Transduction of dendritic cells with adenoviral vectors encoding CTLA4-Ig markedly reduces their allostimulatory activity.
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Abatacept↗
Biomedical subjects
L Lu
Publications and source records attributed to L Lu.
Enhancement of dendritic cell tolerogenicity by genetic modification using adenoviral vectors encoding cDNA for TGF beta 1.
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Adenoviridae↗
Systemic administration of CTLA4-Ig or anti-CD40 ligand antibody inhibits second-set rejection of mouse liver allografts.
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Abatacept↗
Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice.
Influx of Ca2+ into myocytes via Na+/Ca2+ exchange may be stimulated by the high levels of intracellular Na+ and the changes in membrane potential known to occur during ischemia/reperfusion. This increased influx could, in turn, lead to Ca2+ overload and injury. Overexpression of the cardiac Na+/Ca2+ exchanger therefore may increase susceptibility to ischemia/reperfusion injury. To test this hypothesis, the hearts of male and female transgenic mice, overexpressing the Na+/Ca2+ exchange protein, and hearts of their wild-type littermates, were perfused with Krebs-Henseleit buffer and subjected to 20 minutes of ischemia and 40 minutes of reperfusion. Preischemic left ventricular developed pressures and +dP/dtmax, as well as -dP/dtmin, were higher in the male transgenic hearts compared with wild-type, implying a role for Na+/Ca2+ exchange in the contraction, as well as the relaxation, phases of the cardiac beat. Postischemic function was lower in male transgenic than in male wild-type hearts (7+/-2% versus 32+/-6% of preischemic function), but there was no difference between female transgenic and female wild-type hearts, both at approximately 30% of preischemic function. To assess whether this male/female difference was due to female-specific hormones such as estrogen, the hearts of bilaterally ovariectomized and sham-operated transgenic females were subjected to the same protocol. The functional recoveries of ovariectomized female transgenic hearts were lower (17+/-3% of preischemic function) than those of wild-type and sham-operated transgenic females. The lower postischemic functional recovery in the male transgenic and female ovariectomized transgenic hearts correlated with lower recoveries of the energy metabolites, ATP and phosphocreatine, as measured by 31P nuclear magnetic resonance spectroscopy. Alternans were observed during reperfusion in male transgenic and female ovariectomized transgenic hearts only, consistent with intracellular Ca2+ overload. Western analyses showed that alterations in the expression of the Na+/Ca2+ exchange or L-type Ca2+ channel proteins were not responsible for the protection observed in the female transgenic hearts. In conclusion, in males, overexpression of the Na+/Ca2+ exchanger reduced postischemic recovery of both contractile function and energy metabolites, indicating that the Na+/Ca2+ exchanger may play a role in ischemia/reperfusion injury. From the studies of females, however, it appears that this exacerbation of ischemia/reperfusion injury by overexpression of the Na+/Ca2+ exchanger can be overcome partially by female-specific hormones such as estrogen.
Adenosine Triphosphate↗
CD34 stem/progenitor cells purified from cryopreserved normal cord blood can be transduced with high efficiency by a retroviral vector and expanded ex vivo with stable integration and expression of Fanconi anemia complementation C gene.
A future possibility for treatment of genetic diseases may be gene therapy using autologous cord blood (CB) stem/progenitor cells. This might require cryopreservation of CB stem/progenitor cells prior to purification, gene transduction, and ex vivo expansion of cells. To address this possibility, nonadherent low density T-lymphocyte depleted (NALT-) cells from fresh or cryopreserved cord blood were sorted for CD34 phenotype, transduced with a recombinant retroviral vector encoding Fanconi anemia complementation C (FACC) gene, and cells expanded ex vivo in suspension culture for 7 days with growth factors. The results demonstrate: 1) high recovery of viable cells after thawing; 2) high efficiency purification of CD34 cells from NALT- cells prior to and after cryopreservation; 3) high degree of expansion of nucleated cells and immature progenitors from CD34 cells before and after cryopreservation; 4) efficient transduction with stable integration and expression of newly introduced genes in cryopreserved and then sorted stem/progenitor cells, as detected prior to and after ex vivo expansion; and 5) high efficiency transduction of single isolated CD34 cells obtained from cryopreserved NALT- CB. This information should be of value for future studies evaluating the use of cryopreserved cord blood for gene transfer/gene therapy.
