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S R Newcom

Publications and source records attributed to S R Newcom.

16 recordsLinked to original sources
PubMed1992

High molecular weight transforming growth factor beta is excreted in the urine in active nodular sclerosing Hodgkin's disease.

To measure the in vivo secretion of high molecular weight (HMW) transforming growth factor (TGF)beta by Reed-Sternberg cells from patients with nodular sclerosing Hodgkin's disease, we studied the urine samples from untreated patients. The urinary proteins did not promote the proliferation of NIH-3T3 cells in monolayer culture and contained similar amounts of total TGF activity when compared with normal controls. Urinary proteins from 24 different control and test urines were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Either of two primary antibodies were used for immunoblot detection: (a) affinity column purified polyclonal anti-TGF beta 1 prepared against platelet TGF beta 1 or (b) monoclonal anti-HMW-TGF beta prepared against HMW-TGF beta secreted by cloned L-428 Reed-Sternberg cells. All patients with active nodular sclerosing Hodgkin's disease had a detectable HMW-TGF beta (approximately 300,000) which cross-reacted with both anti-TGF beta 1 and anti-HMW-TGF beta. Purification demonstrated HMW-TGF beta which was active at physiological pH. Twelve control urine samples from healthy adults and 5 follow-up samples from the Hodgkin's patients after successful treatment contained no detectable urinary HMW-TGF beta. The in vivo production of HMW-TGF beta in untreated nodular sclerosing Hodgkin's disease supports the conclusion that this growth factor is secreted in large amounts by Reed-Sternberg cells or cells stimulated by Reed-Sternberg cells.

3T3 Cells↗
PubMed1992

Interleukin-4 is an autocrine growth factor secreted by the L-428 Reed-Sternberg cell.

Recent evidence indicates that Reed-Sternberg (RS) cells from many cases of Hodgkin's disease have features of activated lymphocytes and that lymphokines from activated lymphocytes induce proliferation of L-428 RS cells. It is shown here that a lymphokine similar to a lymphokine secreted by activated lymphocytes is secreted by L-428 cells. This lymphokine has a molecular weight approximately equal to 68,000 daltons, identical to glycosylated recombinant interleukin-4 (rIL-4), and cross-reacts with monoclonal anti-IL-4 in Western immunoblotting. This Hodgkin's cell growth factor (HCGF) is 100% neutralized by polyclonal anti-IL-4 antibodies and competes for the IL-4 receptor. After acid-elution, the L-428 RS cell has been shown to have 3,396 +/- 120 high-affinity receptor sites/cell. HCGF competes with rIL-4 for this receptor and L-428 cells contain mRNA for IL-4. Although all evidence indicates that IL-4 is an important secreted autocrine growth factor for L-428 RS cells, anti-IL-4 has no effect on the sustained serum-free growth of these Hodgkin's cells, suggesting that either the IL-4 receptor and the IL-4 receptor-growth factor complex are protected from antibody inhibition or other mechanisms are responsible for the sustained proliferation of L-428 RS cells.

Antibodies↗
PubMed1992

Neutralizing antibodies against transforming growth factor beta potentiate the proliferation of Ki-1 positive lymphoma cells. Further evidence for negative autocrine regulation by transforming growth factor beta.

Activated lymphocytes and malignant lymphoma cells derived from them (Ki-1 positive lymphoma cells) share similar mechanisms of proliferation. To further examine the inhibitory role of endogenous transforming growth factor beta (TGF beta) in Ki-1 positive lymphoma cells, the authors studied anti-TGF beta antibodies and measured their effect on proliferation. A monoclonal antibody (T1A5) prepared against a unique antigenic epitope of high molecular weight Hodgkin's TGF beta and a polyclonal rabbit antibody prepared against highly purified 25,000 D porcine platelet TGF beta 1 were used. Both antibodies are shown here to inhibit the biological activity of Hodgkin's TGF beta and to crossreact with their respective antigens in immunoblotting. DNA synthesis by Ki-1 lymphoma cells was increased 138-fold by anti-TGF beta 1 antibody and 262-fold by anti-Hodgkin's TGF beta. Exogenous TGF beta 1 suppression was completely reversed by anti-TGF beta 1 antibody and IL-2-induced proliferation was markedly potentiated (41 fold). L-428 Reed-Sternberg cells secrete physiologically active TGF beta but have fewer than 500 TGF beta receptor sites per cell; no significant proliferative response was measured for either anti-TGF beta 1 or anti-Hodgkin's TGF beta. These results show the suppressive effect of exogenous TGF beta 1 on indolent Ki-1 lymphoma cells and suggest that the endogenous secretion of high molecular weight physiologically active TGF beta is important in maintaining the indolent nature of this low-grade Ki-1 positive lymphoma.

