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PubMed1984

Effect of local hyperthermia on blood flow and microenvironment: a review.

The blood flow in tumors varies considerably among different tumor types. Even in the same tumor, the distribution of vasculature and blood flow is quite heterogeneous. The tumor blood flow generally decreases as the tumors grow larger, owing partially to progressive deterioration of vascular beds and to the rapid growth of tumor cell population relative to vascular beds. Contrary to the general notion that blood flow is less in tumors than in normal tissues, blood flow in many tumors, particularly in small tumors, is actually greater than that in surrounding normal tissues at normothermic conditions. Compared to the normal tissue blood flow, however, the capacity of tumor blood flow to increase upon heating appears to be rather limited. Consequently, the heat dissipation by blood flow in tumors is slower than that in normal tissues, and thus the temperature of tumor rises higher than that in normal tissue during heating. Preferential heating of tumors, however, may not be achieved all the time because the relative blood perfusion in some tumors remains greater than that in the surrounding normal tissues despite the profound increase in normal tissue blood flow during heating. The vasculature in tumor can be significantly damaged at temperatures which may alter but do not damage the vasculature of normal tissue. Upon heating, the intratumor environment becomes acidic, hypoxic, and nutritionally deprived due probably to vascular damage. Such a suboptimal environment in the heated tumors potentiates the response of tumor cells to hyperthermia, inhibits the repair of thermal damage, and also interferes with the development of thermal tolerance. The acidic environment also appears to potentiate the response of tumor cells to certain drugs at elevated temperatures. The changes in oxygenation of tumors and normal tissues caused by the changes in blood flow may have significant implications in the effectiveness of different sequences of hyperthermia and radiotherapy in the combined use of these two modalities. Changes in the distribution of drugs in tumors and normal tissues due to changes in blood flow will also determine the optimal use of hyperthermia in conjunction with chemotherapy.

Animals↗
PubMed1984

The nature and function of granulopoietic microenvironments.

A significant volume of reviewed literature in combination with observations presented here suggest that fibroblastic reticulum cells of the hematopoietic stroma may play a decisive role in the regulation of granulopoiesis. The histology of both bone marrow and spleen demonstrates an association between granulopoiesis and fibroblastic reticulum cells. Using in vitro cultured primary fibroblastic cells from murine bone marrow (BM) as antigenic source, we have prepared a hybridoma cell line secreting a monoclonal antibody (mAb) to fibroblastic reticular cells of the nonlymphoid domains in the spleen and BM. The mAb (ER-HR1) was demonstrated to exclusively detect primary fibroblastic cells cultured from spleen and bone marrow and in situ reticular cells with characteristic dendritic morphology and a dispersed distribution pattern. These reticular cells had extensive ramifications in the hemopoietic parenchyma. With the exception of some sparse fibroblastic cells in the dermis of the skin, the mAb did not react with any other cell type or extracellular substance elsewhere in the mouse, nor did it cross-react with human hemopoietic tissues. Support for a role of fibroblastic reticular cells in the regulation of granulopoiesis was obtained from in vitro studies. Primary BM fibroblasts produced granulocyte-macrophage colony stimulating activity (CSA). In contrast, we have been unable to detect CSA production by BM macrophages. Rather, we have found that BM macrophages deplete exogenous CSA from their culture medium. It is concluded that CSA may be produced by fibroblastic cells in adherent BM cultures and that the low CSA levels detected in their medium is due to depletion of fibroblastic cell-derived CSA by macrophages. We conclude that fibroblastic reticulum cells of the hemopoietic stroma carry unique antigenic determinants and together with macrophages, endothelial cells, and lymphocytes contribute to a complex network of cellular interactions providing an integrated microenvironmental control of granulopoiesis.

Animals↗
PubMed1983

The intrathymic microenvironment: expression of lectin receptors and lectin-like molecules of differentiation antigens and MHC gene products.

The expression of MHC products, differentiation antigens and lectin receptors has been investigated in the various cell types populating different compartments of the thymus. The ultrastructural classification of suspended thymic epithelial cells was facilitated by using a technique that preserves cortical nursing cells or medullary epithelial cell clusters. A subset of peanut lectin positive lymphocytes could be distinguished by their ability to bind soybean lectin also. This subset corresponds to the large proliferating lymphocytes that populate the area between the thymic capsule and the cortex. Ia and H-2 D/K antigens could be detected on nearly all epithelial and lymphoid cells. Expression of H-2 antigens, however, is more pronounced on medullary epithelial cells. T-cell differentiation antigens such as Thy-1 and Lyt-1 could be demonstrated not only on lymphocytes, but, interestingly enough, on cortical epithelial cells as well. These latter cells, in addition, exhibit a cell membrane-bound lectin with a specificity for D-galactose which might well be the structure responsible for binding the galactosyl residues of the peanut lectin receptor of thymic lymphocytes. Binding sites for a large set of lectins could be demonstrated on both, thymic lymphocytes and epithelium. The intrathymic differentiation pathway of T-lineage cells is discussed with regard to those lymphocytic and epithelial cell surface structures considered to enable cellular interaction.

Animals↗
PubMed1982

An immunohistological analysis of lymphocyte subpopulations and their microenvironment in the synovial membranes of patients with rheumatoid arthritis using monoclonal antibodies.

