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Biomedical subjects

J H Brauker

Publications and source records attributed to J H Brauker.

9 recordsLinked to original sources
PubMed2001

Survival of macroencapsulated allogeneic parathyroid tissue one year after transplantation in nonimmunosuppressed humans.

The use of immunoisolation devices may allow transplantation without need for immunosuppression and could widen the indications for cell transplantation. In this study, we evaluated the survival of encapsulated parathyroid tissue in nonimmunosuppressed humans. Autologous parathyroid implants: Seven patients undergoing parathyroidectomy had devices containing small pieces of their own parathyroid tissue implanted SC. These devices were explanted after 2-4 weeks for histological evaluation. Allogeneic parathyroid implants: Four patients with chronic hypoparathyroidism were transplanted with one to three large (40 microl) and one small (4.5 microl) device filled with meshed parathyroid tissue and implanted SC. The small devices were explanted at 4 weeks, while the large ones were explanted 8.5 to 14 months after implantation. In both studies, control implants were placed in nude mice. Autologous study results: At explantation, the grafts consisted of 22 +/- 6% endocrine tissue and 63 +/- 7% fibrosis, while 15 +/- 5% of the grafts were necrotic. Allogeneic study results: In devices explanted from the patients at 4 weeks, fibrosis dominated and only 1%, 5%, and 23% of the grafts consisted of endocrine tissue. A similar histological appearance was found in grafts from nude mice. In devices explanted at 8.5-14 months, histologically intact endocrine tissue was found in all patients. However, nearly all the tissue consisted of fibrosis. There was no detectable increase in the parathormone (PTH) level in all patients. Macroencapsulated human allogeneic parathyroid tissue can survive up to 1 year after transplantation into nonimmunosuppressed patients. However, marked fibroblast overgrowth occurred, especially in the allogeneic implant study, using meshed parathyroid tissue. This was probably not related to the allo-response, because similar findings were observed in the nude mouse implants. In future studies, better tissue preparation and improvements in the physiological milieu inside the device may help to reduce fibroblast overgrowth and increase survival of the parathyroid cells.

Animals↗
PubMed1997

Immunoisolation of tumor cells: generation of antitumor immunity through indirect presentation of antigen.

In recent years, a number of cancer therapies have been developed based on the augmentation of the immune response in the tumor-bearing individual. We have developed a novel approach to such therapies, using a membrane-bound immunoisolation device containing tumor cells to enhance the immune response of mice to the adenocarcinoma, MCA-38. Use of an immunoisolation device for cancer immunotherapy has several advantages. First, safety is enhanced because the reintroduced tumor cells are sequestered within the device. Second, the immunoisolation device permits introduction and maintenance of live cells that can stimulate the immune system for extended periods. Finally, the cells can be quantitatively removed at the end of the treatment period. Cells derived from the murine adenocarcinoma cell line MCA-38 were implanted into mice within a membrane-enclosed (immunoisolation) device. After 3 weeks, the animals were challenged by injection of free tumor cells. All of the control animals (lacking implants or with empty devices) developed tumor at the challenge site, whereas all of the animals that received devices containing tumor cells remained tumor free. The animals also remained tumor free after a second challenge. It is our hypothesis that antigens shed from tumor cells within the device are taken up by antigen-presenting cells of the host and thus indirectly initiate the activation of the immune system.

Adenocarcinoma↗
PubMed1995

Neovascularization of synthetic membranes directed by membrane microarchitecture.

Transplantation of tissues enclosed within a membrane device designed to protect the cells from immune rejection (immunoisolation) provides an opportunity to treat a variety of disease conditions. Successful implementation of immunoisolation has been hampered by the foreign-body reaction to biomaterials. We screened a variety of commercially available membranes for foreign-body reactions following implantation under the skin of rats. Histologic analysis revealed that neovascularization at the membrane-tissue interface occurred in several membranes that had pore sizes large enough to allow complete penetration by host cells (0.8-8 microns pore size). When the vascularization of the membrane-tissue interface of 5-microns-pore-size polytetrafluoroethylene (PTFE) membranes was compared to 0.02-microns-pore-size PTFE membranes, it was found that the larger pore membranes had 80-100-fold more vascular structures. The increased vascularization was observed even though the larger pore membrane was laminated to a smaller pore inner membrane to prevent cell entry into the prototype immunoisolation device. This significantly higher level of vascularization was maintained for 1 year in the subcutaneous site in rats.

Animals↗
PubMed1991

Syndecan, a cell surface proteoglycan, exhibits a molecular polymorphism during lung development.

