Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel approach to adoptive immunotherapy is described in this study. Of 13 patients with malignant effusions, nine were treated by intraperitoneal (IP) instillation of intracavitary lymphocytes (ICL), activated ex vivo by recombinant interleukin-2 (rIL-2, Cetus Co., Emeryville, CA) with escalating doses of IP rIL-2 and four by IP rIL-2 alone. ICL and rIL-2 were administered by repeated peritoneal punctures. Patients were divided into two groups: group I of six patients, who received activated ICL with low doses of IP rIL-2 (total dose not exceeding 6 X 10(5) units) and group II of seven patients, in whom escalating higher doses of rIL-2 were administered IP with or without activated ICL, in doses ranging from 10(6) up to 16 X 10(6) units, total dose. Total dose of ICL given ranged from 2 X 10(8) to 2 X 10(9) in both groups. The main objectives of this pilot study was to establish the feasibility of treatment by ex vivo activated ICL and IP rIL-2, to assess the toxicity associated with such a treatment, to escalate doses of rIL-2 to a maximal tolerable dose, and to look for clinical responses. The first two goals were achieved: such a treatment approach is feasible and is not associated with severe toxicity. The side effects observed during this study were usually mild in group I patients and more pronounced in group II patients. These included transient fever, chills, nausea, cellulitis at the puncture site, and one case of peritonitis.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Biother 1989
PMID:A pilot study of intraperitoneal recombinant interleukin-2 and ex vivo activated intracavitary lymphocytes in patients with malignant peritoneal spread: I. Clinical aspects. 260 15

Induction of differentiation in B lymphoma/leukemia cells with interleukins was compared with differentiation induced by phorbol ester (TPA) and pokeweed mitogen (PWM) or by 8-bromo-guanosine. Both cell surface changes and monoclonal immunoglobulin (Ig) secretion were followed as markers of differentiation. The results indicate great similarity in the differentiation patterns induced by interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-4 (IL-4), with regard to Ig secretion and changes in surface markers. Induction of Ig secretion and surface marker changes by 8-bromo-guanosine was similar to that induced by TPA and PWM; however, for some markers, cell surface changes induced by TPA and PWM or by 8-bromo-guanosine were quite different from those induced by the three interleukins tested. Whereas all three interleukins stimulated the expression of CD5, PWM and TPA and 8-bromo-guanosine substantially decreased CD5 expression on B lymphoma cells. Differences were also observed in the effect on the expression of surface Ig and on the expression of CD19 and CD20. Interestingly, the three interleukins tested and 8-bromo-guanosine induced differentiation and Ig secretion within 24 to 48 hours with no prior activation by B-cell activators, such as anti-surface Ig antibody. These results suggest that leukemic B cells are arrested at a point distal to activation and first cell division. Moreover, the similarity in Ig secretion and surface changes induced by TPA and PWM or 8-bromo-guanosine suggest a similar pathway; however, this pathway is different from the differentiation signal induced by the three interleukins.
Mol Biother 1989
PMID:Induction of surface marker changes and monoclonal idiotypic immunoglobulin secretion in lymphoma/leukemia cells: comparative study with interleukin-1, interleukin-2, interleukin-4, 8-bromo-guanosine, pokeweed mitogen, and tetradecanoyl phorbol-13-acetate. 261 Sep 49

The effect of indomethacin on murine lymphokine-activated killer (LAK) cell activity was investigated using a natural killer-resistant, spontaneously developed, weakly immunogenic, and highly tumorigenic syngeneic murine mammary adenocarcinoma, mimicking that of human disease, as the target. When used in combination with human recombinant interleukin-2 (rIL-2), indomethacin was found to augment LAK cell activity, which was generated from culture of the normal mouse splenocytes with rIL-2, as compared to that with rIL-2 alone. This increase in LAK cell activity was shown to be indomethacin dose-dependent, and was demonstrated only when indomethacin was added to the rIL-2-containing medium at the beginning of culture. The enhancement of LAK cell activity by indomethacin was abrogated when the nylon-wool nonadherent "macrophage-poor" splenocytes were incubated with rIL-2 plus indomethacin. These results indicated that the rIL-2-induced LAK cell activity generated from murine splenocytes could be augmented by indomethacin, and the macrophages may be involved as the mediator.
Mol Biother 1989
PMID:Augmentation of murine lymphokine (rIL-2)-activated killer cell activity by indomethacin. 261 Sep 50

