tetracycline and Diabetes-Mellitus--Type-1

Autoimmunity is thought to emerge as a consequence of genetic predispositions and environmental tiggering factors. Often the etiology and the mechanisms involved in the autoaggressive destruction of self-components are rather complex and in many cases poorly understood. Chemokines and cytokines are central mediators of inflammatory processes that are involved in initiation and progression of autoimmunity. Many animal models for human autoimmune diseases use transgenic technology to express chemokines and/or cytokines in an organ or tissue specific manner. However, most of these model systems express the transgene irreversibly without considering the time of expression as a very important parameter. Here, we review experiences that were made from using a tetracycline-inducible promotor system (tTA-system) to express TNFalpha at various times during an ongoing autoimmune process, such as the destruction of pancreatic beta-cells in a mouse model for human type 1 diabetes.

Topics: Animals; Autoimmunity; Diabetes Mellitus, Type 1; Disease Models, Animal; Lymphocytic choriomeningitis virus; Mice; Mice, Transgenic; Promoter Regions, Genetic; Tetracycline; Tumor Necrosis Factor-alpha; Virus Diseases

After some initial disappointments, the field of gene therapy is now gaining confidence and momentum. Recent improvements in gene transfer techniques promise targeted and supra-threshold levels of transgene expression leading to the desired therapeutic effects. This increase in optimism has spread to thefield of diabetes research. Firstly, the recent developments in gene transfer techniques are now being tested on the pancreatic insulin producing beta-cell. For many gene therapy strategies in the treatment of diabetes, transfection of insulin producing cells is a prerequisite. Secondly, if efficient and safe vectors that transduce beta-cells in vivo or ex vivo are made available, autoimmune beta-cell destruction in type 1 diabetes could be prevented. In this strategy, it is envisaged that gene therapy will protect the remaining beta-cell mass in newly diagnosed diabetics or pre-diabetic individuals at a high risk of becoming diabetic from autoimmune destruction. Thirdly, attempts are being made to genetically engineer cells to become artificial beta-cells. Such cells could conceivably compensate for the lost endogeneous alpha-cell mass and restore a regulated insulin secretion. This review will attempt to predict the future of gene therapy in the treatment of diabetes.

Topics: Adjuvants, Immunologic; Animals; Apoptosis; Autoantigens; Autoimmune Diseases; Cell Division; Cell Line, Transformed; Cell Survival; Cytokines; Diabetes Mellitus, Type 1; DNA, Recombinant; Fas Ligand Protein; Fibroblasts; Genetic Therapy; Genetic Vectors; Graft Rejection; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Membrane Glycoproteins; Mice; Mice, Transgenic; Pancreatic Ducts; Perforin; Pituitary Neoplasms; Pore Forming Cytotoxic Proteins; Proinsulin; Protein Processing, Post-Translational; Tetracycline; Transfection; Transplantation, Heterologous; Transplantation, Homologous; Tumor Cells, Cultured

Insulin-deficient, adult, diabetic rats were administrated a tetracycline (either minocycline or a chemically-modified non-antimicrobial tetracycline: CMT) by oral gavage over a 3-week period. Untreated diabetic and non-diabetic rats served as controls. On day 21, all rats received an intravenous injection of 3H-proline, as a radioprecursor of procollagen in bone, dentine and periodontal ligament (PDL) or of amelogenin in enamel; perfusion fixation with an aldehyde mixture was carried out at 20 minutes and 4 hours after isotope injection. The parietal bones (calvaria), mandibules including molars, and lower incisors of these rats were dissected and processed for light microscopic autoradiography to study 3H-proline utilization by osteoblasts, PDL fibroblasts, odontoblasts and ameloblasts. In the control rats, at 20 minutes after 3H-proline injection, silver grains of labeled precursor were detected in the osteoblasts of the periosteal surfaces of the parietal bones. At the 4 hour time period, although some radioprecursor was still present in the osteoblasts, most had progressed to the osteoid matrix. In contrast, the flattened bone-lining cells in the untreated diabetics showed minimal uptake and secretion of labeled proline at both time periods. In both minocycline- and CMT-treated diabetic rats, the labeled proline was localized in the osteoblasts and the osteoid in a pattern reminiscent of that seen in the control rats at both time periods. Of interest, CMT administration appeared to increase the labeling of the osteoid matrix more than minocycline treatment. In non-diabetic control rats, the PDL fibroblasts exhibited a polarized elongated profile and incorporated and secreted radioprecursor similar to that described for the osteoblasts in these animals. The PDL fibroblasts in the untreated diabetics lost their regular arrangement and incorporated little if any 3H-proline; once again, tetracycline administration appeared to normalize, at least in part, the structure and 3H-proline incorporation by these connective tissue cells. In contrast, diabetes and tetracycline administration did not affect the incorporation and secretion of radioprecursor by odontoblasts and secretory ameloblasts during tooth development.

Topics: Ameloblasts; Animals; Autoradiography; Bone Matrix; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fibroblasts; Male; Odontoblasts; Osteoblasts; Periodontal Ligament; Periosteum; Proline; Rats; Rats, Inbred Strains; Streptozocin; Tetracycline; Tritium

Topics: Child, Preschool; Diabetes Mellitus, Type 1; Diagnosis, Differential; Drug Stability; Female; Glycosuria, Renal; Humans; Infant; Male; Renal Aminoacidurias; Tetracycline