Syndecan, a cell surface proteoglycan, binds multiple extracellular ligands, and is developmentally regulated in epithelial and mesenchymal tissues. The branching morphogenesis of embryonic lung is dependent on epithelial-mesenchymal interactions and, based on studies with inhibitors, on proteoglycan synthesis. To assess the role of syndecan in lung development, we examined the structure and distribution of syndecan in Day 12 to 18 embryonic mouse lungs using monoclonal antibody 281-2 for histology, immunopurification, and Western blots. At Day 12, syndecan localizes mainly on epithelial cell surfaces, but also stains mesenchymal cells near the epithelium. By Day 14, syndecan is expressed predominantly on epithelia and by Day 18, syndecan remains on airway epithelia but is absent from the alveolar pneumocytes. This change in expression correlates with a change in syndecan structure; the relative mass of syndecan gradually falls from Day 12 to Day 18 without a change in relative mass of the core protein. The difference is due to a developmental reduction in the size of the glycosaminoglycan chains; heparan sulfate chains on syndecan from Day 14 lungs were nearly twofold larger than those from Day 18 lungs. Newly synthesized syndecan in the lungs had the same relative mass as total syndecan, indicating that the change in mass is due to a developmental change in the nature of the syndecan synthesized. The alteration in syndecan structure could alter the function of this proteoglycan during lung development.

Animals↗
PubMed1987

Nonlysosomal processing of cell-surface heparan sulfate proteoglycans. Studies of I-cells and NH4Cl-treated normal cells.

The metabolism of cell-associated proteoglycans, labeled in the glycosaminoglycan portion with 35SO2-4, was studied in normal skin fibroblasts (SL66 cells), NH4Cl-treated SL66 fibroblasts, and in I-cells derived from patients with mucolipidosis II. Kinetic data from label-chase experiments and gel filtration analysis of the molecular weight distribution of the radiolabeled glycosaminoglycans indicated that I-cells and NH4Cl-treated normal fibroblasts (a) internalize cell surface proteoglycans, (b) remove glycosaminoglycan chains from proteoglycan core proteins, and (c) degrade heparan sulfate glycosaminoglycan chains via an endoglycosidic activity. These processes occur with rates comparable to those in normal fibroblasts. The data are consistent with the hypothesis that the glycosaminoglycan chains of cell-surface proteoglycans are separated from the protein cores in a nonlysosomal compartment prior to the transport of these chains to lysosomes for degradation. These observations also raise the possibility that this early step in separation of glycosaminoglycan chains from protein cores may serve to regulate the levels of glycosaminoglycan-free core protein observed in various cells.

Ammonium Chloride↗
PubMed1987

Turnover of sulfated glycosaminoglycans in fibroblasts derived from patients with Werner's syndrome.

Fibroblasts derived from patients with Werner's syndrome (WS) were incubated with radioactive sulfate to study the incorporation of 35S into glycosaminoglycans (GAGs). The accumulation of cell-associated 35S radioactivity in the GAGs of WS fibroblasts was consistently higher than parallel accumulation in normal human fibroblasts, but was substantially less than in fibroblasts derived from patients with Hurler's syndrome (HS). However, when fibroblasts were labeled with 35SO4(2-), trypsinized to remove extracellular and pericellular radioactive GAGs, replated, and chased to follow the fate of the intracellular radioactivity, both WS and normal cells showed a rapid release of the intracellular 35S, while HS cells showed little or no loss of intracellular radioactivity. The radioactivity released from WS and normal cells was of low molecular weight (LMW), eluting from gel filtration columns at the same position as free sulfate. These results establish that WS cells degrade intracellular sulfated GAGs and argue against the hypothesis that a defect in GAG degradation pathways is the basis for the increased level of cell-associated GAGs. Other possible explanations for the increased cell-associated [35S]GAGs in WS cells as compared with normal cells were also considered: increased GAG sulfation; an increase in GAG chain length; an increased rate of GAG synthesis; and a decreased rate of shedding of cell surface proteoglycan into the medium. No difference between normal and WS fibroblasts in any of the above parameters was observed. These results strongly imply that the primary biochemical defect in WS fibroblasts does not involve sulfated GAG metabolism.

Cell Line↗
PubMed1986

The effect of mannose 6-phosphate on the turnover of the proteoglycans in the extracellular matrix of human fibroblasts.

Human fibroblasts (SL66) were cultured in medium containing 35SO2-4 to label the glycosaminoglycans (GAGs). The cells were then detached from the culture dish to leave radioactively-labeled components of the extracellular matrix, hereafter termed 35S-labeled substrate-attached material. When unlabeled SL66 fibroblasts were plated onto this 35S-labeled substrate-attached material, the cells mediated two distinct events: (a) release of radioactivity from the substrate-attached material into the medium; (b) degradation of certain glycosaminoglycans into radioactive components of very low molecular weight including free radioactive sulfate. In the presence of mannose 6-phosphate, however, the degradation of the substrate-attached material by SL66 cells was partially inhibited. Analyses of this effect in terms of the dose-response curve, saccharide specificity, ammonium chloride sensitivity, and the requirement for cells suggest that both an intracellular compartment and the mannose 6-phosphate receptor that binds lysosomal enzymes at the cell surface may play important roles in the turnover and degradation of certain proteoglycans in substrate-attached material.

Ammonium Chloride↗