535 results on '"M. Dardenne"'
Search Results
152. [Analytic study of 69 anti-mouse lymphocyte rabbit serums. I. 'In vivo' activity]
- Author
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J F, Bach, M, Dardenne, P, Galanaud, J M, Watchi, and B, Antoine
- Subjects
Male ,Lymphoid Tissue ,Skin Transplantation ,Transplantation, Autologous ,Mice ,Glomerulonephritis ,Adjuvants, Immunologic ,Transplantation Immunology ,Lymphopenia ,Animals ,Female ,Rabbits ,Antigens ,Immunosuppressive Agents ,Antilymphocyte Serum - Published
- 1970
153. Demonstration of a circulating thymic hormone in mouse and in man
- Author
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J F, Bach, M, Dardenne, and M A, Bach
- Subjects
Thymus Gland ,Thymectomy ,Hormones ,Immune Adherence Reaction ,Mice, Inbred C57BL ,Mice ,Azathioprine ,Splenectomy ,Animals ,Humans ,Lymphocytes ,Antigens ,Spleen ,Antilymphocyte Serum - Published
- 1973
154. [The stable evolution of asymptomatic persistent proteinuria]
- Author
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B, Antoine, A, Symvoulidis, and M, Dardenne
- Subjects
Nephrotic Syndrome ,Biopsy ,Kidney Glomerulus ,Posture ,Blood Pressure ,Urine ,Leukocyte Count ,Proteinuria ,Renal Artery ,Hypertension ,Erythrocyte Count ,Humans ,Kidney Failure, Chronic ,Hematuria - Published
- 1969
155. [Bird breeder's disease in children. Demonstration of lymphocyte sensitization without delayed hypersensitivity]
- Author
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C, Bach, C, Fournier, E, Drouhet, J L, Texier, M, Dardenne, M A, Laborde, and J F, Bach
- Subjects
Male ,Adolescent ,Hemagglutination Tests ,Pneumonia ,Chlamydia Infections ,Lymphocyte Activation ,Precipitin Tests ,Hypergammaglobulinemia ,Farmer's Lung ,Hypersensitivity ,Animals ,Humans ,Female ,Lymphocytes ,Child ,Columbidae ,Immunoelectrophoresis - Published
- 1971
156. [Absence of thymus hormone in the serum of NZB and NZBXNZW mice and patients with systemic lupus erythematosus]
- Author
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J F, Bach and M, Dardenne
- Subjects
Adult ,Male ,Adolescent ,Mice, Inbred NZB ,Thymectomy ,Immune Adherence Reaction ,Mice ,Azathioprine ,Animals ,Humans ,Hybridization, Genetic ,Lupus Erythematosus, Systemic ,Female ,Spleen ,Thymidine - Published
- 1972
157. Antigen recognition by T lymphocytes. Thymus and marrow dependence of spontaneous rosette forming cells in the mouse
- Author
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J F, Bach and M, Dardenne
- Subjects
Sheep ,Hydrocortisone ,Bone Marrow Cells ,Mice, Inbred Strains ,Thymus Gland ,Thymectomy ,Antigen-Antibody Reactions ,Mice ,Animals, Newborn ,Bone Marrow ,Animals ,Lymph Nodes ,Lymphocytes ,Antigens ,Antibody-Producing Cells ,Cyclophosphamide ,Spleen - Published
- 1972
158. [Isolated permanent proteinuria: I. Histologic diversity]
- Author
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B, Antoine, A, Symvoulidis, M, Dardenne, H, de Montera, and J F, Bach
- Subjects
Electrophoresis ,Male ,Hyalin ,Fundus Oculi ,Biopsy ,Kidney Glomerulus ,Arteries ,Kidney ,Juxtaglomerular Apparatus ,Capillaries ,Proteinuria ,Kidney Tubules ,Humans ,Kidney Failure, Chronic ,Female ,Hematuria - Published
- 1969
159. [Isolated permanent proteinuria. 2. Developmental stability. 3. Nosologic significance]
- Author
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B, Antoine, A, Symvouldis, M, Dardenne, H, De Montera, and J F, Bach
- Subjects
Hyalin ,Nephrotic Syndrome ,Adolescent ,Kidney ,Basement Membrane ,Proteinuria ,Glomerulonephritis ,Renal Artery ,Child, Preschool ,Hypertension ,Humans ,Kidney Failure, Chronic ,Nephritis, Interstitial ,Child ,Hematuria - Published
- 1969
160. [Studies on the origin of cells forming spontaneous rosettes]
- Author
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J F, Bach and M, Dardenne
- Subjects
Erythrocytes ,Sheep ,Cell-Free System ,Hydrocortisone ,Tissue Extracts ,Bone Marrow Cells ,Thymus Gland ,Antigen-Antibody Reactions ,Mice ,Animals, Newborn ,Bone Marrow ,Antibody Formation ,Azathioprine ,Animals ,Antibody-Producing Cells ,Chickens ,Spleen - Published
- 1971
161. Streptococcal sensitivity in chronic glomerulonephritis
- Author
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M Dardenne, J.F Bach, and J Zabriskie
- Subjects
Antigens, Bacterial ,Immunity, Cellular ,Chronic proliferative glomerulonephritis ,business.industry ,Glomerular basement membrane ,Streptococcus ,General Medicine ,Basement Membrane ,medicine.anatomical_structure ,Glomerulonephritis ,Cell Wall ,Chronic glomerulonephritis ,Immunology ,Cell Migration Inhibition ,Chronic Disease ,medicine ,Leukocytes ,Humans ,business ,Glomerular diseases ,Cells, Cultured - Abstract
By the leucocyte migration-inhibition test, sensitivity to streptococcal membranes has been found in 46% of cases of chronic proliferative glomerulonephritis with, in some cases, cross-reactivity to glomerular basement membrane. Non-proliferative glomerular diseases and control cases did not show such sensitivity.
- Published
- 1972
162. Isolation of glycopeptide antigenic site from kidney basement membrane
- Author
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Bach Jf, P Mahieu, and M Dardenne
- Subjects
Basement membrane ,Kidney ,Immunity, Cellular ,Nephritis ,business.industry ,Kidney Glomerulus ,Glycopeptides ,General Medicine ,Isolation (microbiology) ,Glycopeptide ,Antibodies ,Basement Membrane ,Microbiology ,medicine.anatomical_structure ,Glomerulonephritis ,Kidney Tubules ,Antigen ,Polysaccharides ,medicine ,Humans ,Antigens ,business ,Peptides ,Glycoproteins - Published
- 1971
163. Antigen recognition by T lymphocytes. II. Similar effects of azathioprine, antilymphocyte serum, and anti-theta serum on rosette-forming lymphocytes in normal and neonatally thymectomized mice
- Author
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J F, Bach and M, Dardenne
- Subjects
Immune Sera ,Bone Marrow Cells ,Mice, Inbred Strains ,Thymus Gland ,Thymectomy ,Mice ,Bone Marrow ,Depression, Chemical ,Azathioprine ,Animals ,Lymphocytes ,Antigens ,Antibody-Producing Cells ,Spleen ,Antilymphocyte Serum - Published
- 1972
164. Thymic epithelial antigen, acquired during ontogeny and defined by the anti-p19 monoclonal antibody, is lost in thymomas
- Author
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W, Savino, S, Berrih, and M, Dardenne
- Subjects
Adult ,Antigens, Differentiation, T-Lymphocyte ,Hyperplasia ,Thymoma ,Histocytochemistry ,Antibodies, Monoclonal ,Fluorescent Antibody Technique ,Thymus Gland ,Thymus Neoplasms ,Middle Aged ,Epithelium ,Antigens, Surface ,Myasthenia Gravis ,Frozen Sections ,Humans ,Binding Sites, Antibody ,Cells, Cultured ,Aged - Abstract
The protein defined by the anti-p19 monoclonal antibody (raised against a 19-kilodalton protein from human T leukemia virus) and normally acquired during the ontogenesis of the human thymic epithelium was studied by indirect immunofluorescence in thymomas and thymic hyperplasias. Hyperplastic (and involuted) thymuses from patients with myasthenia gravis exhibited a clear-cut expression of this differentiation antigen exclusively in epithelial cells, thus qualitatively similar to what was observed in the normal thymus. In thymoma epithelial cells, however, this expression was strongly altered: in the 12 malignant thymomas studied, no anti-p19 reactivity was found. In the four benign cases, a variable number of epithelial cells expressed this antigen. These results suggest that the differentiation antigen of the human thymic epithelium defined by the anti-p19 monoclonal antibody is lost during the malignant transformation occurring in thymomas. Furthermore, this monoclonal antibody provides an additional tool for the study of the degree of dedifferentiation of thymomas.
