Edgar Engleman | Stanford University (original) (raw)

Papers by Edgar Engleman

Research paper thumbnail of Inhibition of Cell Mediated Immune Responses by 8Methoxypsoralen and Long-wave Ultraviolet Light: A Possible Explanation for the Clinical Effects of Photoactivated Psoralen

Journal of Investigative Dermatology, 1980

Human thymus-derived lymphocytes proliferate when cultured with lymphocytes or epidermal cells fr... more Human thymus-derived lymphocytes proliferate when cultured with lymphocytes or epidermal cells from unrelated individuals because such cells express HLA-D antigens, which are recognized as foreign by thymus- derived lymphocytes. The current study demonstrates that these responses are inhibited if either the stimulator cells or responder cells are pretreated with the combination of 8-methoxypsoralen and long-wave ultraviolet light. Additional studies revealed

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Research paper thumbnail of Differentiation of myeloid dendritic cells into CD8a-positive dendritic cells in vivo

Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) wit... more Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) with varying phenotypes. For example, in mice, CD8alpha(+) and CD8alpha(-) DC are thought to represent cells of lymphoid and myeloid origin, respectively. Langerhans cells (LC) of the epidermis are typical myeloid DC; they do not express CD8alpha, but they do express high levels of myeloid antigens such as CD11b and FcgammaR. By contrast, thymic DC, which derive from a lymphoid-related progenitor, express CD8alpha but only low levels of myeloid antigens. CD8alpha(+) DC are also found in the spleen and lymph nodes (LN), but the origin of these cells has not been determined. By activating and labeling CD8alpha(-) epidermal LC in vivo, it was found that these cells expressed CD8alpha on migration to the draining LN. Similarly, CD8alpha(-) LC generated in vitro from a CD8 wild-type mouse and injected into the skin of a CD8alphaKO mouse expressed CD8alpha when they reached the draining LN. The results also show that CD8alpha(+) LC are potent APC. After migration from skin, they localized in the T-cell areas of LN, secreted high levels of interleukin-12, interferon-gamma, and chemokine-attracting T cells, and they induced antigen-specific T-cell activation. These results demonstrate that myeloid DC in the periphery can express CD8alpha when they migrate to the draining LN. CD8alpha expression on these DC appears to reflect a state of activation, mobilization, or both, rather than lineage. (Blood. 2000;96:1865-1872)

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Research paper thumbnail of A SUPPRESSOR T CELL OF THE M IXED L YMPHOCYTE REACTION IN MAN SPECIFIC FOR THE S TIMULATING A LLOANTIGEN Evidence that Identity at HLA-D between Suppressor and Responder is Required for Suppression

Recent investigations from this laboratory have documented the presence of suppressor T cells of ... more Recent investigations from this laboratory have documented the presence of suppressor T cells of the mixed lymphocyte reaction (MLR) ~ in two unrelated individuals (1). 2 That is, when T cells from these individuals were cocultured in an MLR with the responder cells of human leukocyte antigen (HLA) identical persons, the responses of such persons to allogeneic cells were inhibited.

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Research paper thumbnail of Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity

Nature, 2015

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Research paper thumbnail of Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 13, 2015

The goals of the study were to elucidate the immune mechanisms that contribute to desirable compl... more The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non-small cell lung tumors. Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21 day (>1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors. We found that the high dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8+ T cell tumor infiltrate, and a loss of myeloid derived suppressor cells (MDSCs). The change was dependent on antigen cross-presenting CD8+ dendritic cells, secretion of IFN- γ, and CD4+T cells expressing CD40L. Anti-tumor CD8+ T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated ...

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Research paper thumbnail of Regulation of Obesity-Related Insulin Resistance with Gut Anti-inflammatory Agents

Cell Metabolism, 2015

Obesity has reached epidemic proportions, but little is known about its influence on the intestin... more Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.

