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Biomedical subjects

S J Russell

Publications and source records attributed to S J Russell.

At least 109 records · Page 6Linked to original sources
PubMed1992

Adapting antibodies for clinical use.

Techniques for antibody engineering are now overcoming the problems that have prevented monoclonal antibodies being used routinely in clinical practice. With chemical and genetic manipulation antibodies can be linked to bacterial toxins, enzymes, radionuclides, or cytotoxic drugs, allowing targeting of treatment. Antigen binding sites from antibodies raised in mice can be jointed with human IgG to reduce immunogenicity. In vitro gene amplification and genetic engineering of bacteriophage have produced large antibody gene libraries and facilitated large scale production of human monoclonal antibodies with high specificity. The trickle of monoclonal antibodies into clinical practice may soon become a flood.

Antibodies, Monoclonal↗
PubMed1992

Discovery of antibodies.

Passive immunisation has been used in clinical practice since the end of last century, mainly for prophylaxis. Success of early treatments was marred by anaphylactic reactions and serum sickness because antibodies or antitoxins were not raised in humans. Recombination of gene segments during antibody synthesis means that specific antibodies for numerous antigens can be produced from a limited gene pool. Killer lymphocytes, phagocytes, and complement then bind to the constant region of the antibody facilitating elimination of the pathogen. Development of a method of obtaining large quantities of antibodies against a specific antigen (monoclonal antibodies) offers the possibility of initiating host defence mechanisms against any unwanted antigen, though some problems still remain in preventing the body from attacking the monoclonal antibody.

Antibodies↗
PubMed1992

Selection of phage antibodies by binding affinity. Mimicking affinity maturation.

We describe a process, based on display of antibodies on the surface of filamentous bacteriophage, for selecting antibodies either by their affinity for antigen or by their kinetics of dissociation (off-rate) from antigen. For affinity selection, phage are mixed with small amounts of soluble biotinylated antigen (less than 1 microgram) such that the antigen is in excess over phage but with the concentration of antigen lower than the dissociation constant (Kd) of the antibody. Those phage bound to antigen are then selected using streptavidin-coated paramagnetic beads. The process can distinguish between antibodies with closely related affinities. For off-rate selection, antibodies are preloaded with biotinylated antigen and diluted into excess unlabelled antigen for variable times prior to capture on streptavidin-coated paramagnetic beads. To mimic the affinity maturation process of the immune system, we introduced random mutations into the antibody genes in vitro using an error-prone polymerase, and used affinity selection to isolate mutants with improved affinity. Starting with a small library (40,000 clones) of mutants (average 1.7 base changes per VH gene) of the mouse antibody B1.8, and using several rounds of affinity selection, we isolated a mutant with a fourfold improved affinity to the hapten 4-hydroxy-5-iodo-3-nitrophenacetyl-(NIP)-caproic acid (mutant Kd = 9.4(+/- 0.3) nM compared with B1.8 Kd = 41.9(+/- 1.6) nm). The relative increase in affinity of the mutant is comparable to the increase seen in the anti-4-hydroxy-3-nitrophenylacetyl/NIP-caproic acid murine secondary immune response.

Amino Acid Sequence↗
PubMed1992

Immunity to B16 melanoma in mice immunized with IL-2-secreting allogeneic mouse fibroblasts expressing melanoma-associated antigens.

Co-presentation of weak tumour-associated antigens along with strongly immunogenic determinants leads to the development of an anti-tumour immune response in recipients syngeneic with the tumour. Tumour immunity develops in mice immunized with tumour cells modified by the introduction of cDNA for interleukin-2 (IL-2). Here, we report the anti-tumour response following immunization with an IL-2-secreting cell construct that expresses tumour-associated antigens, along with allogeneic major histocompatibility antigens. The construct was prepared by transfecting LM(TK-) mouse fibroblasts (H-2k) with genomic DNA from B16 melanoma cells syngeneic in C57BL/6J mice (H-2b). Transfectants expressing melanoma-associated antigens (MAA) were then infected with an expression-competent retroviral vector containing a cDNA specifying human IL-2. Cytotoxicity toward B16 cells was detected for as long as 5 months in both spleen and macrophage cell populations in C57BL/6J mice immunized with the IL-2-secreting cells. Mice immunized with non-IL-2-secreting, MAA-positive allogeneic cells developed melanoma immunity as well, but to a lesser extent. Immunity to 2 tumour-cell lines expressing the H-2d haplotype and to YAC-1 cells was detected in peritoneal macrophages, but not in spleen cells from C57BL/6J mice immunized with the cell construct, indicating that the response to B16 cells was only partially specific. C57BL/6J mice immunized with the IL-2-secreting cell construct survived significantly longer, following an injection of viable B16 cells, than mice in various control groups. The contribution of allogeneic antigens to the melanoma immunity was indicated by the failure of mice syngeneic with LM(TK-) cells to develop melanoma immunity following immunization with non-IL-2-secreting, MAA-positive cell constructs. The formation of IL-2 partially compensated for the lack of allogeneic antigens.

Animals↗
PubMed1992

Transformation-dependent expression of interleukin genes delivered by a recombinant parvovirus.

The prototype strain of minute virus of mice [MVM(p)] is an autonomous parvovirus with a tropism for cells expressing a neoplastically transformed phenotype. To generate gene transfer vectors for tumor-specific gene expression, human interleukin-2 (IL-2) and murine interleukin-4 (IL-4) genes were cloned under the control of the p38 late promoter of MVM(p). Upon transfection into permissive cells, the recombinant MVMIL2 or MVMIL4 DNA was excised, amplified, and, in the presence of a helper plasmid, packaged into recombinant viral particles. The recombinant viruses were able to transfer fully functional IL-2 and IL-4 genes to permissive target cells and retained the oncotropic host range properties of the parental virus. Following infection with MVMIL2, nontransformed fibroblasts of rodent (FR3T3) or human (MRC-5) origin produced minimal IL-2 compared with the high levels of IL-2 production observed in their transformed derivatives (FREJ4 and MRC-5V1).