We have used monoclonal antibodies of the orthoclone (OKT) series to identify T cell subsets in an immunohistological analysis of the synovial membranes obtained from normal individuals and patients with osteoarthritis or rheumatoid arthritis. T cells of the inducer and the suppressor/cytotoxic subsets were identified by the OKT4 and OKT8 antibodies respectively while HLA-DR (Ia-like) antigens were recognized by a conventional antiserum. In the normal and osteoarthritic synovial membranes, virtually no lymphocytes were identified whereas the mononuclear cell infiltrates of the rheumatoid synovial membranes were composed predominantly of T cells expressing the OKT4 inducer phenotype with few OKT8+ suppressor/cytotoxic cells. The OKT4+ cells were found to be intimately related to B cells and strongly HLA-DR+ cells which morphologically resembled the interdigitating cells of lymph nodes. The micro-anatomical arrangement of these different cell types in the mononuclear infiltrates of the rheumatoid synovial membranes closely resembled that of the paracortical or T cell dependent area of normal lymph nodes except few OKT8+ lymphocytes were present. These findings are explained in terms of rheumatoid arthritis as a disease of altered T lymphocyte/macrophage immunoregulation.

Antibodies, Monoclonal↗
PubMed1981

Nuclear magnetic resonance study on the microenvironments of histidine residues of ribonuclease T1 and carboxymethylated ribonuclease T1.

The 270-MHz 1H NMR spectra and fluorescence of ribonuclease T1 and carboxymethylated ribonuclease T1 were measured in aqueous solution. Histidine C4 proton resonances were assigned to individual residues. From the pH dependences of the chemical shifts of histidine C2 and C4 protons, the pKa values of histidine residues were obtained by the non-linear least-squares method. The hydrogen leads to deuterium exchange rates of histidine C2 protons were determined as a measure of the accessibility of histidine residues to the solvent. Each histidine residue of ribonuclease T1 was found to interact with a carboxylate group of an aspartic or glutamic acid residue; in particular, His-40 was shown to interact with Glu-58. Upon carboxymethylation of Glu-58, His-92 and His-27 are more shielded from the solvent while His-40 remains exposed to the solvent. The 67.9-MHz 13C NMR spectra were measured for the 13C-enriched preparation of carboxymethylated ribonuclease T1. From the pH dependence of 13C chemical shift, the pKa value of the carboxymethylated Glu-58 was found to be unusually low, suggesting the formation of an ionic or hydrogen bond between this carboxymethyl group and a positively charged group, possibly of Arg-77.

Chemical Phenomena↗
PubMed1983

Osteopetrosis associated with premature thymic involution in grey-lethal mice. In vitro studies of thymic microenvironment.

The thymic atrophy developed in osteopetrotic grey-lethal (gl/gl) mouse during the last 10 days of life, and at 35 days of life gl/gl mice had only a few million thymic cells. Maximal survival of gl/gl mice was about 40 days. Earlier, at 20 days of age despite the presence of all signs of osteopetrosis their thymus had normal cellularity. This change in thymus cellularity was associated with relative increase in the frequency of cells forming thymic non-lymphoid (stromal) colonies in vitro. There were no qualitative differences in the presence of major cell types i.e. fibroblastoid, epithelioid and macrophages normally observed in these colonies. However, giant multinucleated cells resembling macrophages in size and appearance of nuclei were observed exclusively in cultures of the thymus from 20 day old control mice and not in cultures of gl/gl mice. On the other hand, in cultures of the thymuses of 35 day old gl/gl mice giant cells were observed that were nearly absent in cultures of the thymuses of control mice. These cells were either polynuclear or their nuclei were segmented and they resembled rather nuclei of epithelioid and fibroblastoid cells than nuclei of macrophages. The significance of all these findings is discussed.

Aging↗
PubMed1978

Dissecting the hematopoietic microenvironment. II. The kinetics of the erythron of the S1/S1d mouse and the dual nature of its anemia.

An analysis of the S1/S1d mouse for ferrokinetics and fate of peripheral red blood cells has shown the cause of its anemia to be dual in nature. While the S1/S1d produces red cells at a slightly greater rate than its normal littermate, its bone marrow and spleen appear to be operating near their maximal capacity and will reduce their output if anemic stress is partly relieved. The cause of the moderately high level of erythropoiesis in the S1/S1d is a mean daily loss of 2.5--3.0% of its total blood volume via the intestinal tract.

Anemia, Macrocytic↗
PubMed1981

Granulopoietic effects of human bone marrow fibroblastic cells and abnormalities in the "granulopoietic microenvironment".

The in vitro granulopoietic effects of adherent bone marrow fibroblastic cells (FC) were studied in normal humans and in patients with acute myelogenous leukemia (AML) and myeloproliferative disorders (MPD). To determine their influence on granulopoiesis, we established FC in liquid-phase cultures, overlaid the adherent FC with normal bone marrow cells in agar, and subsequently measured the growth of CFU-C. When using target marrows containing few spontaneous colonies, increased numbers of CFU-C were found above the FC obtained from normals. No growth greater than controls was observed in those areas lacking FC. If target marrows contained large numbers of spontaneous CFU-C, actual inhibition of colony formation was produced by FC co-incubation. In contrast to normals, FC obtained from untreated AML and MPD patients typically failed to enhance granulopoiesis. Regardless of source, FC were not synergistic with the effects of placenta-conditioned media (typically being inhibitory) for colony number, but were synergistic for colony size. Conditioned media obtained from FC cultures did not enhance colony formation and actually inhibited spontaneous colony formation. Thus, microenvironmental abnormalities in interactions between "stromal cells" and hematopoietic progenitors may be important in the pathogenesis and clinical expression of hematopoietic malignancies in humans.

Bone Marrow Cells↗