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Research paper thumbnail of CD101 surface expression discriminates potency among murine FoxP3+ regulatory T cells

Journal of immunology (Baltimore, Md. : 1950), 2007

CD4+CD25+FoxP3+ regulatory T cells (Treg) have been shown to be protective in animal models of au... more CD4+CD25+FoxP3+ regulatory T cells (Treg) have been shown to be protective in animal models of autoimmunity and acute graft-vs-host disease. However, owing to the functional heterogeneity among CD4+CD25+ T cells, surface markers expressed selectively on functionally active Treg would be useful for purposes of identifying and isolating such cells. We generated a rabbit mAb against murine CD101, a transmembrane glycoprotein involved in T cell activation. Among freshly isolated T cells, CD101 was detected on 25-30% of CD4+CD25+ Treg and approximately 20% of conventional memory T cells. CD101(high) Treg displayed greater in vitro suppression of alloantigen-driven T cell proliferation as compared with CD101(low) Treg. In a model of graft-vs-host disease induced by allogeneic bone marrow transplantation in vivo bioluminescence imaging demonstrated reduced expansion of donor-derived luciferase-labeled conventional T cells in mice treated with CD101(high) Treg, compared with CD101(low) Treg...

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Research paper thumbnail of Statin-AE: a novel angiostatin-endostatin fusion protein with enhanced antiangiogenic and antitumor activity

Angiogenesis, 2001

The combination of angiostatin and endostatin has been shown to have synergistic antiangiogenic a... more The combination of angiostatin and endostatin has been shown to have synergistic antiangiogenic and antitumor effects when the genes for these proteins are delivered to tumor cells by retroviral gene transfer. Here we report the construction of a murine angiostatin-endostatin fusion gene (Statin-AE) which shows enhanced antiangiogenic activity on human umbilical vein endothelial cell (HUVEC) tube formation in vitro compared with angiostatin or endostatin alone. Similarly, the fusion gene demonstrates antiangiogenic effects in vivo and antitumor activity in a B16F10 melanoma model when co-delivered by retroviral packaging cell inoculation in mice. The fusion gene demonstrates significantly greater inhibition of tumor growth compared with angiostatin, endostatin or the combination of genes.

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Research paper thumbnail of Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells

Clinical immunology and immunopathology, 1991

Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid hormone in humans. Although it... more Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid hormone in humans. Although it is well established that DHEA serves as an intermediate in sex steroid synthesis, recent studies in mice suggest that DHEA may also be a physiologic regulator of IL2 secretion. To explore the effect of DHEA on the human immune system, T lymphocytes from healthy adults were exposed to DHEA followed by stimulation with mitogens or antigen. Upon activation with a variety of stimuli, T cells pretreated with 10(-8) to 10(-11) M DHEA produced significantly greater amounts of IL2 and mediated more potent cytotoxicity than T cells activated in the absence of this steroid hormone. The peak effect of DHEA was observed at 10(-9) M, the concentration of hormone present in the blood of normal adults. In contrast to its effect on murine T cells, the IL2 enhancing effect of DHEA on human lymphocytes was limited to fresh CD4+ T cells and CD4+ clones; neither fresh CD8+ cells nor CD8+ clones were direct...

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Research paper thumbnail of Human immunodeficiency virus-infected monocyte-derived macrophages express surface GP120 and fuse with CD4 lymphoid cells in vitro: A possible mechanism of T lymphocyte depletion in vivo

Clinical Immunology and Immunopathology, 1992

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Research paper thumbnail of T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans

Arteriosclerosis, thrombosis, and vascular biology, 2014

The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. W... more The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. We have shown that insulin resistance or glucose intolerance in diet-induced obese mice is related to a shift in the ratio of pro- and anti-inflammatory T cells in adipose tissue. We sought to test the hypothesis that the balance of T-cell phenotypes would be similarly related to insulin resistance in human obesity. Healthy overweight or obese human subjects underwent adipose-tissue biopsies and quantification of insulin-mediated glucose disposal by the modified insulin suppression test. T-cell subsets were quantified by flow cytometry in visceral (VAT) and subcutaneous adipose tissue (SAT). Results showed that CD4 and CD8 T cells infiltrate both depots, with proinflammatory T-helper (Th)-1, Th17, and CD8 T cells, significantly more frequent in VAT as compared with SAT. T-cell profiles in SAT and VAT correlated significantly with one another and with peripheral blood. Th1 frequency in SAT...

