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W E Samlowski

Publications and source records attributed to W E Samlowski.

53 records · Page 3Linked to original sources
PubMed1987

Marrow ablative doses of gamma-irradiation and protracted changes in peripheral lymph node microvasculature of murine and human bone marrow transplant recipients.

Gamma-irradiation has been extensively utilized as a bone marrow ablative agent during human bone marrow transplantation. Although the effects of ionizing radiation on lymphoid and hematopoietic cells are well documented, little is currently known about its effect on the nonhematopoietic tissues which are important for the restoration of normal immune function. The vast majority of lymphocyte movement into peripheral lymph nodes takes place via the bloodstream and requires a specific receptor-ligand interaction between the lymphocyte and anatomically distinct postcapillary venules. Due to the importance of lymphocyte recirculation in the initiation and amplification of immune responses, an understanding of the radiosensitivity of the postcapillary venules may provide insight into the pathogenesis of the immune deficiencies commonly seen after bone marrow transplantation. Our studies disclosed that the ability of normal blood-borne lymphocytes to enter peripheral lymph nodes was markedly depressed (less than 50% of normal) in mice which had been exposed to 7.5 Gy of gamma-irradiation. This radiation-induced effect lasted longer than 6 months after irradiation and syngeneic reconstitution, and its magnitude was radiation-dose dependent. Immunochemical staining of the lymph node microvasculature with the monoclonal antibody MECA-325 established that the radiation protocol induced persistent anatomic changes in the lymphocyte-receptive areas of endothelium (high endothelial venules). These vessels developed the appearance of endothelial cell proliferation. Electron microscopy demonstrated significant intracellular edema, with virtual occlusion of many microvascular lumens by edematous endothelial cells. Lymph nodes from human bone marrow transplant recipients were found to exhibit similar ultrastructural changes. These studies for the first time demonstrate that doses of irradiation similar to those used to prepare bone marrow transplant recipients can have significant anatomic and functional sequellae on host endothelial cells.

Animals↗
PubMed1986

Alterations in lymphocyte recirculation within ultraviolet light-irradiated mice: efferent blockade of lymphocyte egress from peripheral lymph nodes.

Ultraviolet irradiation (uvR) has been demonstrated to have profound effects on many functions of the immune system. In particular, exposure to this physical agent can alter the tissue distribution and function of a number of immunologically active cell types, even at sites remote from direct uvR exposure. The present investigation demonstrates that uvR exposure of mice induces an efferent blockade of lymphocyte egress from the peripheral lymph nodes which drain the irradiated skin, resulting in marked retention of lymphocytes. In vivo studies of this efferent blockade established that the condition appeared similar in mechanism to that induced by the administration of poly-inosinic:poly-citidylic acid, murine interferon alpha/beta and specific antigen. We were able to establish that a common mechanism in the genesis of an efferent lymphatic blockade may involve prostaglandin biosynthesis. The potential contribution of efferent blockade to the development of systemic suppression of contact hypersensitivity induced by uvR exposure is discussed.

Animals↗
PubMed1986

Modification of the murine immune system by glucocorticosteroids: alterations of the tissue localization properties of circulating lymphocytes.

Glucocorticosteroids have proven capable of suppressing both developing and ongoing immune responses via mechanisms that are not fully understood. Most investigations into the mechanisms of glucocorticosteroid-mediated immunosuppression have examined the direct effects of these agents on the lymphocyte itself. In this paper, we have analyzed the effects of glucocorticosteroids on the lymphocyte receptive capacity of lymph nodes and bone marrow in mice. These effects appear to be mediated via reversible changes in the capacity of steroid-treated vascular endothelial cells to interact with normal lymphocytes, and are both dose and time dependent. The most striking effects on lymphocyte localization were observed in mice given microgram quantities of glucocorticosteroids over a 6-day period via a continual release pellet. The direct exposure of lymphocytes to these drugs in vitro was shown to have no effect on their subsequent localization potential in vivo. Further studies revealed that the ability of antigen-sensitized effector lymphocytes to localize into sites of antigen deposition was also markedly depressed in mice pretreated with glucocorticosteroids. Therefore, steroids also appear to have effects on tissue associated endothelial cells which prevent the localization of sensitized effector lymphocytes into sites of active inflammation. Our observations have potential clinical implications, both in understanding the anti-inflammatory effects of glucocorticosteroids more fully, as well as suggesting that low-dose continual-release steroid administration may result in enhanced immunosuppression.

