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Biomedical subjects

B Roessler

Publications and source records attributed to B Roessler.

9 recordsLinked to original sources
PubMed2001

Clinical protocol. Purging of autologous stem cell sources with bcl-x(s) adenovirus for women undergoing high-dose chemotherapy for stage IV breast carcinoma.

High-dose chemotherapy (HDCT) and autologous bone marrow transplantation (BMT) is frequently used to treat patients with metastatic cancer including breast cancer and neuroblastoma. However, the bone marrow of such patients is often contaminated with tumor cells. Recently, we have found that a recombinant adenovirus vector that contains a bcl-x, minigene (a dominant negative inhibitor of the bcl-2 family), called the bcl-x(s) adenovirus, is lethal to cancer cells derived from epithelial tissues, but not to normal human hematopoietic cells. To determine the mechanism, by which this virus spares normal hematopoietic cells, we isolated normal mouse hematopoietic stem cells and infected them with an adenovirus that contains a beta-galactosidase minigene. Such cells do not express beta-galactosidase, indicating that hematopoietic stem cells do not express transgene encoded by adenovirus vectors based upon the RSV-AD5 vector system. When breast cancer cells mixed with hematopoietic cells were infected with the bcl-x(s) adenovirus, cancer cells were selectively killed by the suicide adenoviruses. Hematopoietic cells exposed to the suicide vectors were able to reconstitute the bone marrow of mice exposed to lethal doses of y-irradiation. These studies suggest that adenovirus suicide vectors may provide a simple and effective method to selectively eliminate cancer cells derived from epithelial tissue that contaminate bone marrow to be used for autologous BMT. We therefore propose to initiate a phase I clinical trial to test the safety of this virus in women with breast cancer undergoing high does chemotherapy and autologous BMT.

Adenoviridae↗
PubMed2000

DNA-liposome versus adenoviral mediated gene transfer of transforming growth factor beta1 in vascularized cardiac allografts: differential sensitivity of CD4+ and CD8+ T cells to transforming growth factor beta1.

We have developed a model of transforming growth factor (TGF)beta1 gene transfer into mouse vascularized cardiac allografts to study the use of gene transfer as an immunosuppressive therapy in transplantation. Donor hearts were perfused with either DNA-liposome complexes or adenoviral vectors that encode the active form of human TGFbeta1. DNA-liposome mediated transfection prolonged allograft survival in approximately two-thirds of transplant recipients, while adenoviral delivery of TGFbeta1 was not protective. Protective TGFbeta1 gene transfer was associated with reduced Th1 responses and an inhibition of the alloantibody isotype switch. The protective effects of TGFbeta1 gene transfer were overridden by exogenous interleukin-12 administration. Interestingly, alloreactive CD4+ and CD8+ cells exhibited distinct sensitivities to TGFbeta1 gene transfer: CD4+ Th1 function was abrogated by this modality, although CD8+ Th1 function was not. Transient depletion of recipient CD8+ cells markedly prolonged the survival of grafts transfected with either DNA-liposome complexes or adenoviral vectors. Transgene expression persisted for at least 60 days, and Th1 responses were not detectable until CD8+ T cells repopulated the periphery. However, long-term transfected allografts appeared to exhibit exacerbated fibrosis and neointimal development. These manifestations of chronic rejection were absent in long-term transfected isografts, suggesting that long-term expression of active TGFbeta1 alone is not sufficient to induce fibrosis of the grafts. Collectively, these data illustrate the utility of immunosuppressive gene therapy as a treatment for transplantation when combined with additional conditioning regimens. Further, they illustrate that alloreactive CD4+ and CD8+ cells may be differentially influenced by cytokine manipulation strategies.

Adenoviridae↗
PubMed2000

[Mo]

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Journal Article↗
PubMed2000

Antitumor efficacy of tumor-antigen-encoding recombinant poxvirus immunization in Dunning rat prostate cancer: implications for clinical genetic vaccine development.

One potential use for prostate-cancer-associated genes discovered through ongoing genetics studies entails the construction of virus- or plasmid-based recombinant vector vaccines encoding these new tumor-associated antigens (TAA) to induce TAA-specific immune responses for the prevention or therapy of prostate cancer. Clinical trials evaluating prototypes of such recombinant vaccines are under way. TAA-encoding recombinant vector vaccines, however, have not previously been evaluated in a prostate-cancer animal model. For assessment of the potential susceptibility of prostate cancer to genetic immunization strategies using TAA-encoding recombinant vectors, the antitumor efficacy of a model recombinant viral vector encoding a TAA was evaluated in rat Dunning prostate cancer. Recombinant vaccinia was chosen as a prototype virus vector encoding a TAA for these studies, and beta-galactosidase was chosen as a model target TAA. Dunning AT-2 cells were transduced with a retroviral vector to express beta-galactosidase, and the susceptibility of tumorigenic AT-2-lacZ cells to immunization with vaccinia-lacZ was measured using protection studies in Copenhagen and nu/nu rats. Stably transduced AT-2-lacZ cells expressing beta-galactosidase as measured by enzymatic substrate-based assays were found to retain their tumorigenicity in vivo despite abundant expression of rat major histocompatibility complex (MHC) class I. Immunization with model TAA-encoding recombinant vaccinia-lacZ conferred significant protection against subsequent growth of AT-2-lacZ cells in vivo (P = 0.01); however, the efficacy of such immunization was markedly dependent on the volume of tumor challenge. The antitumor efficacy of TAA-encoding recombinant vaccinia immunization was abrogated in nu/nu rats, suggesting a T-cell-dependent mechanism of activity. These studies suggest that prostate cancer may be a suitable target for immunization strategies using TAA-encoding recombinant vectors. Such immunization strategies may be more effective in settings of minimal cancer burden.