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Research paper thumbnail of B-1a Lymphocytes Attenuate Insulin Resistance

Diabetes, 2014

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Research paper thumbnail of Orthotopic Mouse Model of Colorectal Cancer

Journal of Visualized Experiments, 2007

The traditional subcutaneous tumor model is less than ideal for studying colorectal cancer. Ortho... more The traditional subcutaneous tumor model is less than ideal for studying colorectal cancer. Orthotopic mouse models of colorectal cancer, which feature cancer cells growing in their natural location, replicate human disease with high fidelity. Two techniques can be used to establish this model. Both techniques are similar and require mouse anesthesia and laparotomy for exposure of the cecum. One technique involves injection of a colorectal cancer cell suspension into the cecal wall. Cancer cells are first grown in culture, harvested when subconfluent and prepared as a single cell suspension. A small volume of cells is injected slowly to avoid leakage. The other technique involves transplantation of a piece of subcutaneous tumor onto the cecum. A mouse with a previously established subcutaneous colorectal tumor is euthanized and the tumor is removed using sterile technique. The tumor piece is divided into small pieces for transplantation to another mouse. Prior to transplantation, the cecal wall is lightly damaged to facilitate tumor cell infiltration. The time to developing primary tumors and liver metastases will vary depending on the technique, cell line, and mouse species used. This orthotopic mouse model is useful for studying the natural progression of colorectal cancer and testing new therapeutic agents against colorectal cancer.

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Research paper thumbnail of CLINICAL TRANSPLANTATION TOLERANCE TWELVE YEARS AFTER PROSPECTIVE WITHDRAWAL OF IMMUNOSUPPRESSIVE DRUGS: STUDIES OF CHIMERISM AND ANTI-DONOR REACTIVITY1

Transplantation, 2000

Previous studies showed the feasibility of inducing transplantation tolerance to cadaveric renal ... more Previous studies showed the feasibility of inducing transplantation tolerance to cadaveric renal allografts in patients given pretransplant total lymphoid irradiation (TLI). Microchimerism has been theorized to be an important or necessary factor in long-term graft acceptance and tolerance in humans. A cadaveric renal transplant recipient given pretransplant total lymphoid irradiation and withdrawn from immunosuppressive drugs more than 12 years ago was tested for microchimerism using a sensitive nested polymerase chain reaction technique, and for anti-donor reactivity using the mixed leukocyte reaction and an ELISA screen for anti-HLA antibodies. Donor and recipient were mismatched for all HLA-A, B, and DR antigens. The "tolerant" recipient had good graft function, no detectable donor-type cells in the blood by polymerase chain reaction analysis, vigorous reactivity to donor stimulator cells in the mixed leukocyte reaction, and no detectable serum anti-HLA antibodies. Operational tolerance to HLA-A, B, and DR mismatched organ allografts can be induced prospectively in humans for at least 12 years after withdrawal of immunosuppressive drugs. The allograft can be maintained in the absence of detectable donor microchimerism and in the presence of anti-donor reactivity in the mixed leukocyte reaction, suggesting that neither chimerism nor clonal deletion or anergy of recipient T cells to alloantigens presented by donor Class II HLA molecules is required for persistence of the tolerant state using this total lymphoid irradiation protocol.

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Research paper thumbnail of Detection of Intestinal Cancer by Local, Topical Application of a Quenched Fluorescence Probe for Cysteine Cathepsins

Chemistry & Biology, 2015

Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional... more Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.

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Research paper thumbnail of Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients

Tumor-specific clonal immunoglobulin ex- pressed by B-cell lymphomas (idiotype (Id)) can serve as... more Tumor-specific clonal immunoglobulin ex- pressed by B-cell lymphomas (idiotype (Id)) can serve as a target for active immu- notherapy. We have previously described the vaccination of 4 patients with follicu- lar lymphoma using dendritic cells (DCs) pulsed with tumor-derived Id protein and now report on 35 patients treated using this approach. Among 10 initial patients with measurable lymphoma, 8 mounted

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Research paper thumbnail of Development of CD8alpha-Positive Dendritic Cells from a Common Myeloid Progenitor

Science, 2000

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Research paper thumbnail of AIDS retrovirus induced cytopathology: giant cell formation and involvement of CD4 antigen

Science, 1986

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Research paper thumbnail of Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Proceedings of the National Academy of Sciences, 2010

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Research paper thumbnail of Tolerance and Chimerism after Renal and Hematopoietic-Cell Transplantation

New England Journal of Medicine, 2008

We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched... more We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.