165. Feedback regulation of the secretion of a thymic hormone (thymulin) by human thymic epithelial cells in culture
- Author
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S, Cohen, S, Berrih, M, Dardenne, and J F, Bach
- Subjects
Thymus Hormones ,Thymic Factor, Circulating ,Antibodies, Monoclonal ,Humans ,Thymus Gland ,Cells, Cultured ,Epithelium ,Feedback - Abstract
The production of the thymic hormone, thymulin (FTS), was studied in primary cultures of human thymic epithelium by immunofluorescence using monoclonal anti-thymulin antibodies. The number of thymulin-containing cells and the thymulin level in the culture supernatant increased gradually during the culture. Addition of synthetic thymulin to the culture medium reduced significantly the increase of thymulin-containing cells. Conversely, addition of monoclonal anti-thymulin antibody from the beginning of the culture exacerbated the spontaneous increase of thymulin-containing cells and abrogated the effects of thymulin. Combined with similar data previously reported in vivo, these results demonstrate that thymulin is actively produced by cultured thymic epithelial cells and that its synthesis can be down-regulated by the hormone itself.
166. [In vitro regulation of the secretion of thymulin (STF) by human thymic epithelial cells]
- Author
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S, Cohen, S, Berrih, M, Dardenne, and J F, Bach
- Subjects
Thymus Hormones ,Kinetics ,Thymic Factor, Circulating ,Antibodies, Monoclonal ,Fluorescent Antibody Technique ,Humans ,Thymus Gland ,Cells, Cultured ,Epithelium - Abstract
The presence of thymulin (formerly called Facteur Thymique Sérique, FTS) in cultured human thymic epithelial cells was studied using a monoclonal anti-thymulin antibody in an immunofluorescence technique. The percentage of thymulin-containing cells increases gradually as a function of time, from 10% at day 4 to 90% at day 14. Furthermore, this increase can be prevented by the addition of thymulin in the culture medium. These data suggest a feedback control of thymulin secretion by thymic epithelial cells.
167. Administered viloxazine interferes in liquid-chromatographic assay of normetanephrines
- Author
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I. Scheirs, I. H. Ladmirant, C. J. Bieva, and J. P. M. Dardenne
- Subjects
chemistry.chemical_compound ,Chromatography ,chemistry ,business.industry ,Falso positivo ,Biochemistry (medical) ,Clinical Biochemistry ,medicine ,Normetanephrine ,business ,High-performance liquid chromatography ,Viloxazine ,medicine.drug - Published
- 1987
168. Stimulation of thymic humoral function by cyclomunine, a cyclic peptide, in mice
- Author
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M. Dardenne, N. Simon-Lavoine, P. Niaudet, and Jean-François Bach
- Subjects
Pharmacology ,chemistry.chemical_classification ,chemistry ,Immunology ,Cyclomunine ,Stimulation ,Cyclic peptide ,Function (biology) ,Cell biology - Published
- 1980
169. Clinical use of thymulin (FTS-Zn) in immunodeficiency syndromes
- Author
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M. Dardenne, J.F. Bach, M.C. Bene, and F. Bordigoni
- Subjects
Pharmacology ,Immunodeficiency Syndrome ,Thymulin ,chemistry.chemical_compound ,chemistry ,business.industry ,Immunology ,Medicine ,business - Published
- 1982
170. Thymic NK activity in 3LL tumor-bearing mice: Modulation by thymulin (FTS-Zn)
- Author
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Jean-François Bach, M. Dardenne, and D. Kaiserlian
- Subjects
Pharmacology ,Thymulin ,chemistry.chemical_compound ,medicine.medical_specialty ,Bearing (mechanical) ,Endocrinology ,chemistry ,law ,Internal medicine ,Immunology ,Nk activity ,medicine ,law.invention - Published
- 1982
171. Evidence for a specific zinc-dependent conformation of thymulin, a thymic hormone
- Author
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M. Dardenne, R. Haran, Jean-François Bach, J.-P. Laussac, and W. Savino
- Subjects
Pharmacology ,Thymulin ,chemistry.chemical_compound ,medicine.medical_specialty ,Endocrinology ,chemistry ,Internal medicine ,Immunology ,medicine ,chemistry.chemical_element ,Zinc ,Hormone - Published
- 1985
172. Comparison of Thymulin Activity with Other Measures of Marginal Zinc Deficiency.
- Author
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DiSilvestro RA, Dardenne M, and Joseph E
- Subjects
- Animals, Liver, Metallothionein, Rats, Thymic Factor, Circulating, Zinc
- Abstract
Activity of the immunoregulatory peptide thymulin reflects differences in zinc status. This study compared thymulin activity with four other zinc status measures in rats fed zinc at either 5 or 25 ppm. Rats fed the lower zinc showed the following results compared with rats with adequate zinc intake: serum thymulin activity 61% lower, serum zinc 31% lower, serum extracellular superoxide dismutase 18% lower, serum 5'-nucleotidase activity 26% lower, and liver metallothionein 28% lower. Thus, thymulin activities showed more sensitivity to restricted zinc intake than did four other parameters.
- Published
- 2021
- Full Text
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173. Sphingosine-1-Phosphate Receptor 1 Is Involved in Non-Obese Diabetic Mouse Thymocyte Migration Disorders.
- Author
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Lemos JP, Smaniotto S, Messias CV, Moreira OC, Cotta-de-Almeida V, Dardenne M, Savino W, and Mendes-da-Cruz DA
- Subjects
- Animals, Cell Movement, Diabetes Mellitus, Type 1 immunology, Disease Models, Animal, Gene Expression Regulation, Integrin alpha5 genetics, Integrin alpha5 metabolism, Integrin alpha5beta1 metabolism, Lysophospholipids metabolism, Mice, Mice, Inbred NOD, Receptors, Lysosphingolipid metabolism, Sphingosine analogs & derivatives, Sphingosine metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 metabolism, Receptors, Lysosphingolipid genetics, Thymocytes metabolism
- Abstract
NOD (non-obese diabetic) mice spontaneously develop type 1 diabetes following T cell-dependent destruction of pancreatic β cells. Several alterations are observed in the NOD thymus, including the presence of giant perivascular spaces (PVS) filled with single-positive (SP) CD4⁺ and CD8⁺ T cells that accumulate in the organ. These cells have a decreased expression of membrane CD49e (the α5 integrin chain of the fibronectin receptor VLA-5 (very late antigen-5). Herein, we observed lower sphingosine-1-phosphate receptor 1 (S1P1) expression in NOD mouse thymocytes when compared with controls, mainly in the mature SP CD4⁺CD62L
hi and CD8⁺CD62Lhi subpopulations bearing the CD49e− phenotype. In contrast, differences in S1P1 expression were not observed in mature CD49e⁺ thymocytes. Functionally, NOD CD49e− thymocytes had reduced S1P-driven migratory response, whereas CD49e⁺ cells were more responsive to S1P. We further noticed a decreased expression of the sphingosine-1-phosphate lyase (SGPL1) in NOD SP thymocytes, which can lead to a higher sphingosine-1-phosphate (S1P) expression around PVS and S1P1 internalization. In summary, our results indicate that the modulation of S1P1 expression and S1P/S1P1 interactions in NOD mouse thymocytes are part of the T-cell migratory disorder observed during the pathogenesis of type 1 diabetes.- Published
- 2018
- Full Text
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174. A new adenovector system for implementing thymulin gene therapy for inflammatory disorders.