Animals↗
PubMed1986

Evaluation of the response of unresectable carcinoid tumors to radiotherapy.

Sixteen patients with unresectable primary or metastatic carcinoid tumors were treated with radiotherapy. Objective responses (CR + PR) were documented in 4 of 16 patients (25%). The median survival of the responders was 46 months following radiotherapy, as compared to the 10-month median survival of the entire group of 16 patients. There were five additional patients who improved symptomatically or had minor responses. The seven patients who received the highest doses of radiotherapy (greater than 29 GY), to local or regional treatment ports, had the best response rate (43%). Many patients eventually had objective evidence of relapse or tumor progression within the radiotherapy port, in part reflecting the relatively low radiotherapy doses used in the treatment of the nine patients with abdominal carcinoids. One patient remains disease free at 103 months. Patients who exhibited the carcinoid syndrome appeared to respond less frequently to radiotherapy than patients who did not have ectopic hormone secretion, although the number of patients with ectopic hormone secretion was too small to establish this point in a definitive manner. The results of this study demonstrate that carcinoid tumors respond to moderate doses of radiotherapy in a manner similar to many other epithelial tumors.

Adult↗
PubMed1986

Immunological consequences of ultraviolet radiation exposure.

Depending on the dose and conditions of administration, ultraviolet radiation (UVR) can function as either a complete carcinogen, a co-carcinogenic agent, or an immunologic modulator. Although much is known about its carcinogenic properties, only recently have investigations been aimed at defining the mechanisms by which UVR mediates its effect on the immune system. The objective of this article is to present the necessary background and results of recent studies that provide the basis for defining some of the local and systemic effects that UVR has on an individual's immunologic potential. This discussion focuses on: the histologic alterations in the skin and draining lymph nodes, the changes in lymphocyte localization, the increased release of the immunologic (and physiologic) mediator ETAF/IL-1, and the induction of antigen-specific immunoregulatory circuits that occur subsequent to UVR exposure. It is our hypothesis that the detrimental effects that UVR has on the host's immunologic competence may represent a normal defense mechanism to protect the individual against the adverse consequences of chronic inflammatory stimuli. In this regard, a better understanding of photoimmunology may lead to the development of more effective means of immunologic modulation for altering the clinical course of various human diseases that are either immunologically mediated, photoinduced, or responsive to phototherapy.

Cell Transformation, Neoplastic↗
PubMed1985

Characterization of the in vitro interaction of PNAhi lymphocytes with the bone marrow and hepatic asialoglycoprotein receptors.

We have previously identified an in vivo interaction between circulating PNAhi lymphoid cells and the hepatic asialoglycoprotein receptor, which results in a protracted liver sequestration of these cells. An in vitro frozen section binding assay was developed to study the interaction of PNAhi cells with the receptor in more detail. This assay confirmed that the sequestration of PNAhi lymphoid cells by the liver was mediated by the asialoglycoprotein receptor, as binding was inhibitable by coincubation with galactose, asialoglycoproteins, chelation of divalent cations, or a specific anti-asialoglycoprotein receptor antiserum. This frozen section binding assay was utilized to demonstrate the existence of a bone marrow asialoglycoprotein receptor which was found to be capable of binding to PNAhi lymphocytes or asialoglycoproteins bound to synthetic substrates. We further established that the bone marrow receptor differed both functionally and antigenically from its hepatic analogue.