Twenty patients were treated with metastatic renal cell cancer with 5-day cycles of constant infusion recombinant interleukin-2 (rIL-2) at 3 X 10(6) U/m2/day and with infusion of in vitro activated autologous mononuclear cells. The initial eight patients completed all rIL-2 and cellular therapy in a single 25-day treatment period. The subsequent 12 patients entered a 6-month treatment program involving two separate 15-day cycles of cellular therapy followed by four monthly cycles of maintenance rIL-2. Among eight patients in the 25-day treatment program, there were two with partial response (PR) and one with minor response (MR). None of these responses exceeded 2 months in duration. Among the 12 patients undergoing recycling of therapy, there were two with complete response (CR), two with PR, and one with MR. All four patients with CR or PR in this group demonstrated continuing response with recycling of treatment and none relapsed while receiving maintenance interleukin-2. Three remain in remission at 10, 11, and 12 months. These pilot data confirm that patients can tolerate multiple cycles of adoptive immunotherapy involving constant infusion rIL-2 and suggest that recycling of therapy is necessary to achieve clinically meaningful results.
Mol Biother 1989
PMID:Multiple cycles of constant infusion recombinant interleukin-2 in adoptive cellular therapy of metastatic renal carcinoma. 261 46

Extracts of blood lymphocytes, polymorphonuclear neutrophils and B, T or monocytic cell lines were analyzed by two-dimensional gel electrophoresis and immunoradiometric assay after electro-transfer to nitrocellulose sheets with radiolabelled polyclonal or monoclonal antibodies specific for beta 2-microglobulin. Four different forms of the molecule were identified with an apparent Mr of 12,000 and pI values of 5.7, 5.3 and lower. Lymphocyte activation by phytohemagglutinin and concanavalin A, or incubation with recombinant alpha 2b interferon, resulted in an increased beta 2-microglobulin cell content and release of the protein in supernatants with a predominant elevation of the more acidic minor forms. Recombinant interleukin-2 and recombinant gamma interferon increased the expression of the molecule without significant shift in the relative proportion of beta 2-microglobulin forms. Tumor necrosis factor alpha did not increase cell beta 2-microglobulin (beta 2-m) content and release and did not alter the relative distribution of the different forms of the molecule. Several mechanisms may be considered for the generation of beta 2-m microheterogeneity, including intracytoplasmic post-translational modifications such as proteolysis or modification of the amide groups of internal amino acids.
Mol Immunol 1989 Aug
PMID:Charge heterogeneity of beta 2-microglobulin in lymphoid cells. 268 10

Three lines of transgenic mice carrying the human T-cell lymphotropic virus type 1 tax gene have previously been reported to develop neurofibromas composed of perineural fibroblasts (S. H. Hinrichs, M. Nerenberg, R. K. Reynolds, G. Khoury, and G. Jay, Science 237:1340-1343, 1987; M. Nerenberg, S. H. Hinrichs, R. K. Reynolds, G. Khoury, and G. Jay, Science 237:1324-1329, 1987). Tumors from these mice and tumor cell lines derived from them expressed high levels of tax RNA and protein. They also expressed high levels of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene as measured by proliferative responses of FD-CP1 target cells using conditioned media from tumor cells and by Northern (RNA) blot analysis of RNA from tumors and tumor cell lines. Although other tissues, such as salivary glands and muscles, in the transgenic mice also expressed high levels of tax, they did not express the gene for GM-CSF. This indicates that tissue-specific cellular factors, in addition to tax, are required for GM-CSF gene expression. Systemic effects of excessive GM-CSF production were demonstrated by infiltration of polymorphonuclear leukocytes into tumor tissues which are not necrotic, by peripheral granulocytosis, and by splenomegaly resulting from myeloid hyperplasia. The interleukin-2 (IL-2) receptor was also found to be expressed by the tumors and tumor cell lines as measured by IL-2-binding and cross-linking studies. This is the first demonstration that the IL-2 receptor can be activated by tax in a nonlymphoid cell type. These in vivo findings are consistent with other reports which have demonstrated in vitro cis-regulatory elements within the 5'-flanking regions of the genes for GM-CSF and the IL-2 receptor which are responsive to trans activation by the tax gene.
Mol Cell Biol 1989 Nov
PMID:trans activation of granulocyte-macrophage colony-stimulating factor and the interleukin-2 receptor in transgenic mice carrying the human T-lymphotropic virus type 1 tax gene. 268 63

