuvants, Immunologic, Mice, Inbred NOD, Precursor cell, Internal Medicine, medicine, Animals, Antigens, Ly, Lectins, C-Type, 030304 developmental biology, NOD mice, 0303 health sciences, CD11b Antigen, biology, T-cell receptor, Hematopoietic Stem Cell Transplantation, Membrane Proteins, Hematopoietic stem cell, hemic and immune systems, Dendritic Cells, Dendritic cell, Flow Cytometry, Hematopoietic Stem Cells, Up-Regulation, Cell biology, Diabetes Mellitus, Type 1, medicine.anatomical_structure, Antigens, Surface, Immunology, biology.protein, Cytokines, Female, lipids (amino acids, peptides, and proteins), Immunology and Transplantation, Biomarkers, CD8, NK Cell Lectin-Like Receptor Subfamily B, 030215 immunology

الوصف: OBJECTIVE—Plasmacytoid precursor dendritic cell facilitating cells (p-preDC FCs) play a critical role in facilitation of syngeneic and allogeneic hematopoietic stem cell (HSC) engraftment. Here, we evaluated the phenotype and function of CD8+/TCR− FCs from NOD mice.RESEARCH DESIGN AND METHODS—The phenotype of CD8+/TCR− FCs was analyzed by flow cytometry using sorted FCs from NOD, NOR, or B6 mice. The function of NOD FCs was evaluated by colony-forming cell (CFC) assay in vitro and syngeneic or allogeneic HSC transplantation in vivo.RESULTS—We report for the first time that NOD FCs are functionally impaired. They fail to facilitate engraftment of syngeneic and allogeneic HSCs in vivo and do not enhance HSC clonogenicity in vitro. NOD FCs contain subpopulations similar to those previously described in B6 FCs, including p-preDC, CD19+, NK1.1+DX5+, and myeloid cells. However, the CD19+ and NK1.1+DX5+ subpopulations are significantly decreased in number in NOD FCs compared with disease-resistant controls. Removal of the CD19+ or NK1.1+DX5+ subpopulations from FCs did not significantly affect facilitation. Notably, Flt3 ligand (FL) treatment of NOD donors expanded FC total in peripheral blood and restored facilitating function in vivo.CONCLUSIONS—These data demonstrate that NOD FCs exhibit significantly impaired function that is reversible, since FL restored production of functional FCs in NOD mice and suggest that FL plays an important role in the regulation and development of FC function. FCs may therefore be linked to diabetes pathogenesis and prevention.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd41e0db9edd2357f1af3118a949dbe9Test
https://doi.org/10.2337/db08-0356Test

المؤلفون: Isabelle Fugier-Vivier, Hong Xu, Yiming Huang, Mukunda B. Ray, Francine Rezzoug, Suzanne T. Ildstad, Leslie A. Weeter, Paula M. Chilton

المصدر: Diabetes. 53(8)

مصطلحات موضوعية: Myeloid, Endocrinology, Diabetes and Metabolism, Population, Bone Marrow Cells, Nod, Biology, Islets of Langerhans, Mice, Adjuvants, Immunologic, Mice, Inbred NOD, hemic and lymphatic diseases, Internal Medicine, medicine, Animals, Transplantation, Homologous, IL-2 receptor, Progenitor cell, education, Pancreas, NOD mice, Bone Marrow Transplantation, education.field_of_study, Mice, Inbred BALB C, Transplantation Chimera, Membrane Proteins, medicine.disease, medicine.anatomical_structure, Diabetes Mellitus, Type 1, Immunology, Female, Bone marrow, Lymph Nodes, Insulitis

