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Biomedical subjects

S Gillis

Publications and source records attributed to S Gillis.

At least 199 records · Page 11Linked to original sources
PubMed1984

Autologous mixed lymphocyte reaction in man. XIV. Deficiency of the autologous mixed lymphocyte reaction in acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC). In vitro effect of purified interleukin-1 and interleukin-2.

Peripheral blood mononuclear cells from male homosexuals with acquired immune deficiency syndrome (AIDS) and with AIDS related complex (ARC) were examined for the autologous mixed lymphocyte reaction (AMLR) between responder T and irradiated autologous non-T cells and in vitro influence of purified human interleukin-1 (IL-1) and -2 (IL-2) on the AMLR. The AMLR was significantly (P less than 0.001) deficient in both ARC and AIDS; the deficiency of the AMLR was of the similar magnitude in two groups when compared to asymptomatic homosexuals and healthy heterosexuals. In vitro addition of IL-2 enhanced the AMLR to the baseline levels of control subjects in most patients in ARC group (P less than 0.01) and in four of 15 patients in AIDS group (P less than 0.01). Addition of IL-1 to IL-2 containing cultures resulted in no further increase in the AMLR response over those with IL-2 alone. This study demonstrates deficiency of the AMLR in patients with ARC and AIDS that is corrected by purified IL-2 in the majority of cases with ARC but only a subset of patients with AIDS. The significance of these findings is discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1984

In situ identification of cells in human leprosy granulomas with monoclonal antibodies to interleukin 2 and its receptor.

Leprosy is a chronic granulomatous disease with an immunologic spectrum in which lepromatous leprosy patients have defective cell-mediated immune responses, in comparison to tuberculoid leprosy patients. Immunoregulatory aspects of this spectrum were investigated by using monoclonal antibodies to interleukin 2 (IL 2), IL 2 receptors (Tac), and T lymphocyte subpopulations with immunoperoxidase techniques on frozen sections of skin biopsy specimens from 10 tuberculoid and 10 lepromatous patients. A comparison of IL 2+ cells revealed markedly fewer IL 2+ cells in lepromatous specimens (lep. 0.028% +/- 0.02 vs tub. 0.46% +/- 0.28, p less than 0.001). These IL 2+ cells were large, exhibited cytoplasmic staining, and on double immunostaining were Leu-4+, Leu-3a+, Leu-2a-, Tac-, and OKT6-, consistent with the fact they are IL 2 producers. Equivalent numbers of Tac+ cells were observed in both lepromatous and tuberculoid granulomas (lep. 1.5% +/- 0.5 vs tub. 2.1% +/- 0.7, p, NS), suggesting that the responder cells are present in both conditions. The tuberculoid granuloma was highly organized, composed of a central core of mature macrophages, Leu-3a+ and Tac+ cells with a surrounding mantle of Leu-2a+, Leu-3a+, IL 2+, Tac+, and OKT6+ cells. In lepromatous granulomas, Leu-2a+, Leu-3a+, Tac+, and rare IL 2+ cells were randomly admixed with bacilli-laden macrophages. The defective cell-mediated immune responses in lepromatous leprosy appears to be associated with diminished IL 2 production and disorganization of the granuloma.

Antibodies, Monoclonal↗
PubMed1984

Ineffective cellular interaction and interleukin 2 deficiency causing T cell defects in human allogeneic marrow recipients early after grafting and in those with chronic graft-versus-host disease.

Impairment in T cell proliferation in response to E. coli and in CML to unrelated alloantigens was usually observed in patients early after marrow grafting and persisted in long-term patients with chronic GVHD but not in those without chronic GVHD. We analyzed various cellular functions in the pathway of T cell activation and found that in patients with immunodeficiency, (1) their M phi usually could process and present antigens to normal T cells, (2) their T cells did not proliferate even in the presence of normal antigen-pulsed M phi, (3) IL-2 production by T cells was deficient, and (4) exogenous IL-2 restored CML activity in cells of most patients early after grafting but not in cells of most patients with chronic GVHD. Therefore, failure to induce proliferation and cytotoxicity in T cells of marrow recipients is not likely due to M phi defects but because of ineffective communication among T cell subsets, probably related to impaired IL-2 production and/or unresponsiveness to IL-2.