The current focus on interleukin-2 typifies the transition in cancer immunotherapy from nonspecific immunostimulants that are broadly supportive to highly defined cytokines with greater stress on treatment. With the introduction of lymphokine-activated killer cells, there was a parallel shift in emphasis from the use of allogeneic adoptive lymphocytes to in vitro expanded autologous cells. On the assumption that there should be a place for a more complete biological response modifier (BRM) applicable as a fundamental agent that would provide maximum support for all treatment modalities and that might facilitate the adoptive use of incompatible mononuclear cells when needed, an attempt was made to draw on the extensive experience with the large number of BRMs that have been studied to define the characteristics and therapeutic activities of an agent that would be ideally suited. It is ironic that the mitogenic lectins have tended to be overlooked in BRM classifications, but compelling evidence suggests that PHA-L4, the L4 isolectin of phytohemagglutinin, might at least partially fulfill all of the criteria of an ideal BRM.
Mol Biother 1989
PMID:The ideal biological response modifier. 269 30

Human interleukin-2 (IL-2) is a lymphokine which is capable of activating lymphocytes and supporting the long-term in vitro growth of activated T cell clones. Recombinant human IL-2, expressed in either E. coli or cos cells, was shown to be phosphorylated by protein kinase C. Phosphorylated IL-2 synthesized in E. coli was analyzed by SDS-PAGE, reverse phase HPLC, and tryptic peptide mapping. The phosphorylated tryptic peptide was identified as the N-terminal fragment containing a single phosphorylation site at the serine residue at position 7. There was no difference in biological activity between non-phosphorylated and phosphorylated IL-2, as determined by a T cell growth assay. Although the physiological role of phosphorylation of IL-2 is unclear, IL-2 can be labeled with [gamma-32P] ATP and protein kinase C to a high specific radioactivity, and the synthesis of biologically active 32p-labeled IL-2 may be useful for receptor-binding studies of the cells containing low level of phosphoprotein phosphotases.
Mol Cell Biochem 1989 Aug 15
PMID:Phosphorylation of human interleukin-2 (IL-2). 278 33

The regulation and expression of protein kinase C (PKC) and phosphomyristin C (PMC) (a principal substrate of PKC which is the major myristylated protein in lymphocyte and glioma lines that express it) in murine B and T lymphocytes were investigated. Both PMC and PKC are differentially regulated during T-cell development. The level of PMC expression is highest in CD4-8-, intermediate in CD4+8+, and lowest in J11d-, CD4, or CD8 single-positive thymocytes. PKC is equally expressed by all three thymic populations. In striking contrast to thymocytes, resting peripheral lymph node T cells and T-cell clones express little if any PMC and reduced levels of PKC. Neither PKC nor PMC is significantly induced upon the activation of lymph node T cells: treatment with anti-CD3 antibodies or anti-CD3 and interleukin-2 fails to induce PKC, whereas PMC is not induced by anti-CD3 alone and is only slightly induced by anti-CD3 and interleukin-2. In contrast to the situation with T cells, PMC and PKC are constitutively expressed at moderate levels in mature B cells. PMC is greatly increased in B-cell blasts generated by cross-linking the antigen receptor with anti-immunoglobulin. These results demonstrate that PMC and PKC are differentially regulated during the development and activation of B and T cells, suggesting that cellular events that rely upon PKC and PMC may differ during ontogeny and activation of different lymphocyte subsets.
Mol Cell Biol 1989 Sep
PMID:A major myristylated substrate of protein kinase C and protein kinase C itself are differentially regulated during murine B- and T-lymphocyte development and activation. 278 36

Activated T cells express at least two affinity classes of interleukin-2 (IL-2) receptors. The number of low-affinity receptors is normally 10-30 times greater than that of the high-affinity receptors. In this report, normal human T cells are used in a cellular system in which the number of low-affinity receptors can be manipulated. The resulting receptor composition, which has been characterized in a previous report, contain such decreased levels of low-affinity IL-2 receptors that almost half of the surface pool of anti-IL-2 receptor antibody (anti-Tac) binding sites is associated with high-affinity receptors. By using such cells the dynamics and functions of high-affinity IL-2 receptors were studied and compared with receptors on a cell population expressing the normal 10-30-fold excess of anti-Tac binding sites over high-affinity IL-2 receptors. The results reveal that the rapid turnover of high-affinity IL-2 receptors is independent of the quantitative level of Tac antigen expression. The rapid kinetic of IL-2 internalization results in a 80-90% reduction of the steady-state levels of high-affinity receptors in the presence of IL-2. Most importantly, by using a cell population that expresses very low levels of Tac antigens, it became evident that IL-2 internalization is associated with an immediate substantial decrease of the surface level of anti-Tac binding sites. The Tac antigen thus appeared to be internalized together with the high-affinity IL-2 receptor complex but nevertheless the normal 10-30-fold excess of Tac antigens, over high-affinity IL-2 receptors, seems not to influence the process of internalization.
Mol Immunol 1987 Dec
PMID:Analysis of dynamics and functions of high-affinity interleukin-2 receptors. 282 31


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