Animals↗
PubMed1985

Value of open-lung biopsy in 87 immunocompromised patients with pulmonary infiltrates.

The authors performed a retrospective analysis of 87 consecutive immunocompromised patients who underwent open-lung biopsy at the University of Utah Medical Center, Salt Lake City, Utah, from January 1971 to June 1982. A specific histologic diagnosis was obtained in 62 (71%) of the patients, 33 of whom had infections. Pneumocystis carinii was the most common microbial pathogen (16 patients), but no cases have been observed since 1980 when the routine use of prophylactic trimethoprim/sulfa began. The other specific diagnoses included malignancy or drug-induced lung disease. Specific therapy was available for 52 patients, and in 33 cases, a change in therapy was necessary to treat according to the lung biopsy diagnosis. Forty-one patients received an adequate course of therapy and 27 (66%) of these improved clinically, including 16 of 26 patients with infections, 11 of 14 with malignancies, and 1 of 2 with a vasculitis. Among the subgroup of 33 patients for whom a new, specific therapeutic option was available as a result of the biopsy diagnosis 21 (64%) responded to the treatment. Eleven significant operative complications were encountered, but no deaths were attributable to the biopsy. An open-lung biopsy in immunocompromised patients is a relatively safe, accurate diagnostic procedure which frequently facilitates appropriate therapy and clinical improvement.

Adolescent↗
PubMed1985

Placental-site trophoblastic tumor (trophoblastic pseudotumor): case report demonstrating failure of chemotherapy, surgery, and radiotherapy to control metastatic disease.

A case of metastatic placental-site trophoblastic tumor (trophoblastic pseudotumor) is presented and compared to four previously reported cases. Chemotherapy with MAC (methotrexate, dactinomycin, cyclophosphamide), aggressive surgical debulking, and radiotherapy were ineffective in producing disease regression. Only two of the four similar cases in the literature showed short responses (4-7 months) to several different aggressive multiagent chemotherapy regimens. Optimal therapeutic outcome is likely to result from an early diagnosis and aggressive surgical treatment of localized tumor.

Adult↗
PubMed1985

Bone marrow engraftment efficiency is enhanced by competitive inhibition of the hepatic asialoglycoprotein receptor.

The efficiency of pluripotent stem cell engraftment following bone marrow transplantation is predicated upon many poorly understood factors. These include the processes by which intravenously injected stem cells circulate and localize in microenvironments that contain the stromal elements necessary to facilitate their continued proliferation. We have recently established that lymphoid cells that bind the lectin peanut agglutinin are subject to prolonged sequestration following their interaction with the hepatic asialoglycoprotein receptor. Since bone marrow stem cells are also known to bind peanut agglutinin, we hypothesized that the physiologic function of the asialoglycoprotein receptor might significantly impair their ability to localize in anatomic sites where they are able to proliferate. Competitive inhibition with asialoglycoproteins was employed to establish a temporary receptor blockade during the initial 3-4 hr after transplantation. This procedure resulted in a 5- to 10-fold increase in splenic hematopoietic colony formation. Our findings suggest that inhibition of the liver asialoglycoprotein receptor during murine bone marrow transplantation results in more efficient stem cell localization to hematopoietic-inducing microenvironments. This enhancement in engraftment efficiency was paralleled by a more rapid recovery of peripheral blood leukocyte and platelet counts, an increase in megakaryocytic colony formation, as well as increased recipient survival. Techniques designed to inhibit the liver sequestration of bone marrow stem cells may have direct applicability to human bone marrow transplantation procedures.

Animals↗
PubMed1985

Immunologic studies documenting the development of mycosis fungoides following successful therapy of a large-cell lymphoma.