Antigens, CD34↗
A study of the association between epistaxis and the severity of hypertension.
Hypertension (HTN) has frequently been cited as a general risk factor for epistaxis. However, studies dealing with this association have yielded equivocal results. In this study, a sample of 121 hypertensives (blood pressure > or = 140/90 mmHg) was selected to evaluate the association between the severity of HTN and a previous history of epistaxis. Patients with an average blood pressure > or = 160/100 mmHg were classified as suffering from a more severe form of HTN and were compared with those with a less severe form of the disease (160/100 mm Hg < or = blood pressure > or = 140/90 mm Hg). The frequency of epistaxis did not differ among patients categorized by the severity of HTN. Users of aspirin were found to be twice as likely to have a history of epistaxis. In addition, there was a statistical tendency for an association between a history of epistaxis and the duration of hypertension. We conclude that the severity of HTN and a history of epistaxis were not associated in a cohort of hypertensive patients. The identification of other risk factors for epistaxis, including the duration of HTN, deserves further study.
Adult↗
Purified natural rubber latex antigens show variable reactivity with IgE in the sera of latex allergic patients.
Immediate-hypersensitivity reactions related to latex products have increased rapidly in recent years. However, a reliable diagnosis is hampered by lack of purified and well characterized latex allergens. We have purified allergens in natural rubber latex (NRL) after SDS-PAGE by electroelution, and tested specific IgE-binding activities of these isolated allergens by ELISA. Ten sera from spina bifida patients and 5 sera from health care workers with latex allergy were evaluated for specific IgE antibody in the sera using ELISA. Five normal controls with no evidence of latex allergy were also studied. None of the isolated allergens reacted with normal control sera used. Among the latex allergic patients' sera studied, 11, 9, 9, 2, and 6 sera reacted with 27, 23, 21, 17, and 10 kDa isolated allergens, respectively. Each latex allergic serum reacted with at least one of the purified allergens, indicating a diversity in response to latex. The isolated and purified latex allergens may, however, be useful to identify latex allergy in patients.
Allergens↗
Interleukin-11 enhancement of VLA-5 mediated adhesion of CD34+ cells from cord blood to fibronectin is associated with the PI-3 kinase pathway.
Adhesion is required for cell growth, differentiation, survival, and function. Cell adhesion is mediated by a structurally diverse group of plasma membrane receptors, each exhibiting specialized ligand-binding properties that are needed for specific tasks. Integrin-mediated adhesion is important for hematopoietic stem (HSC)/progenitor (HPC) cell survival and may prevent programmed cell death. Interleukin (IL)-11, a multi-functional cytokine secreted by the bone marrow environment, plays an important role in regulating growth and differentiation of HSCs/HPCs. In this report, we demonstrate that IL-11 enhanced adhesion of freshly isolated and 3 day-expanded CD34+ cells to immobilized fibronectin. the expression of very late antigen (VLA)-4 and VLA-5 integrins was detected on CD34+ cells. CD34+ cells also expressed a-chain and gp130 subunits of the IL-11 receptor (R). Enhanced adhesion by IL-11 was mediated via activation of VLA-5 integrins, since this action could be blocked by monoclonal antibodies against beta 1 and alpha 5, but not alpha 4, integrins. Addition of phosphatidylinositol (PI)-3 kinase inhibitors blocked IL-11 enhanced adhesion of CD34+ cells to fibronectin. The results suggest that this enhanced adhesion is associated with the PI-3 kinase pathway, an inside-out signaling pathway.
Antibodies, Blocking↗
Effects of naturin 2 on colony formation by hematopoietic progenitor cells in human umbilical cord blood mediated by induction of release of growth factors.