- Author
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Zappa-Villar MF, López-León M, Pardo J, Costa M, Crespo R, Dardenne M, Goya RG, and Reggiani PC
- Subjects
- Adenoviridae drug effects, Animals, CHO Cells, Cell Line, Cricetulus, Doxycycline pharmacology, Female, Genetic Therapy methods, Green Fluorescent Proteins genetics, Male, Mice, Mice, Inbred C57BL, Models, Animal, Rats, Rats, Sprague-Dawley, Transgenes drug effects, Transgenes genetics, Adenoviridae genetics, Genetic Vectors genetics, Inflammation genetics, Inflammation therapy, Thymic Factor, Circulating genetics
- Abstract
Thymulin is a thymic peptide possessing anti-inflammatory effects. In order to manipulate thymulin expression in gene therapy studies, we built a bidirectional regulatable two-vector Tet-Off system and the corresponding control system. The experimental two-vector system, ETV, consists of a recombinant adenovector (RAd) harboring an expression cassette centered on a Tet-Off bidirectional promoter flanked by a synthetic gene for thymulin and the gene for humanized Green Fluorescent Protein (hGFP). The second adenovector of this system, RAd-tTA, constitutively expresses the regulatory protein tTA. When cells are co-transduced by the two adenovector components, tTA activates the bidirectional promoter and both transgenes are expressed. In the presence of the antibiotic doxycycline (DOX) transgene expression is deactivated. The control two-vector system, termed CTV, is similar to ETV but only expresses hGFP. In CHO-K1, BHK, and C2C12 cells, ETV and CTV induced a dose-dependent hGFP expression. In CHO-K1 cells, transgene expression was almost completely inhibited by DOX (1mg/ml). After intracerebroventricular injection of ETV in rats, thymulin levels increased significantly in the cerebrospinal fluid and there was high hGFP expression in the ependymal cell layer. When injected intramuscularly the ETV system induced a progressive increase in serum thymulin levels, which were inhibited when DOX was added to the drinking water. We conclude that our regulatable two-adenovector system is an effective molecular tool for implementing short and long-term anti-inflammatory thymulin gene therapy in animal models of acute or chronic inflammation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
175. Hormonal control of T-cell development in health and disease.
- Author
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Savino W, Mendes-da-Cruz DA, Lepletier A, and Dardenne M
- Subjects
- Animals, Cell Movement immunology, Cell Proliferation, Gonadotropin-Releasing Hormone therapeutic use, Growth Hormone immunology, HIV Infections drug therapy, Human Growth Hormone therapeutic use, Humans, Immunologic Deficiency Syndromes drug therapy, Lymphoid Tissue immunology, Protein Precursors therapeutic use, Cell Differentiation immunology, Human Growth Hormone immunology, Prolactin immunology, T-Lymphocytes immunology, Thymocytes immunology, Thymus Gland immunology
- Abstract
The physiology of the thymus, the primary lymphoid organ in which T cells are generated, is controlled by hormones. Data from animal models indicate that several peptide and nonpeptide hormones act pleiotropically within the thymus to modulate the proliferation, differentiation, migration and death by apoptosis of developing thymocytes. For example, growth hormone and prolactin can enhance thymocyte proliferation and migration, whereas glucocorticoids lead to the apoptosis of these developing cells. The thymus undergoes progressive age-dependent atrophy with a loss of cells being generated and exported, therefore, hormone-based therapies are being developed as an alternative strategy to rejuvenate the organ, as well as to augment thymocyte proliferation and the export of mature T cells to peripheral lymphoid organs. Some hormones (such as growth hormone and progonadoliberin-1) are also being used as therapeutic agents to treat immunodeficiency disorders associated with thymic atrophy, such as HIV infection. In this Review, we discuss the accumulating data that shows the thymus gland is under complex and multifaceted hormonal control that affects the process of T-cell development in health and disease.
- Published
- 2016
- Full Text
- View/download PDF
176. Semaphorin 3F and neuropilin-2 control the migration of human T-cell precursors.
- Author
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Mendes-da-Cruz DA, Brignier AC, Asnafi V, Baleydier F, Messias CV, Lepelletier Y, Bedjaoui N, Renand A, Smaniotto S, Canioni D, Milpied P, Balabanian K, Bousso P, Leprêtre S, Bertrand Y, Dombret H, Ifrah N, Dardenne M, Macintyre E, Savino W, and Hermine O
- Subjects
- Antibodies, Blocking immunology, Antibodies, Blocking pharmacology, Cell Movement drug effects, Cells, Cultured, Chemokine CXCL12 pharmacology, Child, Child, Preschool, Gene Expression, Humans, Infant, Infant, Newborn, Lysophospholipids pharmacology, Membrane Proteins metabolism, Membrane Proteins pharmacology, Microscopy, Confocal, Nerve Tissue Proteins metabolism, Nerve Tissue Proteins pharmacology, Neuropilin-2 immunology, Neuropilin-2 metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sphingosine analogs & derivatives, Sphingosine pharmacology, Thymocytes metabolism, Thymus Gland cytology, Thymus Gland metabolism, Cell Movement genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Neuropilin-2 genetics, Precursor Cells, T-Lymphoid metabolism
- Abstract
Neuropilins and semaphorins are known as modulators of axon guidance, angiogenesis, and organogenesis in the developing nervous system, but have been recently evidenced as also playing a role in the immune system. Here we describe the expression and role of semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) in human T cell precursors. NRP2 and SEMA3F are expressed in the human thymus, in both lymphoid and non-lymphoid compartments. SEMA3F have a repulsive effect on thymocyte migration and inhibited CXCL12- and sphingosine-1-phosphate (S1P)-induced thymocyte migration by inhibiting cytoskeleton reorganization prior to stimuli. Moreover, NRP2 and SEMA3F are expressed in human T-cell acute lymphoblastic leukemia/lymphoma primary cells. In these tumor cells, SEMA3F also blocks their migration induced by CXCL12 and S1P. Our data show that SEMA3F and NRP2 are further regulators of human thymocyte migration in physiological and pathological conditions.
- Published
- 2014
- Full Text
- View/download PDF
177. Physiology and therapeutic potential of the thymic peptide thymulin.
- Author
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Reggiani PC, Schwerdt JI, Console GM, Roggero EA, Dardenne M, and Goya RG
- Subjects
- Humans, Immune System physiology, Neurosecretory Systems physiology, Thymus Gland physiology, Thymic Factor, Circulating physiology, Thymic Factor, Circulating therapeutic use
- Abstract
Thymulin is a thymic hormone exclusively produced by the epithelial cells of the thymus. After its discovery and initial characterization in the '70s, it was demonstrated that the production and secretion of thymulin are strongly influenced by the neuro-endocrine system. Conversely, a growing body of evidence, to be reviewed here, suggests that thymulin is a hypophysiotropic peptide. Additionally, a substantial body of information pointing to thymulin and a synthetic analog as anti-inflammatory and analgesic peptides in the central nervous system brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence encoding a biologically active analog of thymulin, metFTS, was constructed and cloned in a number of adenovectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be down-regulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies indicate that gene therapy for thymulin may be an effective therapeutic strategy to prevent some of the hormonal and reproductive abnormalities that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, this article briefly reviews the publications on the physiology of the thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analog. The availability of novel biotechnological tools should boost basic studies on the molecular biology of thymulin and should also allow an assessment of the potential of gene therapy to restore circulating thymulin levels in thymodeficient animal models and eventually, in humans.
- Published
- 2014
- Full Text
- View/download PDF
178. Mouse basophils reside in extracellular matrix-enriched bone marrow niches which control their motility.
- Author
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Smaniotto S, Schneider E, Goudin N, Bricard-Rignault R, Machavoine F, Dardenne M, Dy M, and Savino W
- Subjects
- Animals, Basophils metabolism, Bone Marrow Cells metabolism, Cell Adhesion, Cells, Cultured, Female, Fluorescent Antibody Technique, Gene Expression Profiling, Male, Mice, Mice, Inbred C57BL, Real-Time Polymerase Chain Reaction, Basophils cytology, Bone Marrow Cells cytology, Cell Movement, Extracellular Matrix
- Abstract
Basophils co-express FcεRIα and CD49b, the α-2 chain of integrin-type receptor VLA-2 (α2β1), which recognizes type-1 collagen as a major natural ligand. The physiological relevance of this integrin for interactions with extracellular bone marrow matrix remains unknown. Herein, we examined the expression of several receptors of this family by bone marrow-derived basophils sorted either ex-vivo or after culture with IL-3. Having established that both populations display CD49d, CD49e and CD49f (α-4, α-5 and α-6 integrins subunits, respectively), we addressed receptor functions by measuring migration, adhesion, proliferation and survival after interacting with matched natural ligands. Type I collagen, laminin and fibronectin promoted basophil migration/adhesion, the former being the most effective. None of these ligands affected basophil viability and expansion. Interactions between basophils and extracellular matrix are likely to play a role in situ, as supported by confocal 3D cell imaging of femoral bone marrow sections, which revealed basophils exclusively in type-1 collagen-enriched niches that contained likewise laminin and fibronectin. This is the first evidence for a structure/function relationship between basophils and extracellular matrix proteins inside the mouse bone marrow.