We describe a patient who developed mycosis fungoides, a T-cell neoplasm, two years following the chemotherapy and radiotherapy of a diffuse, large-cell ("histiocytic") lymphoma. Immunologic studies documented a "null-cell" phenotype for the large-cell lymphoma. Therefore, the proliferation of two distinct malignant lymphoid clones is believed to have developed in the patient. The value of immunologic marker studies in this case was to aid in the diagnosis of the two separate neoplasms, as well as to aid in the selection of appropriate specific therapy directed against each neoplasm. As the association of large-cell lymphoma and mycosis fungoides in one patient represents a very rare event, we discuss several hypotheses about the possible interrelation of the two neoplasms.

Adult↗
PubMed1984

Studies on the liver sequestration of lymphocytes bearing membrane-associated galactose-terminal glycoconjugates: reversal with agents that effectively compete for the asialoglycoprotein receptor.

The removal of "effete" glycoproteins from the circulation represents a proposed physiologic role for the hepatocyte asialoglycoprotein receptor. Our experiments support the hypothesis that this receptor may also be directly involved in the removal from the circulation of cells bearing asialoglycoconjugates. We report that the enhanced liver localization of neuraminidase-treated lymphocytes can be competitively inhibited by the coinjection of asialofetuin (ASF). Fetuin itself was without effect. Competitive inhibition of the liver receptor allowed normal localization to lymphoid tissues of the enzyme-treated lymphocytes, a condition which persisted as long as free ASF was present in the circulation. Our studies support the concept that cell surface carbohydrates play an important role in the tissue distribution of circulating lymphocytes. The process of thymocyte maturation, bone marrow transplantation, and the adoptive immunotherapy with continuous T-cell lines represent conditions where recirculation potential may be influenced by the presence of galactose terminal glycoconjugates.

Animals↗
PubMedDate not supplied

Evaluation of Tomudex in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group study.

A phase II trial of Tomudex (raltitrexed, ZD 1694), a new thymidylate synthase inhibitor, was performed in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. This trial demonstrated that Tomudex was well tolerated in this patient population. Nausea and vomiting were minimal, and hematologic toxicities were relatively infrequent. Only one patient was withdrawn from the study due to toxicity (grade 4 diarrhea). One patient exsanguinated from a rent in the carotid artery in an area of tumor involvement, and was categorized as a grade 5 toxicity. Thus 25/27 patients were able to complete at least 2 cycles of treatment. Tomudex demonstrated a 3.7% response rate (95% CI 0.1-19%), with a median survival of 6 months in this highly resistant disease population. Tomudex is not considered active enough as monotherapy for further evaluation in this disease population.

Aged↗
PubMedDate not supplied

Direct and indirect effects of murine interleukin-2, gamma interferon, and tumor necrosis factor on testosterone synthesis in mouse Leydig cells.

It was recently observed that treatment of patients with a high dosage of human interleukin (IL-2) resulted in suppression of plasma concentrations of testosterone. A murine model was developed to assess the direct and indirect effects of murine IL-2 and the secondarily released cytokines, gamma interferon (INF gamma), and tumor necrosis factor (TNF alpha), on testosterone production in isolated Leydig cells. Pretreatment for 24 hours with IL-2 (100 to 500 IU/ml) or INF gamma (100 to 1000 IU/ml) significantly decreased testosterone production in response to luteinizing hormone (LH; P < 0.02 and 0.005, respectively). The combinations of INF gamma with either TNF alpha or IL-2 produced enhanced suppressive effects on Leydig cell testosterone production. Steroidogenic precursors (22-hydroxycholesterol, 17 alpha-hydroxypregnenolone, and dehydroepiandrosterone) restored testosterone secretion to control levels after preincubation with INF gamma or TNF alpha. In contrast, the inhibition of testosterone synthesis produced by either IL-2 or INF gamma plus TNF alpha could be reversed by 17 alpha-hydroxypregnenolone and dehydroepiandrosterone, but not by 22-hydroxycholesterol (P < 0.01). Dibutyryl cyclic adenosine monophosphate was also ineffective in reversing the inhibitory effects of these cytokines on synthesis. Although IL-2 directly inhibited synthesis in isolated Leydig cells, it stimulated testosterone production (P < 0.005) in minced murine testes. This suggests that IL-2 releases regulatory factors from other cells that were able to overcome the direct inhibitory effect of IL-2. This stimulatory effect was not caused by INF gamma and TNF alpha because INF gamma alone or with TNF alpha inhibited (P < 0.005) testosterone production in minced testes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Liver sequestration of murine lymphokine activated killer (LAK) cells is mediated by carbohydrate-specific receptors.