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Research paper thumbnail of Inhibition of Cell Mediated Immune Responses by 8Methoxypsoralen and Long-wave Ultraviolet Light: A Possible Explanation for the Clinical Effects of Photoactivated Psoralen

Journal of Investigative Dermatology, 1980

Human thymus-derived lymphocytes proliferate when cultured with lymphocytes or epidermal cells fr... more Human thymus-derived lymphocytes proliferate when cultured with lymphocytes or epidermal cells from unrelated individuals because such cells express HLA-D antigens, which are recognized as foreign by thymus- derived lymphocytes. The current study demonstrates that these responses are inhibited if either the stimulator cells or responder cells are pretreated with the combination of 8-methoxypsoralen and long-wave ultraviolet light. Additional studies revealed

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Research paper thumbnail of Differentiation of myeloid dendritic cells into CD8a-positive dendritic cells in vivo

Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) wit... more Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) with varying phenotypes. For example, in mice, CD8alpha(+) and CD8alpha(-) DC are thought to represent cells of lymphoid and myeloid origin, respectively. Langerhans cells (LC) of the epidermis are typical myeloid DC; they do not express CD8alpha, but they do express high levels of myeloid antigens such as CD11b and FcgammaR. By contrast, thymic DC, which derive from a lymphoid-related progenitor, express CD8alpha but only low levels of myeloid antigens. CD8alpha(+) DC are also found in the spleen and lymph nodes (LN), but the origin of these cells has not been determined. By activating and labeling CD8alpha(-) epidermal LC in vivo, it was found that these cells expressed CD8alpha on migration to the draining LN. Similarly, CD8alpha(-) LC generated in vitro from a CD8 wild-type mouse and injected into the skin of a CD8alphaKO mouse expressed CD8alpha when they reached the draining LN. The results also show that CD8alpha(+) LC are potent APC. After migration from skin, they localized in the T-cell areas of LN, secreted high levels of interleukin-12, interferon-gamma, and chemokine-attracting T cells, and they induced antigen-specific T-cell activation. These results demonstrate that myeloid DC in the periphery can express CD8alpha when they migrate to the draining LN. CD8alpha expression on these DC appears to reflect a state of activation, mobilization, or both, rather than lineage. (Blood. 2000;96:1865-1872)

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Research paper thumbnail of A SUPPRESSOR T CELL OF THE M IXED L YMPHOCYTE REACTION IN MAN SPECIFIC FOR THE S TIMULATING A LLOANTIGEN Evidence that Identity at HLA-D between Suppressor and Responder is Required for Suppression

Recent investigations from this laboratory have documented the presence of suppressor T cells of ... more Recent investigations from this laboratory have documented the presence of suppressor T cells of the mixed lymphocyte reaction (MLR) ~ in two unrelated individuals (1). 2 That is, when T cells from these individuals were cocultured in an MLR with the responder cells of human leukocyte antigen (HLA) identical persons, the responses of such persons to allogeneic cells were inhibited.

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Research paper thumbnail of Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity

Nature, 2015

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Research paper thumbnail of Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 13, 2015

The goals of the study were to elucidate the immune mechanisms that contribute to desirable compl... more The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non-small cell lung tumors. Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21 day (>1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors. We found that the high dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8+ T cell tumor infiltrate, and a loss of myeloid derived suppressor cells (MDSCs). The change was dependent on antigen cross-presenting CD8+ dendritic cells, secretion of IFN- γ, and CD4+T cells expressing CD40L. Anti-tumor CD8+ T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated ...

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Research paper thumbnail of Regulation of Obesity-Related Insulin Resistance with Gut Anti-inflammatory Agents

Cell Metabolism, 2015

Obesity has reached epidemic proportions, but little is known about its influence on the intestin... more Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.