- Published
- 2013
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- View/download PDF
179. Semaphorins and neuropilins: new players in the neuroendocrine control of the intrathymic T-cell migration in humans.
- Author
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Mendes-da-Cruz DA, Linhares-Lacerda L, Smaniotto S, Dardenne M, and Savino W
- Subjects
- Humans, Neurosecretory Systems metabolism, Thymocytes metabolism, Thymus Gland metabolism, Thymus Gland physiology, Cell Movement physiology, Neuropilins physiology, Neurosecretory Systems physiology, Semaphorins physiology, T-Lymphocytes physiology, Thymocytes physiology
- Abstract
Cell migration is a key event for proper intrathymic T-cell differentiation, and several ligand-receptor interactions contribute to the well-co ordinated movement of developing thymocytes within the thymic lobules. Herein we summarize recent data that place semaphorin 3A (Sema3A) and its receptor neuropilin 1 (NRP1) as further players in the physiological process of cell migration in the human thymus. These molecules, as well as class A plexins (necessary for the intracellular signalling transduction triggered by Sema3A-NRP1 ligation), are constitutively expressed by both developing thymocytes and components of the thymic microenvironment, including epithelial and dendritic cells. Functionally, Sema3A decreases the adhesion of human thymocytes on thymic epithelial cell monolayers and exerts per se a dose-dependent chemorepulsive effect on human thymocytes. Moreover, Sema3A inhibits chemoattractant migratory responses induced by other ligands, including fibronectin, laminin and CXCL12 (chemokine CXC motif ligand 12). These data should be placed in the context of the concept that migration of developing T cells is a multivectorial system, in which the resulting migration vector derives from a balance of several simultaneous and/or sequential ligand-receptor pair interactions. Accordingly, semaphorins and neuropilins can be considered as further players in the system.
- Published
- 2012
- Full Text
- View/download PDF
180. Neonatal thymulin gene therapy prevents ovarian dysgenesis and attenuates reproductive derangements in nude female mice.
- Author
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Reggiani PC, Barbeito CG, Zuccolilli GO, Cónsole GM, Flamini AM, Dardenne M, and Goya RG
- Subjects
- Animals, Animals, Newborn, Estrogens blood, Female, Mice, Mice, Nude, Ovary pathology, Progesterone blood, Thymic Factor, Circulating genetics, Genetic Therapy methods, Ovary metabolism, Thymic Factor, Circulating metabolism
- Abstract
Congenitally athymic (nude) female mice show severe ovarian dysgenesis after puberty, which seems to be consequential to a number of neuroendocrine derangements described in these mutants. Thus, considerable evidence suggests that thymulin, a thymic peptide, may be involved in thymus-pituitary communication. In order to clarify the relevance of thymulin for the maturation of the female reproductive system, we assessed at hypothalamic, pituitary, ovarian, and uterine level the preventive action of neonatal thymulin gene therapy (NTGT) on the changes that typically occur after puberty in congenitally athymic female mice. We injected (im) an adenoviral vector harboring a synthetic DNA sequence encoding a biologically active analog of thymulin, methionine-serum thymic factor, in newborn nude mice (which are thymulin deficient) and killed the animals at 70-71 d of age. NTGT in the athymic mice restored the serum thymulin levels. Morphometric analysis revealed that athymic nudes have reduced numbers of brain GnRH neurons and pituitary gonadotropic cells as compared with heterozygous controls. NTGT prevented these changes and also rescued the premature ovarian failure phenotype typically observed in athymic nude mice (marked reduction in the number of antral follicles and corpora lutea, increase in atretic follicles). Serum estrogen, but not progesterone, levels were low in athymic nudes, a reduction that was partially prevented by NTGT. Little to no morphological changes were observed in the endometrium of female nudes. The delay in the age of vaginal opening that occurs in athymic nudes was significantly prevented by NTGT. Our results suggest that thymulin plays a relevant physiologic role in the thymus-hypothalamo-pituitary-gonadal axis.
- Published
- 2012
- Full Text
- View/download PDF
181. Growth hormone modulates migration of thymocytes and peripheral T cells.
- Author
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Savino W, Smaniotto S, Mendes-da-Cruz DA, and Dardenne M
- Subjects
- Acquired Immunodeficiency Syndrome immunology, Acquired Immunodeficiency Syndrome metabolism, Animals, Chemokine CXCL12 metabolism, Fibronectins metabolism, Growth Hormone metabolism, Humans, Laminin metabolism, Lymph Nodes immunology, Lymph Nodes metabolism, Mice, Mice, Transgenic, Thymocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Chemotaxis, Leukocyte immunology, Growth Hormone immunology, Thymocytes metabolism
- Abstract
In the context of immunoneuroendocrine cross talk, growth hormone (GH) exerts pleiotropic effects in the immune system. For example, GH-transgenic mice, as well as animals and humans treated with GH, exhibit enhanced cellularity in the thymus. GH also stimulates the thymic microenvironment, augmenting chemokine and extracellular matrix (ECM) production, with consequent increase in ECM- and chemokine-driven thymocyte migratory responses. Peripheral T cell migration triggered by laminin or fibronectin was enhanced in cells from GH-transgenic versus wild-type control adult mice, as seen for CD4(+) and CD8(+) T cells from mesenteric lymph nodes. Migration of these T lymphocytes, triggered by the chemokine CXCL12, in conjunction with laminin or fibronectin, was also enhanced compared with control counterparts. Considering that GH can be used as an adjuvant therapy in immunodeficiencies, including AIDS, the concepts defined herein, that GH enhances developing and peripheral T cell migration, provide new clues for future GH-related immune interventions., (© 2012 New York Academy of Sciences.)
- Published
- 2012
- Full Text
- View/download PDF
182. Inhibitory effect of semaphorin-3A, a known axon guidance molecule, in the human thymocyte migration induced by CXCL12.
- Author
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Garcia F, Lepelletier Y, Smaniotto S, Hadj-Slimane R, Dardenne M, Hermine O, and Savino W
- Subjects
- Antibodies, Neutralizing pharmacology, Chemokine CXCL12 metabolism, Chemotaxis, Leukocyte immunology, Child, Preschool, Down-Regulation immunology, Humans, Infant, Infant, Newborn, Semaphorin-3A metabolism, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, Thymus Gland immunology, Thymus Gland metabolism, Axons physiology, Cell Migration Inhibition immunology, Chemokine CXCL12 immunology, Semaphorin-3A physiology, T-Lymphocyte Subsets immunology, Thymus Gland cytology
- Abstract
Intrathymic T cell differentiation takes place within the thymic lobules and depends on interactions between developing thymocytes and cells of the thymic microenvironment. Along with differentiation, thymocytes migrate in an oriented progression, which is tightly regulated by a number of interactions, including one mediated by the chemokine CXCL12. It has been shown recently that SEMA-3A, a soluble member of the semaphorin family, is also involved in this human thymocyte migration and can have a chemorepulsive and de-adhesive role. Herein, we study the role of SEMA-3A on the CXCL12-driven migration of human thymocytes. We have shown that SEMA-3A is able to inhibit the chemotaxis triggered by CXCL12. Such an inhibition was seen in respect to immature and mature CD4/CD8-defined thymocyte subsets and can be reverted specifically by neutralizing anti-SEMA-3A mAb. We have also shown that SEMA-3A consistently down-regulates CXCR4 membrane expression in all CD4/CD8-defined thymocyte subsets, and this down-regulation is accompanied by a decrease in the phosphorylation of FAK and ZAP-70 protein kinases. Taken together, these results demonstrate the involvement of SEMA-3A in the regulation of CXCL12-driven human thymocyte migration, where it acts as a physiological antagonist.
- Published
- 2012
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183. Thymulin related peptide attenuates inflammation in the brain induced by intracerebroventricular endotoxin injection.