Intravenous infusion of radiolabeled lymphokine activated killer (LAK) cells into tumor bearing humans and animals results in retention of a large percentage (40-70%) of cells within the liver. Since LAK cell-tumor cell adhesion is believed to be necessary to initiate effective cytotoxicity, liver sequestration may decrease the therapeutic effectiveness of the adoptively transferred cells. We evaluated the mechanism of liver sequestration in a murine model. When 51Cr labeled LAK cells were infused intravenously into syngeneic recipients, about 45% of the radiolabeled cells were sequestered in the liver by 4 hours after infusion and 55% by 24 hours. Less than 0.4% of the infused cells localized into a 3-4 mm tumor implant. Peanut agglutinin (PNA), which recognizes galactose-terminal glycans, identifies cells at risk for sequestration by hepatic asialoglycoprotein receptors. We demonstrated that LAK cells, particularly the large granular lymphocyte subpopulations, were PNA high by direct immunofluorescence. The majority of LAK cell cytotoxic activity also resided in the PNA high cell population. Lectin blotting revealed that IL-2 incubation caused an increased expression of multiple cell membrane asialoglycoproteins. Experiments in vitro suggested that LAK cells were capable of binding to asialoglycoprotein and fucose-specific receptors within the liver. This binding could be inhibited by mild LAK cell surface trypsinization, suggesting that binding was mediated via cell surface glycoproteins. We conclude that LAK cells have a surface phenotype which can mediate their interaction with multiple hepatic carbohydrate-specific receptors. These interactions may result in LAK cell sequestration and decrease the delivery of cytotoxic cells into cancers during adoptive immunotherapy.

Animals↗
PubMedDate not supplied

The role of macrophages in the regulation of high endothelial venule expression within the peripheral lymph nodes of mice exposed to ultraviolet radiation.

A number of direct and indirect immunologic consequences follow the exposure of the skin to ultraviolet radiation (UVR). One of the remote effects of UVR is the increased accumulation of lymphocytes within peripheral lymph nodes that drain irradiated skin sites. The present study was designed to evaluate the mechanisms responsible for this increased lymphocyte accumulation. Primary lymphocyte localization into draining regional lymph nodes was found to be markedly increased (up to 81%) by UVR exposure of the skin. The changes in lymphocyte localization correlated closely with increases in the number and density of lymphocyte-receptive endothelial structures (high endothelial venules, or HEV) within these regional lymph nodes. Because macrophages or their products are believed to maintain resting HEV expression and function, we assessed the role of these cells in the expansion of HEV due to UVR exposure. Our studies demonstrated that a peripheral injection of antigen-activated macrophages caused an increase in HEV expression within lymph nodes draining the injection site. Conversely, treatment of mice with silica or carrageenan to depress macrophage function produced both histologic and functional hyporesponsiveness of the microvascular endothelium to UVR-stimulated HEV expansion. These changes in endothelial cell responsiveness correlated with the absolute number of MAC-1+ cells present within the regional nodes of UVR-exposed mice. Our studies have demonstrated a striking similarity between lymph node microvascular changes in response to cutaneous UVR- and antigen-exposure. We therefore suggest that macrophage-mediated signals may initiate a general mechanism that increases lymphocyte recirculation through the regional lymph nodes in response to both antigenic and inflammatory challenge.

Animals↗