Biomedical subjects

G R Thrush

Publications and source records attributed to G R Thrush.

6 recordsLinked to original sources

PubMed1996

Immunotoxins: an update.

The use of immunotoxins (ITs) in the therapy of cancer, graft-vs-host disease (GvHD), autoimmune diseases, and AIDS has been ongoing for the past two decades. ITs contain a targeting moiety for delivery and a toxic moiety for cytotoxicity. Theoretically, one molecule of a toxin, routed to the appropriate cellular compartment, will be lethal to a cell. Newly developed MoAbs, toxins, and molecular biological technologies have enabled researchers to construct ITs that can effectively kill many different cell types. In fact, phase I/II clinical trials have given promising results. Although nonspecific toxicity and immunogenicity still limit the use of IT therapy, these agents hold enormous promise in an optimal setting to treat minimal disease.

Animals↗

PubMed1995

Staphylococcal enterotoxin B induces the expression of activation markers on murine memory T cells in the absence of proliferation or lymphokine secretion.

Superantigens have been used to study peripheral tolerance in CD4+ T cells. The superantigen SEB induces T cell anergy by promoting the differentiation of SEB-activated virgin T cells into anergic memory T cells. Memory T cells from SEB or antigen-primed mice do not proliferate when they are cultured with SEB. The present studies were performed to determine whether memory T cells fail to interact with SEB antigen-presenting cells or whether SEB promotes incomplete or negative signals in memory T cells. When murine virgin and memory T cells were separated on the basis of CD45RB expression and cultured with SEB-pulsed B cells, SEB induced the expression of CD25, which then mediated proliferation when IL-2 was added to the cultures. In addition, SEB promoted the expression of the CD40L, which is required for T helper cell function. Finally, PMA induced a costimulatory signal leading to the proliferation of these cells. Surprisingly, the agents, i.e., IL-2 and PMA, which induced TM cell proliferation in conjunction with SEB failed to induce lymphokine secretion. However, in the presence of IL-4 plus IL-5, the T memory cells induced the SEB-pulsed B cells to secrete IgM and IgG. These results suggest that memory T cells are not simply unresponsive to SEB but are actively anergized.

Animals↗

PubMed1991

Loss of myb expression in an aggressive SJL/J B-cell lymphoma.

SJL mice spontaneously develop B-cell lymphomas that can be propagated by transplantation into syngeneic mice. These tumors usually have an indolent phenotype and require at least several weeks to produce morbidity following transplantation. However an aggressive lymphoma (RCS5) has been found that produces morbidity within days of transplantation. RCS5 cells fail to express the H-2Ds class I major histocompatibility complex antigen, whereas indolent tumors express H-2Ds. To identify genetic factors that may contribute to the tumorigenicity of B-cell lymphomas in SJL mice, tumor genomes were analyzed for mutations in cellular oncogenes. No rearrangements were detected by Southern hybridization analysis in tumors at the abl, myc, mbcl-2, Ha-ras, Ki-ras and raf loci. Indolent tumors were not rearranged at the myb oncogene, however alterations were detected in both myb alleles in RCS5. Northern hybridization analysis on RNA from in vivo-derived tumor preparations failed to detect any myb transcripts in RCS5. The loss of normal myb expression could directly contribute to the aggressive phenotype of RCS5. Alternatively, expression of the RCS5 myb allele may have contributed to early stages of tumor development. The possibilities that the observed myb mutations affect tumor aggressiveness and H-2Ds expression are discussed.

Alleles↗

PubMed1989

Progression of transplanted SJL/J lymphomas attributed to a single aggressive H-2Ds-negative lymphoma.

Spontaneously arising, H-2Ds-positive SJL/J lymphomas have been reported to become irreversibly more aggressive and H-2Ds-negative upon successive transplantation in syngeneic mice. In an effort to determine whether this process was one of tumor progression, we sought to: (a) establish whether a clonal relationship exists between readily transplantable aggressive SJL/J lymphomas and their respective indolent predecessors; and (b) identify genetic events critical to the process of acquisition of increased malignancy. Examination of putatively distinct, aggressive, H-2Ds-negative lymphomas, including the long term transplantable line RCS5, revealed them to have the same heavy and light immunoglobulin chain gene rearrangement patterns, a characteristic karyotype marked by nine chromosomal abnormalities, and approximately ten newly acquired ecotropic murine leukemia proviruses at similar genomic sites. Independent, spontaneously arising H-2Ds-positive lymphomas, in early transplant, were found to be genetically distinct from the respective more malignant H-2Ds-negative tumors to which they gave rise during successive transplantation. The data are interpreted as indicating that the aggressive H-2Ds-negative tumors in this study originated from a common source, most likely the RCS5 tumor, rather than through progression of separate spontaneously arising SJL/J lymphomas. It cannot be concluded which of the multiple genetic abnormalities of the H-2Ds-negative tumors were critical to their highly malignant phenotype. However, chromosomal abnormalities and newly acquired murine leukemia proviruses are discussed as to the roles they might play in SJL/J lymphomas.

Animals↗

PubMed1989

CD8 suppressor cell activity and its effect on CD4 helper cell-dependent growth of SJL/J B-cell lymphomas.

CD8 cells, flow cytometrically sorted from the lymph nodes of tumor-bearing and normal SJL/J mice, suppressed in vitro proliferation of syngeneic CD4 cells in response to concanavalin A, two independent SJL/J lymphomas, and LPS-activated syngeneic B-cell blasts. The data confirm earlier reports that nonspecific suppressor cells are generated as a consequence of SJL/J lymphoma-stimulated T-cell proliferation. Earlier reports are extended, in that the suppressor cell is identified as expressing CD8, and the suppressor activity is shown to decrease the tumor-stimulated CD4 cell proliferation which is essential to growth of these CD4-dependent murine B-cell lymphomas. In three separate experiments, anti-CD8 treatment of mice, in which CD4 cells were made limiting by injection with anti-CD4, increased growth of transplantable SJL/J lymphomas with corresponding increases in numbers of CD4 cells. The data imply that, under certain conditions, CD8 suppressor cells measurably influence growth of SJL/J lymphomas by regulating the tumor-stimulated CD4 cell proliferation essential to maximum growth of SJL/J lymphomas.

Animals↗

PubMed1989

The CD4 cell dependency of SJL/J B-cell lymphomas as a target for cyclophosphamide therapy.

SJL/J B-cell lymphomas induce proliferation of syngeneic CD4 cells, on which the tumors are dependent for growth. We sought to determine whether cyclophosphamide (CY) treatment of tumor-bearing mice would be successful through effects on tumor cells, CD4 cells, or both. The markedly increased survival of treated mice derived predominantly from reduced proliferation of CD4 cells in response to tumor. Reduced proliferation of CD4 cells created a microenvironment that was not conducive to tumor growth, as evidenced by the failure of a subsequent tumor cell challenge to treated mice to significantly increase the rate of the mice. We concluded that CY affected the tumor-stimulated environment of SJL/J mice by killing CD4 cells that had been activated by a pre-existing tumor stimulus and by promoting the appearance of a population of CD8 cells that suppressed the ability of residual or recovering CD4 cells to proliferate in response to tumor. The CD8 population from treated mice was specific, based on the ability to suppress a tumor-stimulated mixed lymphocyte response (MLR) and the related autologous MLR and an inability to suppress an allogeneic- or Con A-induced response. Since CD8 cells from CY treated mice had no demonstrable antitumor activity, the most likely suppressor targets were responder CD4 cells in the tumor-stimulated MLR. The results emphasize that the design of a treatment protocol can take advantage of the immunodependency of a tumor.

Animals↗