- Author
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Safieh-Garabedian B, Jabbur SJ, Dardenne M, and Saadé NE
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Brain pathology, Disease Models, Animal, Endotoxins administration & dosage, Inflammation chemically induced, Inflammation prevention & control, Infusions, Intraventricular, Male, Pain Measurement drug effects, Pain Measurement methods, Rats, Rats, Sprague-Dawley, Thymic Factor, Circulating administration & dosage, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Brain drug effects, Endotoxins toxicity, Neurodegenerative Diseases chemically induced, Neurodegenerative Diseases prevention & control, Thymic Factor, Circulating pharmacology
- Abstract
Based on significant amount of evidence, it is now generally believed, that one underlying cause for neurodegenerative diseases, could be dysregulation in inflammatory processes. The actual mechanisms involved are not yet well understood. Several studies have demonstrated the potent analgesic and anti-inflammatory actions of thymulin related peptide (PAT), in different animal pain models. In this study, we investigated the efficacy of PAT in a recently developed model of neuroinflammation, in conscious rats, caused by intracerbroventricular (ICV) injection of endotoxin (ET). Our results indicate that ICV injection of PAT alone did not elicit significant alteration of nociceptive thresholds, while ET injections produced significant thermal hyperalgesia and cold allodynia. Pretreatment with PAT resulted in significant alleviation of ET-induced hyperalgesia and increased body temperature. In other sets of experiments, ICV injection of ET resulted in a significant elevation in the concentration of pro-inflammatory mediators measured in different areas of the brain; this elevation was significantly following pretreatment with PAT. Taken together these results provide evidence in support of our hypothesis that as a potent anti-inflammatory and analgesic peptide, PAT might have potential therapeutic use for the treatment of neurodegenerative conditions induced by silent or overt inflammation., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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184. Thymulin-based gene therapy and pituitary function in animal models of aging.
- Author
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Reggiani PC, Poch B, Cónsole GM, Rimoldi OJ, Schwerdt JI, Tüngler V, Garcia-Bravo MM, Dardenne M, and Goya RG
- Subjects
- Animals, Genetic Vectors, Green Fluorescent Proteins genetics, Humans, Mice, Mice, Nude, Models, Animal, Thymic Factor, Circulating metabolism, Aging genetics, Genetic Therapy, Pituitary Gland physiology, Thymic Factor, Circulating genetics
- Abstract
Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. After its discovery and initial characterization in the 1970s, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to thymulin as a hypophysiotropic peptide. Additionally, thymulin was shown to possess anti-inflammatory and analgesic properties in the brain. In recent years, a synthetic DNA sequence coding for a biologically active analog of thymulin, metFTS, was constructed and cloned in different adenoviral vectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be downregulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies suggest that thymulin gene therapy may be a suitable therapeutic strategy to prevent some of the endocrine and reproductive alterations that typically appear in congenitally athymic (nude) mice, taken as a suitable model of neuroendocrine and reproductive aging. The present article briefly reviews the literature on the physiology of the thymulin-pituitary axis as well as on the new molecular tools available to exploit the therapeutic potential of thymulin., (Copyright © 2011 S. Karger AG, Basel.)
- Published
- 2011
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185. Growth hormone is a modulator of lymphocyte migration.
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Smaniotto S, Martins-Neto AA, Dardenne M, and Savino W
- Subjects
- Animals, Cell Differentiation drug effects, Cell Differentiation physiology, Cell Movement physiology, Chemokines metabolism, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Growth Hormone genetics, Humans, Lymphocyte Activation drug effects, Lymphocytes metabolism, Mice, Mice, Transgenic, Thymocytes drug effects, Cell Movement drug effects, Growth Hormone pharmacology, Growth Hormone physiology, Lymphocytes drug effects, Thymocytes cytology
- Abstract
Cell migration is crucial for intrathymic T cell differentiation and export of mature T lymphocytes to the peripheral lymphoid organs. The intrinsic regulation of T cell migration, mediated by adhesion molecules and chemokines, can be influenced by a number of endogenous factors, such as hormones, as for instance growth hormone (GH). Laminin deposition was enhanced in GH-treated mice and in GH-transgenic animals, compared with corresponding controls, and thymocyte adhesion to laminin was increased by in vivo GH treatment. An enhancing effect was also observed ex vivo in relation to the number of migrating cells in laminin-coated transwell chambers. Additionally, we found that the chemokine CXCL12, in conjunction with laminin, further enhanced the migration of thymocytes previously exposed to high concentrations of GH in vivo. Moreover, an increase in CXCL12 production has been detected in the thymus of GH-transgenic mice as well as in primary thymic epithelial cell cultures derived from these animals, as compared to age-matched wild-type counterparts. In keeping with these data, in vivo experiments showed that GH favors the trafficking of naive CD4+CD8- recent thymic emigrants to the peripheral lymph nodes. In addition, we found that migration of lymphocytes from mesenteric lymph nodes of GH-transgenic mice, triggered by the chemokine CXCL12, in conjunction with laminin or fibronectin, was enhanced, when compared to lymphocytes from control mice. Since GH-based therapy has been used in human and experimental infectious diseases, this hormone can be envisioned as an additional therapeutic tool in situations in which increasing lymphocyte numbers and migration are required for correcting a given pathological state., (Copyright © 2011 S. Karger AG, Basel.)
- Published
- 2011
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186. Neuroendocrine interactions in the thymus: from physiology to therapy.
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Savino W and Dardenne M
- Subjects
- Humans, Neurosecretory Systems physiology, Thymus Gland physiology
- Published
- 2011
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187. RNA interference-mediated knockdown of CD49e (α5 integrin chain) in human thymic epithelial cells modulates the expression of multiple genes and decreases thymocyte adhesion.
- Author
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Linhares-Lacerda L, Ribeiro-Alves M, Nogueira AC, Mendes-da-Cruz DA, Magalhães DA, Dardenne M, Passos GA, and Savino W
- Subjects
- Cell Adhesion genetics, Cell Differentiation physiology, Cell Movement physiology, Fibronectins metabolism, Gene Knockdown Techniques, Humans, Integrin alpha5 metabolism, RNA Interference, Cell Adhesion physiology, Epithelial Cells metabolism, Gene Expression Regulation genetics, Integrin alpha5 genetics, T-Lymphocytes physiology, Thymus Gland cytology
- Abstract
Background: The thymus is a central lymphoid organ, in which bone marrow-derived T cell precursors undergo a complex process of maturation. Developing thymocytes interact with thymic microenvironment in a defined spatial order. A component of thymic microenvironment, the thymic epithelial cells, is crucial for the maturation of T-lymphocytes through cell-cell contact, cell matrix interactions and secretory of cytokines/chemokines. There is evidence that extracellular matrix molecules play a fundamental role in guiding differentiating thymocytes in both cortical and medullary regions of the thymic lobules. The interaction between the integrin α5β1 (CD49e/CD29; VLA-5) and fibronectin is relevant for thymocyte adhesion and migration within the thymic tissue. Our previous results have shown that adhesion of thymocytes to cultured TEC line is enhanced in the presence of fibronectin, and can be blocked with anti-VLA-5 antibody., Results: Herein, we studied the role of CD49e expressed by the human thymic epithelium. For this purpose we knocked down the CD49e by means of RNA interference. This procedure resulted in the modulation of more than 100 genes, some of them coding for other proteins also involved in adhesion of thymocytes; others related to signaling pathways triggered after integrin activation, or even involved in the control of F-actin stress fiber formation. Functionally, we demonstrated that disruption of VLA-5 in human TEC by CD49e-siRNA-induced gene knockdown decreased the ability of TEC to promote thymocyte adhesion. Such a decrease comprised all CD4/CD8-defined thymocyte subsets., Conclusion: Conceptually, our findings unravel the complexity of gene regulation, as regards key genes involved in the heterocellular cell adhesion between developing thymocytes and the major component of the thymic microenvironment, an interaction that is a mandatory event for proper intrathymic T cell differentiation.
- Published
- 2010
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188. Nutritional imbalances and infections affect the thymus: consequences on T-cell-mediated immune responses.