Bone Marrow Transplantation↗
PubMed1984

Limiting dilution analysis of interleukin 2 and colony-stimulating factor producer cells in normal and autoimmune mice.

MRL/MP lpr-lpr (MRL-lpr) mice spontaneously develop an age-related disease characteristic of human systemic lupus erythematosus (SLE). Old MRL-lpr mice (4 mo of age) develop antibodies to nucleic acids, display immune complex glomerulonephritis, and have a massive T cell-associated lymphadenopathy. In concert with disease development is data showing an age-related loss of interleukin 2 (IL 2) production by mitogen-stimulated lymphoid cells from these mice. The loss of IL 2 production has been suggested to be involved in the onset and/or development of autoimmune disease seen in these animals. In this report, we examined the frequency of both IL 2 and colony-stimulating factor (CSF) producer T cells in the MRL-lpr mouse by using a limiting dilution analysis assay. Our results show that the number of IL 2 and CSF producer cells present in autoimmune animals is similar to the number found in normal control mice. In addition, IL 2 and CSF producer T cells from autoimmune MRL-lpr mice make similar levels of lymphokine activity, as do producer T cells from normal mice. Our data argue against the previously hypothesized role that a paucity of IL 2 production may be involved in the etiology of autoimmune disease.

Aging↗
PubMed1984

Interleukin 2 administered in vivo induces the growth of cultured T cells in vivo.

The capacity of exogenous IL 2 to induce the growth of antigen-activated T lymphocytes in vivo was evaluated. The in vivo growth of adoptively transferred T lymphocytes that had been previously cultured long-term with IL 2 was initially examined, because in vitro such T cells are exquisitely dependent upon exogenous IL 2 for proliferation and survival. Daily administration of IL 2 in vivo, beginning on the day of cell transfer, induced these IL 2-dependent long-term cultured T lymphocytes to proliferate in vivo, and the magnitude of in vivo growth was proportional to the dose of IL 2 administered. The capacity of IL 2 to induce the in vivo growth of antigen-activated T cells not previously exposed in vitro to exogenous IL 2 was similarly studied. T lymphocytes from the spleens of immune mice, activated by 5-day culture with tumor antigen before transfer, survived poorly in vivo when injected with antigen alone, but demonstrated marked proliferation in vivo in response to antigen and exogenous IL 2. By contrast, immune spleen cells transferred with antigen, but without prior culture, proliferated without supplementary exogenous IL 2. Moreover, the growth of noncultured donor T cells was not augmented by the administration of exogenous IL 2, implying that noncultured spleen cells immune to tumor antigens can produce sufficient amounts of endogenous IL 2 in vivo to sustain maximal T cell growth over the time period examined. Importantly, the ability of exogenous IL 2 to induce donor T cell growth in vivo correlated with its ability to function in vivo to augment the anti-tumor efficacy of specifically immune donor T cells in models for the adoptive therapy of disseminated antigenic murine leukemia. Thus, the current studies highlight the potential of exogenous IL 2 to induce T cell growth in vivo and suggest that the administration of IL 2 in vivo may be useful for augmenting T cell responses that are relatively deficient in the production of endogenous IL 2.

Animals↗
PubMed1984

Biochemical comparison of murine colony-stimulating factors secreted by a T cell lymphoma and a myelomonocytic leukemia.

Factors that stimulate the proliferation and differentiation of murine bone marrow cells have been purified from a cloned T cell lymphoma, LBRM-33, and a cloned myelomonocytic leukemia cell line, WEHI-3. These colony-stimulating factors (CSF) have been purified by sequential fractionation by using salt precipitation, gel filtration, anion and cation exchange chromatography, and high pressure liquid chromatography. Both LBRM-33 and WEHI-3 cells secrete a CSF species with similar chemical and biologic properties. This CSF species appears to exist in two forms, termed CSF-2 alpha and CSF-2 beta, both of which stimulate the growth of bone marrow cells in the granulocyte, macrophage, megakaryocyte, mast cell, and erythrocyte lineages, as well as the growth of a CSF-dependent cell line, FDC-P2. These properties of CSF-2 alpha and -2 beta are similar to those reported for interleukin 3, hematopoietic cell growth factor, mast cell growth factor, and persisting cell growth factor. However, LBRM-33 cells secrete another CSF species, not produced by WEHI-3 cells. This CSF species, unique to LBRM cells, is termed here CSF-2 gamma and it stimulates the proliferation of granulocytes and macrophages from bone marrow but does not support the growth of FDC-P2 cells.