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Research paper thumbnail of CD101 surface expression discriminates potency among murine FoxP3+ regulatory T cells

Journal of immunology (Baltimore, Md. : 1950), 2007

CD4+CD25+FoxP3+ regulatory T cells (Treg) have been shown to be protective in animal models of au... more CD4+CD25+FoxP3+ regulatory T cells (Treg) have been shown to be protective in animal models of autoimmunity and acute graft-vs-host disease. However, owing to the functional heterogeneity among CD4+CD25+ T cells, surface markers expressed selectively on functionally active Treg would be useful for purposes of identifying and isolating such cells. We generated a rabbit mAb against murine CD101, a transmembrane glycoprotein involved in T cell activation. Among freshly isolated T cells, CD101 was detected on 25-30% of CD4+CD25+ Treg and approximately 20% of conventional memory T cells. CD101(high) Treg displayed greater in vitro suppression of alloantigen-driven T cell proliferation as compared with CD101(low) Treg. In a model of graft-vs-host disease induced by allogeneic bone marrow transplantation in vivo bioluminescence imaging demonstrated reduced expansion of donor-derived luciferase-labeled conventional T cells in mice treated with CD101(high) Treg, compared with CD101(low) Treg...

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Research paper thumbnail of Statin-AE: a novel angiostatin-endostatin fusion protein with enhanced antiangiogenic and antitumor activity

Angiogenesis, 2001

The combination of angiostatin and endostatin has been shown to have synergistic antiangiogenic a... more The combination of angiostatin and endostatin has been shown to have synergistic antiangiogenic and antitumor effects when the genes for these proteins are delivered to tumor cells by retroviral gene transfer. Here we report the construction of a murine angiostatin-endostatin fusion gene (Statin-AE) which shows enhanced antiangiogenic activity on human umbilical vein endothelial cell (HUVEC) tube formation in vitro compared with angiostatin or endostatin alone. Similarly, the fusion gene demonstrates antiangiogenic effects in vivo and antitumor activity in a B16F10 melanoma model when co-delivered by retroviral packaging cell inoculation in mice. The fusion gene demonstrates significantly greater inhibition of tumor growth compared with angiostatin, endostatin or the combination of genes.

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Research paper thumbnail of Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells

Clinical immunology and immunopathology, 1991

Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid hormone in humans. Although it... more Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid hormone in humans. Although it is well established that DHEA serves as an intermediate in sex steroid synthesis, recent studies in mice suggest that DHEA may also be a physiologic regulator of IL2 secretion. To explore the effect of DHEA on the human immune system, T lymphocytes from healthy adults were exposed to DHEA followed by stimulation with mitogens or antigen. Upon activation with a variety of stimuli, T cells pretreated with 10(-8) to 10(-11) M DHEA produced significantly greater amounts of IL2 and mediated more potent cytotoxicity than T cells activated in the absence of this steroid hormone. The peak effect of DHEA was observed at 10(-9) M, the concentration of hormone present in the blood of normal adults. In contrast to its effect on murine T cells, the IL2 enhancing effect of DHEA on human lymphocytes was limited to fresh CD4+ T cells and CD4+ clones; neither fresh CD8+ cells nor CD8+ clones were direct...

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Research paper thumbnail of Human immunodeficiency virus-infected monocyte-derived macrophages express surface GP120 and fuse with CD4 lymphoid cells in vitro: A possible mechanism of T lymphocyte depletion in vivo

Clinical Immunology and Immunopathology, 1992

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Research paper thumbnail of T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans

Arteriosclerosis, thrombosis, and vascular biology, 2014

The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. W... more The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. We have shown that insulin resistance or glucose intolerance in diet-induced obese mice is related to a shift in the ratio of pro- and anti-inflammatory T cells in adipose tissue. We sought to test the hypothesis that the balance of T-cell phenotypes would be similarly related to insulin resistance in human obesity. Healthy overweight or obese human subjects underwent adipose-tissue biopsies and quantification of insulin-mediated glucose disposal by the modified insulin suppression test. T-cell subsets were quantified by flow cytometry in visceral (VAT) and subcutaneous adipose tissue (SAT). Results showed that CD4 and CD8 T cells infiltrate both depots, with proinflammatory T-helper (Th)-1, Th17, and CD8 T cells, significantly more frequent in VAT as compared with SAT. T-cell profiles in SAT and VAT correlated significantly with one another and with peripheral blood. Th1 frequency in SAT...