Animals↗
PubMed1996

Adenovirus-mediated over-expression of interleukin-1 receptor antagonist reduces susceptibility to excitotoxic brain injury in perinatal rats.

In seven-day-old rats, intracerebral injection of N-methyl-D-aspartate transiently stimulates expression of Interleukin-1 beta messenger RNA. To evaluate the role of Interleukin-1 beta in the pathogenesis of excitotoxic injury, we sought to determine if Interleukin-1 receptor antagonist, an endogenous competitive inhibitor of Interleukin-1 beta, could attenuate N-methyl-D-aspartate-induced injury. To induce sustained over-expression of Interleukin-1 receptor antagonist in the brain, a recombinant adenovirus encoding Interleukin-1 receptor antagonist was administered by intracerebroventricular injection into three-day-old rats. Increased brain concentrations of Interleukin-1 receptor antagonist two to six days later were documented by assays of tissue homogenates and by immunocytochemistry. To evaluate the impact of Interleukin-1 receptor antagonist on N-methyl-D-aspartate neurotoxicity, three-day-old animals received intracerebroventricular injections of either adenovirus encoding Interleukin-1 receptor antagonist or a control adenovirus encoding beta-galactosidase, followed four days later by right intrastriatal injections of N-methyl-D-aspartate (10 nmol/0.5 microliter), a dose that typically elicits excitotoxic injury in the ipsilateral striatum and adjacent hippocampus, or saline. Animals were killed five days later, and brain damage was quantitated by measurement of bilateral cross-sectional areas of the striatum and anterior hippocampus. In three independent experiments, in N-methyl-D-aspartate-lesioned animals, both striatal and hippocampal injuries were reduced in animals that had been infected with adenovirus that encoded Interleukin-1 receptor antagonist, in comparison with littermates infected with the control adenovirus (right striatal volume loss ranged from 16 to 24%, compared with 54-65% volume loss in control). There was no striatal atrophy in adenovirus-infected saline-injected animals. These results provide strong support for the hypothesis that Interleukin-1 beta is a mediator of excitotoxic brain injury in perinatal rats.

Adenoviruses, Human↗
PubMed1987

Fluid trapping of erythrocytes under hypoosmolar conditions.

125I albumin was used to assess the amount of trapped fluid after microhematocrit centrifugation of erythrocytes suspended in buffers of different osmolality. Surprisingly the total amount of trapped fluid per volume unit of packed erythrocytes decreased with decreasing osmolality of the suspending buffer despite erythrocyte swelling. However, if the contribution of the individual erythrocyte to the trapped fluid was calculated, the trapped fluid per erythrocyte did not change between 311 mosm/kg and 256 mosm/kg. For osmolalities below 256 mosm/kg a significant increase of trapped fluid was obtained. It is concluded that the packing ability of erythrocytes is not impaired in suspending fluid of moderate to severe infraphysiological tonicity. The daily clinical experience that considerable degrees of plasma hypoosmolality are tolerated in vivo without hemolysis or impairment of oxygen transport by erythrocytes may be explained by the excellent ability of shape adaptation of erythrocytes to each other and to other surfaces such as vascular endothelia. The method of trapped fluid determination might be of potential value as a complementary method in the evaluation of erythrocyte rheology if the amount of trapped fluid is related to the individual erythrocyte.

Adult↗
PubMed1986

The mean red cell volume in long distance runners.

Red cell indices were determined in 6 well trained runners before and after a 100 km race, and Coulter Counter (CC) determinations compared with calculated values derived from centrifuged hematocrit (ctrf), red cell count (CC) and hemoglobin measurements. The following changes were observed immediately after the race, as compared to values 3 days before: MCV(ctrf) decreased by 4.9% (p less than 0.001), MCV(CC) increased by 1.9% (p less than 0.05), MCHC(ctrf) increased by 4% and MCHC(CC) decreased by 3%. The increase in MCV(CC) suggests that intraerythrocyte osmolality was increased, this probably leading to swelling of the cells induced by a shift of water from the diluting Coulter Counter solution into the red cells prior to the MCV measurement. The decrease in MCV(ctrf) immediately after the race was not correlated with the increase in plasma osmolality. This suggests that plasma osmolality alone was not the key factor for regulation of red cell volume. The changes in MCV(ctrf), which contributed to a surprising stability of the hematocrit value and plasma volume, might represent a physiological principle for the maintenance of a favourable blood viscosity.

Adult↗
PubMed1985

Creatine kinase and creatine kinase MB in endurance runners and in patients with myocardial infarction.

Following a 100 km race creatine kinase (CK) creatine kinase MB (CKMB) activities were serially measured in well trained athletes and compared with enzyme activities in patients with acute myocardial infarction (AMI). The half-time of disappearance of CK (CKt1/2) was 1.75 +/- 0.70 days in runners who trained within the 1st week after the race, and was 0.81 +/- 0.18 days in patients with AMI, P less than 0.005. CKt1/2 in runners was shorter (1.17 +/- 0.28 days) when no training was performed in the first postrace week. CKt1/2 was linearly correlated with age (P less than 0.01) in the runners but not in the patients. CKMBt1/2 was 1.30 and 1.11 days in two runners and 0.56 +/- 0.10 days in patients with AMI (P less than 0.05). In line with histologic and enzymatic findings in skeletal muscle of long distance runners as reported by other workers, our kinetic data provide further evidence that CK and CKMB are released from muscular compartments in runners other than those in patients with AMI.

Adult↗