- Author
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Savino W and Dardenne M
- Subjects
- Deficiency Diseases physiopathology, Humans, Infections physiopathology, Protein-Energy Malnutrition physiopathology, Thymus Gland pathology, Thymus Gland physiopathology, Deficiency Diseases immunology, Immunity, Cellular physiology, Infections immunology, Micronutrients deficiency, Protein-Energy Malnutrition immunology, T-Lymphocytes physiology, Thymus Gland immunology
- Abstract
The thymus gland, where T lymphocyte development occurs, is targeted in malnutrition secondary to protein energy deficiency. There is a severe thymic atrophy, resulting from massive thymocyte apoptosis (particularly affecting the immature CD4+CD8+ cell subset) and decrease in cell proliferation. The thymic microenvironment (the non-lymphoid compartment that drives intrathymic T-cell development) is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production, as well as an increase of intrathymic contents of extracellular proteins. Profound changes in the thymus can also be seen in deficiencies of vitamins and trace elements. Taking Zn deficiency as an example, there is a substantial thymic atrophy. Importantly, marginal Zn deficiency in AIDS subjects, children with diarrhoea and elderly persons, significantly impairs the host's immunity, resulting in an increased risk of opportunistic infections and mortality; effects that are reversed by Zn supplementation. Thymic changes also occur in acute infectious diseases, including a severe thymic atrophy, mainly due to the depletion of CD4+CD8+ thymocytes, decrease in thymocyte proliferation, in parallel to densification of the epithelial network and increase in the extracellular matrix contents, with consequent disturbances in thymocyte migration and export. In conclusion, the thymus is targeted in several conditions of malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered as adjuvant therapeutics to improve immunity in malnutrition and/or acute infectious diseases.
- Published
- 2010
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- View/download PDF
189. Pleiotropic modulation of thymic functions by growth hormone: from physiology to therapy.
- Author
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Savino W and Dardenne M
- Subjects
- Animals, Epithelial Cells physiology, Genes, T-Cell Receptor physiology, Human Growth Hormone physiology, Humans, Insulin-Like Growth Factor I physiology, Mice, Mice, Transgenic, Neuroimmunomodulation, Receptor, IGF Type 1 physiology, Growth Hormone physiology, T-Lymphocytes physiology, Thymus Gland physiology
- Abstract
In the context of the cross-talk between the neuroendocrine and immune systems, it is well known that growth hormone (GH) exerts physiological effects in central as well as peripheral compartments of the immune system. GH modulates a variety of thymic functions, including proliferation of thymocytes and thymic epithelial cells (TEC). Accordingly, GH-transgenic mice, as well as animals and humans treated with exogenous GH, exhibit an enhanced cellularity in the organ. GH also stimulates the secretion of cytokines and chemokines by the thymic microenvironment, as well as the production of extracellular matrix proteins. These effects lead to an increase in thymocyte migratory responses and intrathymic traffic of developing T cells, including the export of thymocytes from the organ, as ascertained by experimental studies with intrathymic injection of GH in normal mice and with GH-transgenic animals. Most likely, GH effects in the thymus are mediated by an IGF-1/IGF-1 receptor circuitry, which physiologically operates in nonstimulated conditions in both thymocytes and TECs. Since GH enhances thymus replenishment and increases intrathymic T-cell traffic, ultimately modulating thymocyte exit, it should be placed as a potential adjuvant therapeutic agent in the treatment of immunodeficiencies associated with thymic atrophy, and examples recently appeared in the literature are promising and strongly indicate that GH can be beneficial for individuals suffering severe immunodeficiency., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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190. Combined role of extracellular matrix and chemokines on peripheral lymphocyte migration in growth hormone transgenic mice.
- Author
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Smaniotto S, Mendes-da-Cruz DA, Carvalho-Pinto CE, Araujo LM, Dardenne M, and Savino W
- Subjects
- Animals, B-Lymphocyte Subsets physiology, Cell Movement, Chemotaxis, Leukocyte, Female, Fibronectins metabolism, Image Cytometry, Immunohistochemistry, Lymph Nodes pathology, Male, Mice, Mice, Transgenic, Spleen pathology, T-Lymphocyte Subsets physiology, Chemokines metabolism, Extracellular Matrix physiology, Growth Hormone genetics, Growth Hormone physiology, Lymphocytes physiology
- Abstract
Previous evidence indicated that growth hormone (GH) modulates cell migration in the thymus, and that extracellular matrix and chemokines are involved. Herein, we studied migration of peripheral lymphocytes derived from spleen and lymph nodes of GH-transgenic (GH-Tg) mice. We initially found that the relative cell numbers (normalized per gram of body weight) in lymph nodes and spleens from GH-Tg were higher at all ages tested (2-3, 7 and 12 months), as compared to wild type age-matched controls. Functionally, we found that lymphocyte migration triggered by laminin or fibronectin was enhanced in cells from GH-Tg versus control mice, independent of the organ from which the cells were derived (as ascertained in young adult animals). However, such an enhancement in migration was statistically significant only for CD4+ and CD8+ T cells from mesenteric lymph nodes. Migration of lymphocytes from mesenteric lymph nodes of GH-Tg mice, triggered by the chemokine CXCL12, in conjunction with laminin or fibronectin, was enhanced compared to lymphocytes from control mice. Rather surprisingly, the membrane levels of the corresponding extracellular matrix or chemokine receptors in peripheral lymphoid organs of GH-Tg mice did not necessarily correlate with the changes seen in migratory responses. In conclusion, our data show for the first time that GH alters lymphocyte migration in the periphery of the immune system. Considering that GH is used as an adjuvant therapeutic agent in immunodeficiencies, including AIDS, the concepts defined herein provide relevant background knowledge for future GH-related immune interventions., (2009 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
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191. The thymus-neuroendocrine axis: physiology, molecular biology, and therapeutic potential of the thymic peptide thymulin.
- Author
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Reggiani PC, Morel GR, Cónsole GM, Barbeito CG, Rodriguez SS, Brown OA, Bellini MJ, Pléau JM, Dardenne M, and Goya RG
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Homeostasis, Humans, Molecular Sequence Data, Peptides chemistry, Thymic Factor, Circulating biosynthesis, Thymic Factor, Circulating chemistry, Genetic Therapy, Neurosecretory Systems physiology, Peptides genetics, Peptides therapeutic use, Thymic Factor, Circulating genetics, Thymic Factor, Circulating therapeutic use, Thymus Gland metabolism
- Abstract
Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. It consists of a nonapeptide component coupled to the ion zinc, which confers biological activity to the molecule. After its discovery in the early 1970s, thymulin was characterized as a thymic hormone involved in several aspects of intrathymic and extrathymic T cell differentiation. Subsequently, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to thymulin as a hypophysotropic peptide. In recent years, interest has arisen in the potential use of thymulin as a therapeutic agent. Thymulin was shown to possess anti-inflammatory and analgesic properties in the brain. Furthermore, an adenoviral vector harboring a synthetic gene for thymulin, stereotaxically injected in the rat brain, achieved a much longer expression than the adenovirally mediated expression in the brain of other genes, thus suggesting that an anti-inflammatory activity of thymulin prevents the immune system from destroying virus-transduced brain cells. Other studies suggest that thymulin gene therapy may also be a suitable therapeutic strategy to prevent some of the endocrine and metabolic alterations that typically appear in thymus-deficient animal models. The present article briefly reviews the literature on the physiology, molecular biology, and therapeutic potential of thymulin.
- Published
- 2009
- Full Text
- View/download PDF
192. Neuropilins, semaphorins, and their role in thymocyte development.
- Author
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Mendes-da-Cruz DA, Lepelletier Y, Brignier AC, Smaniotto S, Renand A, Milpied P, Dardenne M, Hermine O, and Savino W
- Subjects
- Animals, Cell Movement, Humans, Nervous System metabolism, T-Lymphocytes cytology, T-Lymphocytes metabolism, Thymus Gland pathology, Neuropilins metabolism, Semaphorins metabolism, Thymus Gland cytology, Thymus Gland metabolism
- Abstract
Some molecules described in the nervous system are also expressed in cells involved in the control of the immune response, suggesting they have a role as common mechanisms between neuroendocrine and immune systems. In this review, we focus on the expression and role of neuropilins (NPs) and their soluble ligands class 3 semaphorins in thymus physiology, particularly migration of developing thymocytes. We also discuss the concept of multivectorial thymocyte migration, including semaphorins, as a new individual cell migration vector.