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Research paper thumbnail of B-1a Lymphocytes Attenuate Insulin Resistance

Diabetes, 2014

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Research paper thumbnail of Orthotopic Mouse Model of Colorectal Cancer

Journal of Visualized Experiments, 2007

The traditional subcutaneous tumor model is less than ideal for studying colorectal cancer. Ortho... more The traditional subcutaneous tumor model is less than ideal for studying colorectal cancer. Orthotopic mouse models of colorectal cancer, which feature cancer cells growing in their natural location, replicate human disease with high fidelity. Two techniques can be used to establish this model. Both techniques are similar and require mouse anesthesia and laparotomy for exposure of the cecum. One technique involves injection of a colorectal cancer cell suspension into the cecal wall. Cancer cells are first grown in culture, harvested when subconfluent and prepared as a single cell suspension. A small volume of cells is injected slowly to avoid leakage. The other technique involves transplantation of a piece of subcutaneous tumor onto the cecum. A mouse with a previously established subcutaneous colorectal tumor is euthanized and the tumor is removed using sterile technique. The tumor piece is divided into small pieces for transplantation to another mouse. Prior to transplantation, the cecal wall is lightly damaged to facilitate tumor cell infiltration. The time to developing primary tumors and liver metastases will vary depending on the technique, cell line, and mouse species used. This orthotopic mouse model is useful for studying the natural progression of colorectal cancer and testing new therapeutic agents against colorectal cancer.

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Research paper thumbnail of CLINICAL TRANSPLANTATION TOLERANCE TWELVE YEARS AFTER PROSPECTIVE WITHDRAWAL OF IMMUNOSUPPRESSIVE DRUGS: STUDIES OF CHIMERISM AND ANTI-DONOR REACTIVITY1

Transplantation, 2000

Previous studies showed the feasibility of inducing transplantation tolerance to cadaveric renal ... more Previous studies showed the feasibility of inducing transplantation tolerance to cadaveric renal allografts in patients given pretransplant total lymphoid irradiation (TLI). Microchimerism has been theorized to be an important or necessary factor in long-term graft acceptance and tolerance in humans. A cadaveric renal transplant recipient given pretransplant total lymphoid irradiation and withdrawn from immunosuppressive drugs more than 12 years ago was tested for microchimerism using a sensitive nested polymerase chain reaction technique, and for anti-donor reactivity using the mixed leukocyte reaction and an ELISA screen for anti-HLA antibodies. Donor and recipient were mismatched for all HLA-A, B, and DR antigens. The "tolerant" recipient had good graft function, no detectable donor-type cells in the blood by polymerase chain reaction analysis, vigorous reactivity to donor stimulator cells in the mixed leukocyte reaction, and no detectable serum anti-HLA antibodies. Operational tolerance to HLA-A, B, and DR mismatched organ allografts can be induced prospectively in humans for at least 12 years after withdrawal of immunosuppressive drugs. The allograft can be maintained in the absence of detectable donor microchimerism and in the presence of anti-donor reactivity in the mixed leukocyte reaction, suggesting that neither chimerism nor clonal deletion or anergy of recipient T cells to alloantigens presented by donor Class II HLA molecules is required for persistence of the tolerant state using this total lymphoid irradiation protocol.

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Research paper thumbnail of Detection of Intestinal Cancer by Local, Topical Application of a Quenched Fluorescence Probe for Cysteine Cathepsins

Chemistry & Biology, 2015

Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional... more Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.

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Research paper thumbnail of Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients

Tumor-specific clonal immunoglobulin ex- pressed by B-cell lymphomas (idiotype (Id)) can serve as... more Tumor-specific clonal immunoglobulin ex- pressed by B-cell lymphomas (idiotype (Id)) can serve as a target for active immu- notherapy. We have previously described the vaccination of 4 patients with follicu- lar lymphoma using dendritic cells (DCs) pulsed with tumor-derived Id protein and now report on 35 patients treated using this approach. Among 10 initial patients with measurable lymphoma, 8 mounted

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Research paper thumbnail of Development of CD8alpha-Positive Dendritic Cells from a Common Myeloid Progenitor

Science, 2000

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Research paper thumbnail of AIDS retrovirus induced cytopathology: giant cell formation and involvement of CD4 antigen

Science, 1986

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Research paper thumbnail of Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Proceedings of the National Academy of Sciences, 2010

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Research paper thumbnail of Tolerance and Chimerism after Renal and Hematopoietic-Cell Transplantation

New England Journal of Medicine, 2008

We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched... more We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.

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