الوصف: The mechanism by which mixed chimerism reverses autoimmunity in type 1 diabetes has not been defined. NOD mice have a well-characterized defect in the production of myeloid progenitors that is believed to contribute significantly to the autoimmune process. We therefore investigated whether chimerism induces a correction of this defect. Mixed chimerism restored production of myeloid progenitors in NOD mice to normal levels. Notably, NOD bone marrow cells as well as donor bone marrow cells produced the mature myeloid progeny, and the level of donor chimerism was not correlated with the degree of restoration of the defect. Moreover, NOD bone marrow cells cultured with Flt3-ligand developed a heat-stable antigen-positive/Ly6C+ population comprised primarily of mature myeloid dendritic cells, suggesting that the underlying abnormality is not cell intrinsic but rather due to a block in development of mature myeloid progeny, including myeloid dendritic cells. Strikingly, treatment of NOD mice with Flt3-ligand significantly decreased insulitis and progression to diabetes and was associated with a significant increase in myeloid dendritic cells and in vivo induction of CD4+/CD25+ cells in the pancreatic lymph node. Therefore, Flt3-ligand treatment and/or the establishment of mixed chimerism in prediabetic candidates may provide a benign and novel approach to treat diabetes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b63148043226d95ef42ce41b2b9c0fb3Test
https://pubmed.ncbi.nlm.nih.gov/15277378Test

المؤلفون: Yiming Huang, Fugier-Vivier, Isabelle J., Miller, Thomas, Elliott, Mary J., Tanner, Michael K., Atay, Safinur, Chilton, Paula M., Hong Xu, Ildstad, Suzanne T.

المصدر: Diabetes. Jun2007 Supplement 1, Vol. 56, pA520-A520. 1/4p. 1 Graph.

مصطلحات موضوعية: *CELLS, *BONE marrow, *HEMATOPOIETIC stem cells, *DENDRITIC cells, *MONOCYTES, *T cells, *LABORATORY mice

مستخلص: We previously reported that bone marrow-derived CD8[sup +]/TCR[sup -] grafting facilitating cells (FC) enhance hematopoietic stem cell (HSC) engraftment in allogeneic and syngeneic recipients and that B220[sup +]/CD11C[sup +]/CD11[sup -] precursor plasmacytoid dendritic cell (p-pre DC) FC subpopulation plays a critical and dominant role in facilitation. NOD mice exhibit a number of defects in innate and adaptive immunity including impaired myeloid differentiation and function in antigen presenting cell, NK cells, NKT cells and regulatory T cells. In the present studies, we evaluated the function of NOD FC. We reported for the first time that FC from NOD mice are functionally impaired in vivo and in vitro. CD8[sup +]/TCR[sup -] FC were sorted from NOD, NOR or B6 bone marrow and evaluated for subpopulations we previously found in B6 FC: NK FC, myeloid cells, CD19 FC, monocytes, and p-preDC. p-pre DC FC represented the major FC subpopulation in all strains examined. The CD 19[sup +] FC subpopulation was selectively significantly decreased in NOD FC compared to those from B6 or NOR mice (12% versus 26%, P <0.05). To test the function of NOD or NOR FC, 500 NOR HSC (c-Kit[sup +]/Sca-l[sup +]/Lin[sup -]) were sorted and transplanted with 30,000 NOR FC (n = 10) or without FC (n=16) into conditioned 950 cGy NOR recipients. The NOR FC significantly enhanced engraftment of NOR HSC compared to the HSC alone (p = 0.029) (Figure 1a). In striking contrast, NOD FC did not facilitate, as evidenced by the similar engraftment of HSC with NOD FC (n=13) compared to the NOD HSC alone (n=17; p = 0.579) (Figure lb). Impaired function of NOD FC was confirmed in vitro using colony forming cell (CFC) assay. NOD FC did not increase colony production when cultured with NOD HSC (Figure 1c), while NOR FC did (Figure ld). These results point without ambiguity to a defect in NOD FC that is not present in the NOR FC. Studies are underway to determine: (1) the mechanism of defective FC in NOD mice; (2) whether function of the FC can be restored in NOD mice with flt3-ligand treatment. [ABSTRACT FROM AUTHOR]