- Published
- 2009
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- View/download PDF
193. Growth hormone modulates migration of developing T cells.
- Author
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Dardenne M, Smaniotto S, de Mello-Coelho V, Villa-Verde DM, and Savino W
- Subjects
- Animals, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cytokines metabolism, Extracellular Matrix metabolism, Growth Hormone therapeutic use, Humans, Cell Movement, Growth Hormone metabolism, T-Lymphocytes cytology
- Abstract
In the context of the cross-talk between the neuroendocrine and immune systems, it is well known that growth hormone (GH) exerts physiological effects in central as well as peripheral compartments of the immune system. GH modulates a variety of thymic functions. For example, GH upregulates proliferation of thymocytes and thymic epithelial cells. Accordingly, GH-transgenic mice, as well as animals and humans treated with exogenous GH, exhibit an enhanced cellularity in the thymus organ. GH also stimulates the secretion of thymic hormones, cytokines, and chemokines by the thymic microenvironment as well as the production of extracellular matrix proteins. These effects lead to an increase in thymocyte migratory responses and intrathymic traffic of developing T cells, including the export of thymocytes from the thymus organ, as ascertained by experimental studies with intrathymic injection of GH in normal mice and with GH-transgenic animals. Because GH promotes a replenishment of the thymus and an increase of thymocyte export, it has been applied as a potential adjuvant therapeutic agent in the treatment of immunodeficiencies associated with thymic atrophy.
- Published
- 2009
- Full Text
- View/download PDF
194. Multivectorial abnormal cell migration in the NOD mouse thymus.
- Author
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Mendes-da-Cruz DA, Smaniotto S, Keller AC, Dardenne M, and Savino W
- Subjects
- Animals, Chemokine CXCL12 immunology, Chemokine CXCL12 metabolism, Endothelium cytology, Extracellular Matrix immunology, Extracellular Matrix metabolism, Female, Integrin alpha5beta1 metabolism, Ligands, Mice, Mice, Inbred NOD, Thymus Gland metabolism, Cell Movement immunology, Thymus Gland cytology, Thymus Gland immunology
- Abstract
We previously described a fibronectin/VLA-5-dependent impairment of NOD thymocyte migration, correlated with partial thymocyte arrest within thymic perivascular spaces. Yet, NOD thymocytes still emigrate, suggesting the involvement of other cell migration-related alterations. In this context, the aim of this work was to study the role of extracellular matrix ligands, alone or in combination with the chemokine CXCL12, in NOD thymocyte migration. Intrathymic contents of CXCL12, fibronectin, and laminin were evaluated by immunohistochemistry while the expression of corresponding receptors was ascertained by flow cytometry. Thymocyte migration was measured using Transwell chambers and transendothelial migration was evaluated in the same system, but using an endothelial cell monolayer within the chambers. NOD thymocytes express much lower VLA-5 than C57BL/6 thymocytes. This defect was particularly severe in CD4(+) thymocytes expressing Foxp3, thus in keeping with the arrest of Foxp3(+) cells within the NOD giant perivascular spaces. We observed an enhancement in CXCL12, laminin, and fibronectin deposition and colocalization in the NOD thymus. Furthermore, we detected altered expression of the CXCL12 receptor CXCR4 and the laminin receptor VLA-6, as well as enhanced migratory capacity of NOD thymocytes toward these molecules, combined or alone. Moreover, transendothelial migration of NOD thymocytes was diminished in the presence of exogenous fibronectin. Our data unravel the existence of multiple cell migration-related abnormalities in NOD thymocytes, comprising both down- and up-regulation of specific responses. Although remaining to be experimentally demonstrated, these events may have consequences on the appearance of autoimmunity in NOD mice.
- Published
- 2008
- Full Text
- View/download PDF
195. Prominently decreased hippocampal neurogenesis in a spontaneous model of type 1 diabetes, the nonobese diabetic mouse.
- Author
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Beauquis J, Saravia F, Coulaud J, Roig P, Dardenne M, Homo-Delarche F, and De Nicola A
- Subjects
- Age Factors, Analysis of Variance, Animals, Bromodeoxyuridine metabolism, Cell Count, Corticosterone blood, Disease Models, Animal, Female, Glial Fibrillary Acidic Protein metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Phosphopyruvate Hydratase metabolism, Cell Proliferation, Diabetes Mellitus, Type 1 pathology, Hippocampus pathology, Hippocampus physiopathology, Neurons pathology
- Abstract
In human diabetes, degenerative and functional disorders of the central nervous system, including depression, are common findings. Defective dentate gyrus (DG) neurogenesis is associated with affective-related disorders and depression. We previously demonstrated reduced DG neurogenesis in a pharmacological type 1 diabetes model, the streptozotocin (STZ)-treated mouse. Here, we explored DG neurogenesis in a spontaneous T1D model, the nonobese diabetic (NOD) mouse, at prediabetic and diabetic stages. Cell proliferation was assessed in the DG of 5, 8 and 12-week-old control C57BL/6 and BALB/c strains and NOD mice, killed 2 h after bromodeoxyuridine (BrdU) administration. Survival of the newly generated cells was studied in 15-week-old animals that were killed 21 days after BrdU injection. The number of proliferative BrdU-positive cells in the DG was, regardless of age, constantly and significantly lower in NOD than in control strains, showing the presence of hippocampal alterations far before clinical diabetes onset in NOD mice. Diabetes also strongly decreased cell survival in NOD DG. However, cell phenotype proportion, as assessed by co-localization with neuronal or glial markers and confocal microscopy, was not modified. Hippocampal neurogenesis is strongly diminished in the spontaneous NOD model, like in the STZ model. Notably, NOD hippocampal DG cell proliferation defect takes place during the prediabetic stage. Whether this early alteration might result, in this autoimmune strain, from hypothalamo-pituitary adrenal axis alterations and/or ongoing brain inflammatory process sharing many characteristics of aging is discussed and deserves further investigation.
- Published
- 2008
- Full Text
- View/download PDF
196. The thymus is a common target in malnutrition and infection.
- Author
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Savino W, Dardenne M, Velloso LA, and Dayse Silva-Barbosa S
- Subjects
- Acute Disease, Atrophy etiology, Atrophy immunology, Communicable Diseases immunology, Humans, Immunophenotyping, Malnutrition immunology, Opportunistic Infections complications, Opportunistic Infections immunology, T-Lymphocytes pathology, Thymus Gland immunology, Communicable Diseases complications, Malnutrition complications, Thymus Gland pathology
- Abstract
Malnutrition, secondary to deficiency in intake of proteins, minerals or vitamins, consistently results in changes in the thymus. This organ undergoes a severe atrophy due to apoptosis-induced thymocyte depletion, particularly affecting the immature CD4+CD8+ cells, as well as a decrease in cell proliferation. This feature is apparently linked to a hormonal imbalance, involving a decrease in leptin and consequent increase in glucocorticoid hormone levels in the serum. The thymic microenvironment is also affected in malnutrition: morphological changes in thymic epithelial cells have been found, together with a decrease of thymic hormone production by these cells. Additionally, intrathymic contents of extracellular proteins, such as fibronectin, laminin and collagens, are increased in thymuses from malnourished children. Taken together, these data clearly point to the notion that the thymus is significantly affected in malnutrition. Similar patterns of thymic changes occur in acute infectious diseases, including a severe atrophy of the organ, mainly due to the apoptosis-related depletion of immature CD4+CD8+ thymocytes. Additionally, thymocyte proliferation is compromised in acutely-infected subjects. The microenvironmental compartment of the thymus is also affected in acute infections, with an increased density of the epithelial network and an increase in the deposition of extracellular matrix. In conclusion, it seems clear that the thymus is targeted in malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered in therapeutic approaches, in both malnutrition and acute infectious diseases.
