Strategies for improving responses to DNA vaccines.
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Animals↗
Biomedical subjects
I G Barr
Publications and source records attributed to I G Barr.
ISCOMs: an adjuvant with multiple functions.
Aluminum salts are currently the only widely used adjuvant for human vaccines. Over the past 10-15 years, a large research effort has attempted to find novel adjuvants with ability to induce a broad range of immune responses, including cell-mediated immunity. The immunostimulating complex or ISCOM is one adjuvant with multiple adjuvant properties. ISCOMs are open cage-like complexes typically with a diameter of about 40 nm that are built up by cholesterol, lipid, immunogen, and saponins from the bark of the tree Quillaia saponaria Molina. ISCOMs have been demonstrated to promote antibody responses and induce T helper cell as well as cytotoxic T lymphocyte responses in a variety of experimental animal models, and have now progressed to phase I and II human trials. This review describes recent developments in the understanding of the structure, composition, and preparation of ISCOMs and will cover important aspects of the understanding of the adjuvant functions of ISCOMs and how they act on the immune system.
Adjuvants, Immunologic↗
ISCOMs (immunostimulating complexes): the first decade.
A little over a decade ago, novel immunostimulating complexes (ISCOMs) were described. This review examines the position and progress that ISCOM technology has achieved in the fields of vaccine research and medicine over this period. Much of the work on ISCOMs has remained in the area of vaccine research where there is still an urgent need for improved adjuvants to help combat important diseases such as AIDS, malaria and influenza. Currently the only widely licensed adjuvants for human use are the aluminium salts, but with the trend towards highly purified subunit vaccines, which are inherently less immunogenic than some of the older vaccines, potent adjuvants capable of promoting specific immune responses are required. ISCOMs are one such technology that offers many of these requirements and as their use in vaccines enters its second decade clinical trials are commencing that will establish whether these submicron, non-living particles composed of saponin, cholesterol, phospholipid and in many cases protein, are useful components for a range of human vaccines.
Adjuvants, Immunologic↗
In vivo localization of a bispecific antibody which targets human T lymphocytes to lyse human colon cancer cells.
A bispecific MAb was derived from the fusion of a hybridoma producing MAb CD3 with a hybridoma producing MAb L-DI (which is directed against a 41-kDa glycoprotein expressed in most gastro-intestinal and pancreatic carcinomas). Bispecific antibody molecules were isolated from parental antibody molecules by the use of hydroxylapatite-HPLC and shown to target human cytolytic T lymphocytes, irrespective of their original specificity, to specifically lyse human colon carcinoma cells. Localization studies in vivo using nude mice bearing human colon carcinoma xenografts showed significant accumulation of the HPLC-purified 125I-labelled bispecific antibodies into the tumor compared to 131I-labelled control CD3 antibody.
Animals↗
Retargeting of cytolytic T lymphocytes by heteroaggregated (bispecific) antibodies.
The specificity and efficiency of tumor cell lysis by the retargeting of murine and human cytolytic T lymphocytes (CTL) with heteroaggregated (also known as bispecific or hybrid) antibodies were examined. Both murine and human CTL were capable of lysing various tumor cell targets in the presence of low concentrations of an appropriate heteroaggregated antibody. However, CTL (excluding clones) were lytic only when activated using reagents such as concanavalin A and interleukin 2 (IL2) with murine effector cells and with mitogenic mAb with human effector cells. The addition of IL2 (at 50-100 U/ml) did not cause enhanced lysis of the target cells used in the presence of heteroaggregated antibody with the murine effector cells. Furthermore, the lysis of target cells by heteroaggregated antibodies and CTL did not cause the lysis of bystander cells (cells not expressing an antigen recognized by the antibody that are mixed with the target cells). The efficient CTL-mediated lysis observed with these antibodies makes this a promising approach for the immunotherapy of human cancer.
Animals↗
Lysis of tumor cells by the retargeting of murine cytolytic T lymphocytes with bispecific antibodies.
The specificity and efficiency of tumor-cell lysis by the retargeting of murine cytolytic lymphocytes (CTL) with bispecific antibodies was examined. Bispecific antibodies (also known as heteroaggregated or hybrid antibodies) were produced by the chemical coupling of monoclonal antibodies (MAbs) against H-2 antigens and the murine T-cell receptor (TCR). Murine tumor cell lines which expressed on their plasma membrane an antigen reactive with one component of the bispecific antibody were efficiently lysed in the presence of polyclonal murine CTL. CTL capable of lysis were generated by stimulating spleen or lymph-node cells with ConA and IL-2, while unstimulated cells or cells incubated only with IL-2 showed no lysis of target cells with bispecific antibodies. Furthermore, the lysis of target cells by bispecific antibodies and CTL did not cause the lysis of bystander cells (cells not expressing an antigen recognized by the antibody which are mixed with the target cells). The efficient CTL-mediated lysis observed with these antibodies makes this a promising approach for the immunotherapy of human cancer.
Animals↗
Lymphoma immunotyping by paraffin immunoperoxidase and cell suspension methods--a comparative study.