Naturin 2, a health drink, contains a mixture of Chinese herb plants and is a potent immunomodulator. It has anti-tumor effects mediated by immune system. In the present study, low density (LD) and purified CD34+ cells (enriched for hematopoietic stem [HSC] and progenitor [HPC]) from human umbilical cord blood (CB) were assayed for colony formation in response to Naturin 2. First, we examined the in vitro activity of Naturin 2 on HPC. Naturin 2 by itself stimulated colony formation derived from either LD or CD34+ CB cells. The stimulatory effect by Naturin 2 was mediated by both direct and indirect action on HSCs/HPCs. The indirect action is via releasing of cytokines in the 5 day-conditioned media by LD CB cells with Naturin 2. The stimulatory activities in the 5 day-conditioned media (CM) could be blocked by the neutralization antibodies against interleukin (IL)-3, granulocyte macrophage (GM)-colony stimulating factor (CSF), IL-1 alpha, IL-1 beta and M-CSF. Therefore, the stimulatory activities detected in the media conditioned are due to the cytokines released in the cultures. In addition, we have also determined that addition of Naturin 2 to the cultures with LD or CD34+ cells stimulated by IL-3 and/or GM-CSF resulted in a decrease of colony formation. The inhibitory effect of Naturin 2 was mediated, at least in part, by releasing suppressive cytokines, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, in the 3 day--CM, since antibodies against these two suppressive cytokines partially blocked the inhibitory activity. These results demonstrate that Naturin 2 has differential effects on hematopoiesis.
Antineoplastic Agents, Phytogenic↗
Bio-immunotherapy for cancer in experimental studies and clinical application: current status and future challenges.
Although successful treatment of patients with primary tumor by conventional surgery and radiotherapy is often possible, death frequently results from tumor metastases. Since metastasis has already occurred in many cancer patients at the time of diagnosis, a major emphasis of cancer treatment is and will continue to be the prevention or successful management of tumor metastases. Systemic chemotherapy has been widely used in the past in the hope of preventing or controlling micrometastases. The results of this treatment have been disappointing with little impact on survival in the vast majority of solid tumors. Bio-immunotherapy has emerged as another modality and is finding acceptance and use in treating patients with cancer. The role of bio-immunotherapy in traditional surgery, radiotherapy, chemotherapy and hyperthermia will be discussed. In order to evaluate new and innovative treatments, we and others have used murine models of erythroleukemia and solid tumors with metastatic potential to assess the effects in vivo of bio-immunotherapy. Tumor metastases can be dampened and immunosuppression restored by bio-immunotherapy, especially when used in combination with other forms of treatment. Most of the combination treatments used in animal models are encouraging but are by no means totally adequate or curative yet. The molecular basis of cancer is now understood to involve activation of dominant oncogenes and inactivation of tumor suppressor genes. These genetic events may represent novel targets for cancer treatment. The potential use and ethical implications of gene transfer to alter the behavior of somatic cells in patients with cancer has been noted. Also reported is genetic immunomodulation by introducting genes for cytokines into tumor cells or lymphocytes to stimulate a cytotoxic immune response against the tumor. As with bone marrow, human cord blood can be used for transplantation in the autologous, related allogeneic and unrelated allogeneic settings, and as a target cell for gene treatment. It is believed that the greatest therapeutic results of bio-immunotherapy, including biological response modifiers, cytokines, gene treatment and bone marrow transplantation, will come in combination with other established effective modalities including surgery, radiation treatment, chemotherapy and hyperthermia in the treatment of patients with cancer.
Animals↗
Anti-Ly-6E.1-monoclonal-antibody-mediated augmentation of interleukin-2-dependent generation of natural killer cell activity from mouse bone marrow cells.
Studies have shown that the administration of anti-Ly-6E.1 monoclonal antibody (mAb) to tumor-bearing mice augments their T-cell-dependent functional activities, splenic natural killer (NK) cell activity, and antitumor resistance. The effect of the mAb on splenic NK cell activity resembles that of biological-response modifiers, which involves enhanced large granular lymphocyte (LGL) development in the bone marrow (BM) from pre-NK cells, and their subsequent migration and localization in peripheral organs. We analyze here the effect of anti-Ly-6E.1 mAb on the IL-2-dependent generation of NK cell activity in short-term cultures of mouse BM cells. The results indicate that an increase in the population of LGLs paralleled the mAb-mediated augmentation of IL-2-induced generation of NK cell activity in the cultures. Although pre-NK and T cells present in the BM expressed Ly-6 antigens, the augmentation of NK cell generation appears to be due to the mAb interacting with the T cells, not the pre-NK cells, resulting in increased synthesis of tumor necrosis factor-alpha, which in turn enhanced the interleukin-2-dependent development of NK cell activity.