Animals↗
PubMed1983

Serological visualization of interleukin 2.

Interleukin 2, a lymphokine that acts as a second signal of cellular immune response by way of its action as a T-cell growth factor, was morphologically identified by immunoperoxidase staining. With the use of a monoclonal antibody to interleukin 2 and several complex-forming antisera, the lymphokine was readily distinguished in cytocentrifuge preparations of peripheral blood leukocytes stimulated with a T-cell mitogen. When preparations of cloned interleukin 2 producer and responder cells were stained by the same procedures, discrete patterns of both responder and producer cell phenotypes were revealed. Interleukin 2 producer T cells exhibited a characteristic intense, ringlike cytoplasmic staining, whereas the responder cells (as exemplified by interleukin 2-dependent cell lines) exhibited a less intensive, spotlike membrane staining. In addition, intense membrane localization of interleukin 2, reminiscent of potential capping phenomena, could be observed in stained preparations of cloned responder cells.

Animals↗
PubMed1983

Interleukin 2: biology and biochemistry.

Since its discovery as a T-cell growth factor, interleukin 2 (IL-2) has attracted considerable scientific attention, not only as a useful reagent for the maintenance of large numbers of effector T lymphocytes but as a potentially potent immunoregulatory molecule, which could be of therapeutic usefulness in a number of clinical conditions. Outlined in this communication is a summary of the more salient biochemical features of murine and human IL-2, as well as the results of initial molecular biology experimentation aimed at the eventual production of IL-2 by recombinant DNA methodologies. These studies, together with those detailing the in vivo effectiveness of IL-2 therapy in a number of murine model situations, provide a current glimpse of future IL-2 aims and directions.

Animals↗
PubMed1983

Characterization of IL-2-dependent cytotoxic T-cell clones. II. Cell-surface phenotypes, histochemical and ultrastructural properties.

This report examines the histochemical staining patterns, ultrastructure, and cell-surface phenotypes of six antigen-specific T-cell clones. Histochemical analyses indicated that all cell lines expressed alpha-napthyl butyrate esterase characteristic of the monocytic isoenzyme, intense napthol AS-D chloroacetate reactivity characteristic of granulocytes, and were negative for leucoperoxidase, alkaline phosphatase, and Sudan black. Only one clone stained weakly for acid phosphatase. The esterase staining patterns became evident in newly established cell lines after growth for only 1 week in interleukin 2-conditioned medium. Ultrastructurally, the outstanding feature was numerous membrane-bound granules containing a complex-appearing globular material. The cell-surface phenotypes of the lines as determined by protein A-sheep red blood cell rosetting and indirect immunofluorescence was Ly-5+, T200+, Qa-5-, MAC-1-, and Lyt-1+,2,3- for the helper line and Lyt-1-2,3+ for the five cytotoxic lines. By quantitative absorption analyses, low levels of Lyt-1 antigens were detected on all examined cytotoxic lines. The results strengthen the view that long-term T-cell lines can retain normal T-cell characteristics while also expressing markers that are either absent or in undetectable levels on uncultured T lymphocytes. The presence of the esterases may be associated with an expanded functional role in the T-cell lines.

Animals↗
PubMed1983

Changes in surface antigens of immature thymocytes under the influence of T-cell growth factor and thymic factors.