Antibodies↗
PubMed1990

Production of monoclonal antibodies that detect Hodgkin's high molecular weight transforming growth factor-beta.

High molecular weight transforming growth factor-beta (TGF beta) is a physiologically active TGF secreted by nodular sclerosing Reed-Sternberg cells. Five monoclonal murine antibodies were prepared that distinguished Hodgkin's TGF beta from platelet-derived TGF beta using an enzyme-linked immunosorbent assay, neutralization of biologic activity, and Western blotting. These monoclonal antibodies directed at unique antigenic determinants (epitopes) of Hodgkin's TGF beta will allow further characterization of the role of Hodgkin's TGF beta in Hodgkin's disease and related entities.

Antibodies, Monoclonal↗
PubMed1990

Immunohistochemical evidence of a role for transforming growth factor beta in the pathogenesis of nodular sclerosing Hodgkin's disease.

Transforming growth factor beta (TFG-beta) is a multifunctional growth factor that promotes the growth of fibroblasts, collagen synthesis and angiogenesis, and stimulates monocyte migration and activation, but suppresses the growth and differentiation of immune lymphocytes and killer cells. Previously we demonstrated biologic activity for TGF-beta in supernatants of fresh Hodgkin's disease (HD) cell cultures and the cell line L428 derived from nodular sclerosing HD. This study was undertaken to find evidence of TGF-beta activity directly in tissues affected by HD. Formalin-fixed tissue from 14 patients with HD, including 8 nodular sclerosis, 4 mixed cellularity, 1 lymphocyte predominance, and 1 lymphocyte depletion type were studied by immunoperoxidase technique with antibody CC (1-30) raised against a synthetic polypeptide with the same N-terminal amino acid sequence as TGF-beta 1. Transforming growth factor beta activity was demonstrated in six cases of nodular sclerosis but not in other histologic types of HD. Staining for TGF-beta was found in the cytoplasm of Reed-Sternberg (RS) cells in one case and on the surface of RS cells and their lacunar variants in five cases. Transforming growth factor beta activity associated with the extracellular matrix was localized mainly around blood vessels, zones of necrosis, at the margins of bands of collagen sclerosis, and in areas containing syncytia of RS cells. In two cases TGF-beta was associated with collections of epithelioid histiocytes or granulomas. Small lymphocytes, granulocytes, and germinal center cells were unreactive. These results suggest that TGF-beta is a growth factor of biologic importance in HD and may be responsible for many of the histologic features, such as nodular sclerosis and granulomas, that may have prognostic significance.

Adolescent↗
PubMed1988

L-428 Reed-Sternberg cells and mononuclear Hodgkin's cells arise from a single cloned mononuclear cell.

The L-428 cell line derived from nodular sclerosing Hodgkin's disease was verified to be a human female cell line with surface marker and morphologic characteristics similar to native Hodgkin's cells. Single cells were cloned and subcloned twice to determine the characteristics of the clonogenic L-428 Hodgkin's cell (resulting in a 10% cloning efficiency). Both mononuclear L-428 cells and classical Reed-Sternberg cells arose from solitary cells. The clonogenic cell was the mononuclear Hodgkin's cell, although small abortive colonies sometimes arose from classical binucleate Reed-Sternberg cells. Cytogenetic and phenotypic analysis supported the clonality of three subclones and indicated, among many findings, consistent abnormalities of the long arm of chromosome 7 (beta-chain of the T cell receptor) and 14q32 (Ig heavy chain). Distinctive abnormalities of cytogenetics, phenotyping and transforming growth factor-beta production were exhibited for each clone as well. These observations demonstrate the relationship of the continuum of malignant mononuclear and multinuclear Reed-Sternberg cells in this cell culture from nodular sclerosing Hodgkin's disease and suggest that a similar relationship exists in native Hodgkin's disease tissue. These observations also support the theory of clonality in Hodgkin's disease and suggest that in vivo contiguous metastasis in the L-428 Hodgkin's disease patient was most likely accomplished by a Ki-1 positive small mononuclear cell.

Cell Line↗
PubMed1988

L-428 nodular sclerosing Hodgkin's cell secretes a unique transforming growth factor-beta active at physiologic pH.