Animals↗
Recombinant human interleukin-1 alpha: a potent bio-immunomodifier in vivo in immunosuppressed mice induced by cyclophosphamide, retroviral infection and surgical stress.
Recombinant human Interleukin-1 Alpha (rhu IL-1 alpha) was assessed for its efficacy in modifying the immunosuppression of mice compromised by Cyclophosphamide (CY), retrovirus infection or surgical stress. Sublethal dose (300 mg/kg) of CY caused neutropenia, decreased cellularity of bone marrow and inhibited Natural Killer (NK) cell activity and lymphokine-activated killer (LAK) cell activity in DBA/2 mice. A single dose of rhu IL-1 alpha (1000 units/per mouse) i.p. accelerated recovery of blood neutrophils and bone marrow cellularity and restored NK and LAK cell activity in CY-treated mice. Mice infected with Friend Virus Complex (FVC) had decreased percentages of L3T4+ cells and a reversed L3T4+/Lyt-2+ ratio; NK and LAK cell activity also decreased. These impaired cellular parameters were restored by rhu IL-1 alpha treatment (1000 units/per mouse/daily i.p. starting on day 5 for 5 days). NK and LAK cell activity was impaired by surgical stress. A single dose of rhu IL-1 alpha (1000 units/per mouse) i.p. 20 hours before transfemoral amputation restored NK and LAK cell activity to normal levels in these mice. These studies indicate that rhu IL-1 alpha possesses immunomodulatory effects in vivo for a broad range of stresses.
Animals↗
Generation of natural killer cells from long-term cultures of mouse bone marrow.
The features of a mouse long-term bone marrow culture (LTBMC) system that produces natural killer (NK) cell activity are described. Over a 4-week period in the NK-LTBMC, cellularity dropped from approximately 2.5 x 10(7) to 8 x 10(5) cells/25-cm2 flask. About 3 x 10(5) of these cells were loosely adherent. The cultures at this time contained about one-third the spleen colony forming units, one-tenth the granulocyte macrophage colony forming units and about one-third the transplantable NK progenitor activity of fresh bone marrow (BM), and no detectable NK cell activity. In the 4-week NK-LTBMC, IL-2-responsive precursor cells appeared to be selectively maintained and gave an 8-fold higher activity after culture with human recombinant IL-2 (rIL-2) than did fresh BM. The addition of 50-5,000 IU/ml of rIL-2 resulted, after a minimal 3-day lag, in progressively increased cellularity for as long as 13 days. The percentage and staining intensity of NK-1.1+ cells increased with time after addition of rIL-2. CD3 epsilon + cells were occasionally seen and B220+ cells were present in low numbers at day 7 and slowly increased through day 13. The stroma was necessary for IL-2-dependent development of NK activity.
Animals↗
Curative effect of split low dosage total-body irradiation on murine AIDS induced by Friend virus: the results and the possible mechanism.
Mice infected with Friend Leukemia Virus (FLV) rapidly develop erythroleukemia and severe immune deficiency which resembles human AIDS. We have reported that mice infected with a lethal dose of FLV can be 100% cured by 150 cGy total body irradiation (TBI). This curative effect was associated with restoration of cellular immunity which was compromised by the virus. This restoration may result from activation of the IFN-gamma system and IL-2 production. Our research work further demonstrated that no spleen focus-forming virus (SFFV) specific mRNAs, no 6.0kb SFFV fragments and SFFV envelope glycoproteins were detectable in FLV-infected mice treated with low dose TBI. Predicated on our report, del Regato has initiated clinical trials to treat AIDS patients with low dose TBI. The preliminary results are encouraging and the study is continuing. We have also studied the effects of low dose TBI on the expression of the P53 gene. The results show loss or inactivation of P53 tumor suppressor genes in FLV-infected mice, but P53 expression was restored in FLV-infected mice treated by low dose TBI. It is intriguing to speculate that in the curative effect of low dose TBI on mice infected with retrovirus, the P53 tumor suppressor gene may play an important role. It would be of interest to see if this type of treatment, which was well tolerated by mice, would be beneficial in other types of virally induced disease, including AIDS.