Peanut agglutinin-positive thymocytes, peanut agglutinin-negative thymocytes, cortisone-resistant thymocytes, and unfractionated thymocytes were prepared from congeneic C57BL/6 Tla mice. By using surface iodination and immunoprecipitation of solubilized antigen with specific antisera (e.g., anti-H-2D, anti-TL, anti-Qa2/3, and anti-gp70), the released specific antigens were electrophoresed on polyacrylamide gels, and their radioactivity was measured. The relative percentages of surface antigens H-2D, TL, Qa2/3, and gp70 were 3.2%, 47.5%, 2.5%, and 46.8%, respectively, for peanut agglutinin-positive thymocytes; 31.8%, 4.4%, 32.7%, and 31.1%, respectively, for cortisone-resistant thymocytes; 13.2%, 28.7%, 12.3%, and 45.8%, respectively, for peanut agglutinin-negative thymocytes; and 7.7%, 27.1%, 4.3%, and 60.9%, respectively, for unfractionated thymocytes. After incubation with thymosin fraction V or T-cell growth factor (interleukin II) for 20 hr, the changes in surface antigens of peanut agglutinin-positive thymocytes closely correlated with their normal maturation (i.e., H-2D increases and TL decreases). Thymic factors (e.g., thymosin alpha 1, thymopoietin pentapeptide, facteur thymic serique) had only small or no effects on surface antigens of peanut agglutinin-positive thymocytes. The results suggest that peptides yet to be identified in thymosin fraction V may play an important role in intrathymic evolution and that T-cell growth factor is possibly a peripheral signal derived from activated T cells that modulates T-cell receptors and may be a critical regulator of intrathymic cellular development.

Animals↗
PubMed1983

Cellular interactions in marrow-grafted patients. I. Impairment of cell-mediated lympholysis associated with graft-vs-host disease and the effect of interleukin 2.

Forty patients with hematologic malignancy or aplastic anemia were given allogeneic marrow after conditioning with high-dose cyclophosphamide alone or in combination with total body irradiation. Between 28 and 3857 days after transplantation, their peripheral blood mononuclear leukocytes were tested for reactivity in indirect cell-mediated lympholysis against normal leukocytes from unrelated individuals, and the results were compared to those with cells from their healthy marrow donors. An impairment of cell-mediated lympholysis was found with cells from most patients with acute and chronic graft-vs-host disease (GVHD) whereas cells from most short-term and long-term patients without GVHD had cell-mediated lympholysis reactivity comparable to that of cells from the marrow donors. When interleukin 2 was added to the mixed leukocyte cultures during the sensitization phase, the impaired cell-mediated immunity of cells from most short-term patients with acute GVHD, but not that of cells from most patients with chronic GHVD, could be restored to normal levels. These results suggest the impairment of cell-mediated immunity seen in cells of short-term patients with acute GVHD is attributable to helper cell defects or to ineffective communication between antigen-presenting cells and helper T cells. The impairment in cell-mediated immunity seen in patients with chronic GVHD, however, may reside on the effector cells (or their precursors) or may be due to the presence of suppressor cell activity.

Acute Disease↗
PubMed1983

Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE).

The objective of this study was to define some causes of the immunologic impairment characteristic of systemic lupus erythematosus. Blood mononuclear cells from 19 patients were stimulated to produce interleukin 1 and interleukin 2 and compared with controls. A severe defect in both IL 1 and IL 2 activity was observed. The low cytokine levels did not correlate with clinical or serologic activity of disease. These defects could not be explained by concurrent corticosteroid therapy. There was no correlation between a lower number of OKT4+ cells observed in these patients and the levels of IL 2 production, nor did removal of monocytes bring IL 2 to normal. Impaired IL 2 production could not be restored to normal by IL 1. The observed deficiency in these regulatory cytokines may therefore be a primary defect that is important in the pathogenesis of this disorder.

Animals↗
PubMed1983

Interleukin 2 induces gamma-interferon production: participation of macrophages and NK-like cells.