Nodular sclerosing Hodgkin's disease is characterized by dense collagen fibrosis. Although transforming growth factor-beta (TGF-beta) is an important bifunctional growth factor for fibroblasts and is stored and released by many cells, it requires acidification to pH 2.0-3.0 before it becomes a biologically active growth factor. We show here that the L-428 Hodgkin's cell releases a high molecular weight TGF that competes for the TGF-beta cell membrane receptor but not the TGF-alpha receptor. This growth factor is most active at physiologic pH and is 97% inactivated by acidification. Hodgkin's TGF is also inactivated by proteases and can be preserved by protease inhibitors. The Hodgkin's TGF can be separated from an autocrine growth factor using either column chromatography or electroelution from gels and is shown to have a molecular weight of approximately 350,000. Incubation of the Hodgkin's TGF in SDS releases a 25,000-D protein with reduced biological activity but which cross-reacts with anti-TGF-beta IgG. We propose that L-428 nodular sclerosing Hodgkin's disease fibrosis is mediated by a potent high molecular weight TGF-beta which, unlike TGF-beta characterized to date, is secreted in a form most active at physiologic pH.

Blotting, Northern↗
PubMed1988

Cytology or biopsy.

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Acquired Immunodeficiency Syndrome↗
PubMed1988

Production of transforming growth factor-beta activity by Ki-1 positive lymphoma cells and analysis of its role in the regulation of Ki-1 positive lymphoma growth.

The growth of activated human T lymphocytes in response to interleukin-2 (IL-2) is suppressed by transforming growth factor-beta (TGF-beta). This study presents data that show a diminished response of two human lymphoma cell lines to physiologic regulation by TGF-beta. Cell line L-428 was derived from the malignant pleural effusion of a patient with far advanced nodular sclerosing Hodgkin's disease and has been shown to have clonal gene rearrangements characteristic of both B and T lymphocytes. Cell line Mac-1 was derived from the blood of a patient with clinically indolent cutaneous T-cell lymphoma. Both cell lines express the Hodgkin's disease associated antigen, Ki-1. These Ki-1 positive lymphomas are shown to secrete TGF-beta into serum-free culture media. The addition of picogram quantities of exogenous TGF-beta to cell cultures of indolent Ki-1 lymphoma (Mac-1) suppresses IL-2-dependent mitosis; however, the suppression is less than 45%. This suppression correlates with a decrease in the number of IL-2 receptors. No inhibition of Ki-1 positive Hodgkin's cells (L-428) was observed, and proliferation dependent on polyclonal IL-2 was either not affected or was slightly potentiated by TGF-beta. Receptor analysis indicates the absence of IL-2 and TGF-beta receptors on L-428 cells. Thus, these Ki-1 lymphomas derived from activated lymphocytes appear to secrete TGF-beta activity but continue to proliferate because of defective suppression of IL-2 (and related lymphokine)-dependent DNA synthesis.

Cell Division↗
PubMed1985

The Hodgkin's cell in nodular sclerosis does not release interleukin-1.

Cell cultures were established from lymph nodes from eight patients with nodular sclerosing Hodgkin's disease and 12 controls. The patient cultures were demonstrated to produce a transforming growth factor for fibroblasts; none of the control cultures produced this transforming growth factor. The serum-containing and serum-free conditioned media were also tested for interleukin-1 activity produced by these cultures. Two nodular sclerosing Hodgkin's disease cell cultures produced measurable levels of interleukin-1 activity, and one had persistent levels of interleukin-1 activity after depletion of normal macrophages. However, nonspecific esterase stains confirmed the persistence of many normal macrophages. Two alveolar macrophage cultures had measurable interleukin-1 but did not induce fibroblast colony formation in soft agar. These data suggest that the Hodgkin's cell does not produce measurable levels of interleukin-1 and that interleukin-1 derived from the Hodgkin's cell is not the mediator responsible for the fibroblast hyperplasia and agar colony formation produced by cell cultures from nodular sclerosing Hodgkin's disease.

Animals↗
PubMed1979

Prednisone in treatment of allergen-associated angio-immunoblastic lymphadenopathy.

Angio-immunoblastic lymphadenopathy with dysproteinaemia (A.I.L.D.) is a lymphoproliferative disorder associated in one third of the patients with exposure to an allergen. In four patients with allergen-associated A.I.L.D. single cytotoxic drugs were ineffective but maintenance low-dose prednisone for 6--12 months induced complete remission for up to 13 years. In contrast, three patients with non-allergen-associated A.I.L.D. did not respond to prednisone but achieved remission with combination chemotherapy.

Aged↗
PubMed1979

T-cell leukemia with thymic involution.

The prognosis of acute lymphoblastic leukemia is affected adversely by T-cell markers on the malignant lymphoblasts. Direct involvement of the thymus has been assumed because of frequent mediastinal enlargement in these patients and the important role of the thymus in certain mouse leukemias. We report here an adult with T-cell leukemia and mediastinal enlargement who had physiologic involution of the thymus. The possible role of diphenylhydantoin in the pathogenesis of this disease is reviewed. The possible usefulness of Nu/Nu mouse xenografting for the study of this lethal disorder is discussed.

Adult↗