- Published
- 2007
- Full Text
- View/download PDF
197. Thymulin gene therapy prevents the reduction in circulating gonadotropins induced by thymulin deficiency in mice.
- Author
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Goya RG, Reggiani PC, Vesenbeckh SM, Pléau JM, Sosa YE, Cónsole GM, Schade R, Henklein P, and Dardenne M
- Subjects
- Adenoviridae genetics, Amino Acid Sequence, Animals, Animals, Newborn, Base Sequence, Cells, Cultured, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Molecular Sequence Data, Pregnancy, Thymic Factor, Circulating immunology, Thymic Factor, Circulating physiology, Genetic Therapy, Gonadotropins blood, Thymic Factor, Circulating genetics
- Abstract
Integrity of the thymus during perinatal life is necessary for a proper maturation of the pituitary-gonadal axis in mice and other mammalian species. Thus congenitally athymic (nude) female mice show significantly reduced levels of circulating gonadotropins, a fact that seems to be causally related to a number of reproductive derangements described in these mutants. Interestingly, a number of in vitro studies suggest that the thymic peptide thymulin may be involved in thymus-pituitary communication. To determine the consequences of low serum thymulin in otherwise normal animals, we induced short (8 days)- and long (33 days)-term thymulin deficiency in C57BL/6 mice by neonatally injecting (intraperitoneally) an anti-thymulin serum and assessed their circulating gonadotropin levels at puberty and thereafter. Control mice received an irrelevant antiserum. Gonadotropins were measured by radioimmunoassay and thymulin by bioassay. Both long- and short-term serum thymulin immunoneutralization resulted in a significant reduction in the serum levels of gonadotropins at 33 and 45 days of age. Subsequently, we injected (intramuscularly) an adenoviral vector harboring a synthetic DNA sequence (5'-ATGCAAGCCAAATCTCAAGGTGGATCCAACTAGTAG-3') encoding a biologically active analog of thymulin, methionine-FTS, in newborn nude mice (which are thymulin deficient) and measured circulating gonadotropin levels when the animals reached 52 days of age. It was observed that neonatal thymulin gene therapy in the athymic mice restored their serum thymulin levels and prevented the reduction in circulating gonadotropin levels that typically emerges in these mutants after puberty. Our results indicate that thymulin plays a relevant physiological role in the thymus-pituitary-gonadal axis.
- Published
- 2007
- Full Text
- View/download PDF
198. Control of human thymocyte migration by Neuropilin-1/Semaphorin-3A-mediated interactions.
- Author
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Lepelletier Y, Smaniotto S, Hadj-Slimane R, Villa-Verde DM, Nogueira AC, Dardenne M, Hermine O, and Savino W
- Subjects
- Cell Adhesion, Chemotaxis, Extracellular Matrix metabolism, Humans, Integrins metabolism, Interleukin-7 metabolism, Ligands, Protein Binding, Receptors, Antigen, T-Cell metabolism, Thymus Gland metabolism, Up-Regulation, Cell Movement, Gene Expression Regulation, Neuropilin-1 metabolism, Semaphorin-3A metabolism, Thymus Gland cytology
- Abstract
It is largely established that molecules first discovered in the nervous system are also found in the immune system. Neuropilin-1 (NP-1) was initially identified to mediate semaphorin-induced chemorepulsion during brain development and is also involved in peripheral T cell/dendritic cell interactions. Herein, we studied NP-1 during T cell development in the human thymus. NP-1 is expressed in both cortex and medulla of thymic lobules, being found in distinct CD4/CD8-defined thymocyte subsets. NP-1 is also found in thymic epithelial cells (TEC) in situ and in vitro, and is recruited at the site of TEC-thymocyte contact. Moreover, NP-1 was rapidly up-regulated during thymocyte stimulation by T cell receptor (TCR) and IL-7 or after adhesion to TEC. Semaphorin-3A (Sema-3A), a natural ligand of NP-1, is also present in human thymus, both in TEC and thymocytes, being up-regulated in thymocytes after TCR engagement. Functionally, Sema-3A decreases the adhesion capacity of NP-1(+) thymocytes and induces their migration by a repulsive effect. In conclusion, we show here that NP-1/Sema-3A-mediated interactions participate in the control of human thymocyte development.
- Published
- 2007
- Full Text
- View/download PDF
199. Role of thymulin or its analogue as a new analgesic molecule.
- Author
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Dardenne M, Saade N, and Safieh-Garabedian B
- Subjects
- Analgesics immunology, Animals, Humans, Hyperalgesia immunology, Immunologic Factors immunology, Pain immunology, Thymic Factor, Circulating immunology, Analgesics pharmacology, Hyperalgesia drug therapy, Immunologic Factors pharmacology, Pain drug therapy, Thymic Factor, Circulating analogs & derivatives
- Abstract
The thymic peptide thymulin is known for its immunomodulatory role. However, several recent reports have indicated that thymulin is capable of interacting directly and/or indirectly with the nervous system. One of the first lines of evidence of this interaction was obtained in a series of experiments showing the hyperalgesic actions of this peptide. We demonstrated that, at low doses (ng), local (intraplantar) or systemic (intraperitoneal) injections of thymulin resulted in hyperalgesia with an increase in proinflammatory mediators, and that this peptide could act directly on the afferent nerve terminals through prostaglandin-E2 (PGE2)-dependent mechanisms, thus forming a neuroimmune loop involving capsaicin-sensitive primary afferent fibers. In further experiments, systemic injections of relatively high doses (1-25 microg) of thymulin or of an analogue peptide (PAT) deprived of hyperalgesic effect, have been shown to reduce the inflammatory pain and the upregulated levels of cytokines induced by endotoxin (ET) injection. In addition, PAT treatment appeared to alleviate the sickness behavior (motor behavior and fever) induced by systemic inflammation. These effects could be attributed, at least partly, to the downregulation of proinflammatory mediators. Furthermore, when compared with the effects of other anti-inflammatory drugs, PAT exerted equal or even stronger analgesic effects, and at much lower concentrations. Subsequent experiments were designed to examine the effects of intracerebroventricular (i.c.v.) injections of thymulin on cerebral inflammation induced by i.c.v. injection of ET. Pretreatment with thymulin reduced, in a dose-dependent manner, the ET-induced hyperalgesia, and exerted differential effects on the upregulated levels of cytokines in different areas of the brain, suggesting a neuroprotective role for thymulin in the central nervous system (CNS). Preliminary results demonstrate that thymulin inhibits in the hippocampus the ET-induced nuclear activation of NF-kappaB, the transcription factor required for the expression of proinflammatory cytokines genes. Although the mechanism of action of these molecules is not totally elucidated, our results indicate a possible therapeutic use of thymulin or PAT as analgesic and anti-inflammatory drugs.
- Published
- 2006
- Full Text
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200. Partial prevention of hepatic lipid alterations in nude mice by neonatal thymulin gene therapy.
- Author
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García de Bravo MM, Polo MP, Reggiani PC, Rimoldi OJ, Dardenne M, and Goya RG
- Subjects
- Animals, Animals, Newborn, Blood Glucose metabolism, Mice, Mice, Nude, Thymic Factor, Circulating physiology, Genetic Therapy, Lipid Metabolism genetics, Liver metabolism, Thymic Factor, Circulating genetics
- Abstract
During adult life athymic (nude) male mice display not only a severe T-cell-related immunodeficiency but also endocrine imbalances and a moderate hyperglycemia. We studied the impact of congenital athymia on hepatic lipid composition and also assessed the ability of neonatal thymulin gene therapy to prevent the effects of athymia. We constructed a recombinant adenoviral vector, RAd-metFTS, expressing a synthetic DNA sequence encoding met-FTS, an analog of the thymic peptide facteur thymique sérique (FTS), whose Zn-bound biologically active form is known as thymulin. On postnatal day 1-2 homozygous (nu/nu) nude and heterozygous (nu/+) mice were injected with 10(8) pfu of RAd-metFTS or RAd-betagal (control vector) intramuscularly. The animals were processed at 52 d of age. Serum thymulin, glycemia, hepatic phospholipid FA composition and free and esterified cholesterol were determined. Adult homozygous male nudes were significantly (P < 0.01) hyperglycemic when compared with their heterozygous counterparts (2.04 vs. 1.40 g/L, respectively). The relative percentage of 16:0, 18:1 n-9, and 18:1n-7 FA was lower, whereas that of 18:0, 20:4n-6, and 22:6n-3 FA was higher, in hepatic phospholipid (PL) of nu/nu animals as compared with their nu/+ counterparts. Some of these alterations, such as that in the relative content of 22:6n-3 in liver PL and the unsaturation index, were completely or partially prevented by neonatal thymulin gene therapy. We conclude that the thymus influences lipid metabolism and that thymulin is involved in this modulatory activity.
- Published
- 2006
- Full Text
- View/download PDF
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