Animals↗
Naturin: a potent bio-immunomodifier in experimental studies and clinical trials.
A number of traditional Chinese medicinal herbs have become extremely interesting in the search for potential BRMs in the international medical community, especially in the United States and Japan. Naturin, a new Chinese medical herb produced by XingYa Pharmaceutical Co., Ltd., has enhanced immune response, inhibited tumor metastases and retroviral infection in animal models as well as in clinical studies. The results demonstrated that the inhibition of Natural Killer (NK) and Lymphokine-activated Killer (LAK) cell activity and lymphocyte proliferation was compromised by tumor metastases and retrovirus infection (Murine AIDS), even immunosuppression induced by surgical amputation can be restored by Naturin. It is also shown that Naturin can protect the mice from lethal total body irradiation. These studies indicated that Naturin possesses immunomodulatory effects in vivo for a broad range of stresses. The results of the clinical studies on Naturin have demonstrated: (a) significantly improved symptoms of patients, including MDS, acute and chronic leukemia, aplastic anemia, lung cancer, and association with the increased number and percentage of CD4 (Helper T-cell) which have been reduced in some patients, (b) Lymphocyte proliferation and NK cell activity which were suppressed in cancer patients can be significantly restored by Naturin treatment, (c) the addition of Naturin treatment to patients receiving radiotherapy and chemotherapy augments immune response and reduces radiation and chemotherapy injury, and (d) no cytotoxic side effects were found in patients given Naturin treatment for up to eight months.
Animals↗
Recovery and characterization of CD34+ cord blood cells after cryopreservation.
Hematopoietic stem and progenitor cell transplantation is an important therapy for certain hematological and malignant disorders, and these cells are being used as vehicles for potential gene therapy approaches to treatment. Umbilical cord blood is a rich source of stem and progenitor cells, which can be efficiently transduced by viral vectors with new genetic material, and these cells have been used in both allogeneic and autologous transplant settings, the latter setting used by others for gene transfer as a possible means of gene therapy. Since cord blood banking is increasingly being considered as an adjunct for allogeneic and autologous transplantation, the present studies were done in order to evaluate the consequences of cryopreserving highly purified CD34+ cells from cord blood. The results demonstrate that CD34+ cord blood cells can be frozen in cryopreserved form and recovered efficiently with cell cycle, proliferative and cell expansion characteristics equivalent to the pre-freeze samples of cells. This information complements previous studies from our group demonstrating the efficient freezing of relatively unseparated populations of cord blood cells, and should be of practical use for future studies involving banking and use of cord blood stem and progenitor cells.
Antigens, CD34↗
The prognostic value of HER-2/neu oncogene in cervical cancer.
BACKGROUND: Expression of the HER-2/neu oncogene has been suggested to confer added virulence or aggressive behavior in gynecologic malignancies. The aim of this study is to determine the frequency of HER-2/neu expression in invasive cervical cancer and its impact on survival in women with cervical cancer. DESIGN: Archival tissue from 150 patients with cervical carcinoma was evaluated immunohistochemically for HER-2/neu oncoprotein expression. Survival information was retrieved retrospectively from patients' medical records. RESULTS: The HER-2/neu expression was observed in 34 out of 150 tumors (22%). The HER-2/neu positive tumors exhibited considerable heterogeneity in the distribution of immunoreactive tumor cells. Tumor grade and histology did not influence the pattern or intensity of HER-2/neu expression. There was no statistically significant difference in survival of patients with HER-2/neu positive and those with HER-2/neu negative tumors (P = 0.50). Tumor stage at diagnosis was the only covariate with prognostic significance in patient survival (P < 0.001). CONCLUSION: Expression of HER-2/neu oncogene is a rare event in cervical cancer. Immunohistochemical detection of HER-2/neu expression is neither a predictor of survival of patients with cervical cancer nor does it identify subgroups of patients at higher risk for recurrence of disease.
Female↗