Immunoperoxidase staining incorporating an enzyme digestion step was performed on paraffin sections of 84 biopsy cases of lymphoproliferative disorders. Monoclonality was demonstrated in 100% of plasmacytomas and related tumours, and in 66% of non-Hodgkin's lymphomas. In 83% of lymphomas the immunoglobulin class was IgM and the light chain distribution was kappa 64% and lambda 36%. Polyclonality was found in 89% of cases of reactive lymphoid hyperplasia and within Reed-Sternberg cells in 55% of cases of Hodgkin's disease. Similar results were obtained by dispersed cell studies in 56 overlapping cases. The concordance rate between the two methods in 40 cases of non-Hodgkin's lymphoma was 67.5%. Reasons for the inconsistencies are discussed. Immunoperoxidase staining of enzyme digested paraffin sections is useful in the diagnosis of B cell lymphoproliferative disorders with a particular role in centres where cell suspension studies are not available or when there is no access to fresh tissue.
Cytological Techniques↗
PHM 14: a novel monoclonal antibody that reacts with both normal and neoplastic human B cells but not B-CLL.
The reactivity of PHM 14, a monoclonal antibody to B cells produced in our laboratory was compared with Leu 10, a commercially produced antibody. Flow microfluorometric analysis showed that both PHM 14 and Leu 10 reacted with normal B cells, a variety of B cell lines and with B cell leukaemias and lymphomas, except in the case of B-CLL where PHM 14 reacted with a minority of cases, whereas Leu 10 reacted with a majority. PHM 14 and Leu 10 did not react with normal monocytes, granulocytes, T cells, T cell lines or with T cell leukaemias or lymphomas. Specificity of PHM 14 for B cells was further supported by the demonstration that PHM 14-positive blood cells, sorted from PHM 14-negative blood cells, reacted with polyclonal anti-immunoglobulins and with a panel of B cell markers but did not react with markers for T cells, monocytes, granulocytes or NK cells. Our results suggest that both PHM 14 and Leu 10 should be useful diagnostic reagents in the investigation of B cell-derived leukaemias and lymphomas.
Antibodies, Monoclonal↗
Thymic sensitivity to sex hormones develops post-natally; an in vivo and an in vitro study.
In vitro thymic organ cultures were used to examine the effects of the sex hormones estradiol and dihydrotestosterone on thymocytes. In contrast with the marked loss of cortical thymocytes seen in vivo with these hormones, no effect was apparent in vitro even at concentrations up to 10(-6) M. The glucocorticoid dexamethasone caused severe depletion in vivo and in vitro. Thymic androgen and estrogen receptors were determined; in the newborn animals up to 2 wk of age, receptor levels were barely detectable. The possibility of indirect modulation of thymic function by steroids in vivo was investigated by culturing thymic lobes in media containing serum from animals treated with these hormones. Only sera from dexamethasone-injected animals caused changes in cell size, number, viability, or phenotype in the culture system. The mechanism for the previously reported effects of sex steroids on the neonatal thymus therefore remains to be elucidated.
Aging↗
Routine flow cytometric diagnosis of lymphoproliferative disorders.
The results of the analysis of suspected lymphoproliferative disorders using flow cytometry (FACS II) over the past 12 months have been evaluated and assessed with respect to "conventional" microscopical examination. The major advantages in using these methods is the speed, the number of parameters which are capable of measurement, the sensitivity, and the ability to quantitate large numbers of cells for a particular criterion. These qualities have proved extremely helpful in the diagnosis of chronic lymphocytic leukemia, acute lymphoblastic leukemia, lymphoma, and other abnormalities. The combination of flow cytometry and a panel of monoclonal antisera (many of which are available commercially) allows the investigator a system of fine resolution which can confidently identify or characterize an abnormal clone or population of cells. With the increase in advanced flow cytometers, it is suggested that time should be allocated for the routine analysis of possible lymphomas and leukemias to allow quick and accurate evaluations of the disease status.
Antibodies, Monoclonal↗
Dexamethasone induces different cellular protein synthetic responses in PNA+ and PNA- mouse thymocyte subpopulations.
Thymocytes from adrenalectomized BALB/c male mice were separated by peanut agglutination (PNA) into cortical, corticosensitive, PNA+ cells and larger, medullary, corticoresistant, PNA- cells; the extent of cross-contamination of PNA+ and PNA- cells, and vice versa, was checked by flow microfluorometry. Glucocorticoid receptor profiles were established with 3H-dexamethasone as probe; no differences in receptor affinity or cellular concentration, or in cytoplasmic and nuclear compartmentalization were seen between PNA+ and PNA- cells. On two-dimensional gel electrophoresis, PNA+ and PNA- thymocytes from oil-injected (control) adrenalectomized mice showed patterns of incorporation of 35S-methionine into protein that differed in at least 12 spots, as revealed by autoradiography. PNA+ and PNA- cells from mice treated with submaximal (6 micrograms/day) or near-maximal thymolytic doses of dexamethasone (20 micrograms/day) were also examined by two-dimensional gel electrophoresis. Both PNA+ and PNA- cells showed substantial, overlapping dexamethasone-induced changes in protein synthetic profiles.
Animals↗
Antigens associated with bursal and thymic reticular epithelial cells.
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Animals↗
Dihydrotestosterone and estradiol deplete corticosensitive thymocytes lacking in receptors for these hormones.
The sex steroids dihydrotestosterone (DHT) and estradiol (E2), were found to deplete the same cortical population of thymocytes as the glucocorticoid dexamethasone (DM) in intact and in adrenalectomized, castrated mice. Although receptors for DM were demonstrated in this cortical population, none were found for E2 or DHT. We suggest that the sex steroids bind to other thymic elements, possibly thymic reticular epithelial cells, which may in turn act secondarily on cortical thymocytes, or their precursors within the thymus.
Animals↗
Triglyceride analysis: neatsfoot oil and sperm whale oil.
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Animals↗