Cell Line, Transformed↗
PubMed1991

Decreased tumorigenicity of a transplantable rat sarcoma following transfer and expression of an IL-2 cDNA.

The notion that tumour-cell-derived IL-2 might lead to paracrine stimulation of the host anti-tumour response was tested in a transplantable rat sarcoma model. Three HSNLV clones induced to secrete different amounts of human IL-2 following retroviral gene transfer showed reduced tumorigenicity and metastatic potential in athymic (nu/nu) and immunocompetent syngeneic rats which was directly related to the level of IL-2 secretion. In contrast, the tumorigenicity of HSNLV clones secreting a biologically inactive form of IL-2 (IL-2Lys20) was unaltered. T-lymphocyte-mediated rejection of ZipI, the highest IL-2 producer, was demonstrated histologically in hooded rats and infiltrating mononuclear cells were also observed in ZipI tumours growing in athymic rats. Tumours derived from IL-2-secreting HSNLV showed reduced or absent IL-2 secretion in immunocompetent rats, sometimes with associated loss of the IL-2 provirus, but continued to secrete IL-2 in nude rats. The host response to Moloney-helper-virus-infected HSNLV was also examined and the results represent a cautionary note to those undertaking experiments of a similar nature.

Animals↗
PubMed1991

GELYMAC: a Macintosh application for calculating DNA fragment size from gel electrophoresis migration data.

A program called GELYMAC takes data on the distances migrated by DNA fragments in a one-dimensional electrophoretic gel and, using a cubic-spline best-fit of marker fragment distance migrated versus molecular size, calculates the molecular sizes of the fragments. Written in the Rascal (Real-time Pascal) programming language, the program runs on the Macintosh family of microcomputers. Rapid entry of marker and experimental fragment migration data is afforded using a scroll bar system adjacent to a graphic representation of a gel. Output includes tabular listing of the data, graphic cartoons of the gel, and the fragment locations and molecular sizes for individual gel lanes, and the calibration curve used in data computations.

Calibration↗
PubMed1990

Lymphokine gene therapy for cancer.

The plethora of recombinant lymphokines that have recently become available has led to renewed hope for an immunotherapeutic solution to cancer. Many lymphokines, either singly or in combination, have already shown promise in animal trials and in preliminary human trials. Systemic lymphokine toxicity has been the major constraint on this type of therapy, often precluding the use of doses sufficient to induce tumour regression. To realize the therapeutic potential of recombinant lymphokines against cancer, alternative modes of delivery are needed which maximally stimulate local anti-tumour responses whilst causing minimal systemic toxicity. In this article, Stephen Russell proposes that tumour cell targeted lymphokine gene therapy would optimize lymphokine delivery. Some of the practical difficulties likely to be encountered with such an approach are also discussed.

Animals↗
PubMed1989

Polyacrylamide gel electrophoretic characterization of isoenzymes in the marine algal genus Callithamnion.

Techniques have been developed for the visualisation of a range of enzyme species extracted from field collected marine algal populations, to provide biochemical data in the form of zymogram patterns that closely reflect the genetic identity of these plants. These patterns provide an alternative basis for increasingly accurate recognition to complement that provided by morphology, thus helping to clarify the taxonomic problems which exist in the marine algal genus Callithamnion Lyngbye as currently conceived.

Acetone↗
PubMed1989

Medical indications for splenectomy.

The spleen, whether anatomically and physiologically normal or diseased, may significantly worsen the clinical picture in a variety of medical disorders. However, splenectomy should be undertaken only after a careful balancing of the short- and long-term risks and potential benefits to the patient, which are discussed in the following review.

Humans↗
PubMed1988

Granulocytic sarcoma of the small intestine preceding acute myelomonocytic leukemia with abnormal eosinophils and inv(16).

We report a case of preleukemic granulocytic sarcoma of the small intestine preceding the development of acute myelomonocytic leukemia with abnormal eosinophils and inversion of chromosome 16, inv(16)(p13q22). A literature review suggests that this is a recurring cytogenetic-clinicopathologic association and carries a favorable prognosis, especially if treated aggressively with antileukemic therapy at the time of diagnosis.

Chromosome Inversion↗
PubMed1988

Atypical mycobacterial infection in alpha interferon-treated hairy cell leukaemia.

A patient whose hairy cell leukaemia had begun to respond to alpha interferon therapy developed overt atypical mycobacterial infection. This eventually responded to combination antimicrobial therapy. The clinical difficulties involved in this unique case included difficulty in isolation of the organism, failure of an empirical trial of antituberculous therapy and false attribution of the patient's infective symptoms to alpha interferon.

Aged↗
PubMed1987

Use of teicoplanin for Hickman catheter associated staphylococcal infection in immunosuppressed patients.

Antibiotic-resistant coagulase-negative staphylococci are a frequent cause of infection in indwelling central venous (Hickman) catheters. Teicoplanin has been evaluated in the treatment of 19 immunosuppressed patients with staphylococcal Hickman catheter infections, nine of whom were septicaemic. All infections were eradicated, with minimal side effects. In 16 cases, the catheter was retained until no longer required. Two recurrent infections were eradicated by a second course of teicoplanin. We conclude that teicoplanin is an effective and well-tolerated antibiotic in the treatment of Hickman catheter infections in immunosuppressed patients.

Anti-Bacterial Agents↗