Interleukin 2 (IL 2) has been shown to be a potent stimulator of natural killer (NK) cells. In the present studies, partially purified mouse and human IL 2 preparations were also found to induce interferon (IFN) from mouse spleen cells. By the criteria of sensitivity to treatment at pH 2 and failure to be neutralized by a potent anti-alpha, beta IFN serum, the species of IFN produced was of type gamma. Cooperation between two types of cell, a macrophage and an NK-like cell, was required for IFN production by murine spleen cells treated with IL 2. The requirement for macrophages could be replaced with supernatant obtained by incubating macrophages for 24 hr with lymphokine preparations containing IL 2. Interestingly, mature T cells apparently played no role in the process. Furthermore, the beige (bg/bg) mutation, which severely impairs NK cell lytic activity, had no effect on the ability of NK-like cells to participate in IFN production. Cell fractionation experiments revealed no dissociation between the requirements for augmentation of NK cytotoxic activity and for IFN production, and it is concluded that at least a portion of the NK boosting induced by IL 2-containing preparations is mediated through gamma-IFN.

Animals↗
PubMed1983

In vivo interleukin 2 administration augments the generation of alloreactive cytolytic T lymphocytes and resident natural killer cells.

Interleukin 2 (IL 2) is a T cell growth factor that has been shown to modulate several in vitro immune responses. Produced by T cells, the lymphokine has been highly purified and used in a series of in vivo studies to examine the effect of IL 2 on murine cytotoxic T cell (CTL) and natural killer (NK) cell reactivity. By employing an immunization protocol known to generate CTL activity against allogeneic tumors, in vivo administration of highly purified IL 2, either in concert, with or 2 days after, tumor administration, resulted in an augmented CTL response as compared to effector cells harvested from untreated, alloimmunized control animals. Characterization of the effector cells responsible for the augmented cytolytic activity showed them to be of the T cell lineage and to be specific for the appropriate immunizing tumor cell. Furthermore, we were able to demonstrate that administration of purified IL 2 to naive, non-antigen-challenged recipients resulted in substantial potentiation of NK cell activity. The augmented cytolytic reactivity was mediated by NK cells as evidenced by effector cell lysis of NK-susceptible but not NK-insusceptible tumor targets. The results of these studies suggest IL 2 functions in vivo as an immune response regulator and may have a beneficial effect as an in vivo immunopotentiator.

Animals↗
PubMed1983

Generation of alloreactive cytotoxic T lymphocytes: evidence for a differentiation factor distinct from IL 2.

In this report we provide evidence that the generation of cytotoxic T lymphocytes (CTL) involves a differentiation signal in addition to a proliferative signal, and that the differentiation signal is mediated by a factor distinct from interleukin 2 (IL 2). Generation of CTL from nylon wool-nonadherent splenocytes stimulated by heat-treated thymocytes did not correlate with the addition of IL 2-containing supernatants to this factor-dependent bioassay. IL 2 from two different sources and prepared by different methods (purified IL 2 from the LBRM33 cell line and partially purified IL 2 from the EL4 cell line) was not sufficient to generate a cytotoxic response in the bioassay. The inability of IL 2 to generate a cytotoxic response was not due to the use of heat-treated stimulator cells because similar results were obtained with UV-treated cells. As we previously reported, supernatant fluids containing a differentiation/activation factor did generate CTL from nylon wool-nonadherent splenocytes. Supernatant fluid from co-cultures of activated T cells and M phi as well as from cultures of activated M phi contained this CTL helper factor; however, only the former supernatant contained IL 2 activity. These results suggest a factor distinct from IL 2 is providing a differentiation/activation signal that is necessary for CTL development. Although IL 2 was not effective at generating CTL from nylon wool-nonadherent splenocytes, it was capable in some, but not all, experiments of generating a cytotoxic response from unseparated splenocytes. The ability of IL 2 to induce a cytotoxic response from unseparated splenocytes appeared to correlate with the presence of a weak background response seen when unseparated cells were used as responder cells.

Animals↗
PubMed1983

Molecular characterization of interleukin 2.

The isolation of specific T cell growth factors termed interleukin 2 (IL 2) is changing the approach to understanding T cell function. This class of growth factors has allowed te establishment of a number of human and murine T cell lines. We summarize the biochemical properties of human and murine IL 2. Studies have been initiated to isolate mRNA encoding for IL 2. Such RNA can be translated in rabbit reticulocyte lysates yielding IL. 2. This RNA may be useful for the development of probes to isolate lymphokine genes.

Animals↗