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P Bossu

Publications and source records attributed to P Bossu.

8 recordsLinked to original sources
PubMed1996

Structure-function relationship in the IL-1 family.

The interleukin 1 (IL-1) family is a group of related cytokines including two agonist proteins (IL-1alpha and IL-1beta), each derived by enzymatic cleavage of precursor proteins (pro-IL-1alpha and pro-IL-1beta), and three forms of an antagonist protein (IL-1ra, icIL-1raI, icIL-1raII). IL-1 plays a key role in the onset and development of the host reaction to invasion, being an important factor in the initiation of the inflammatory response and in the triggering of immune functions. Due to its pleiotropic activity and to the high potency of its inflammatory effects, IL-1 activity is tightly regulated in the body by a complex network of control systems. These include the presence of two types of inhibitors, the receptor antagonist IL-1ra and the second type of IL-1 receptor (IL-1RI), which is a natural scavenger of IL-1. Furthermore, regulation of IL-1 activity is attained by a strict hierarchy of binding affinity of the two receptors (the activating IL-1RI and the inhibitory IL-1RII) for the various members of the IL-1 family. Additional levels of control are represented by the presence of soluble forms of both receptors and of immature pro-IL-1 forms with different characteristics of activity and receptor binding capacity. To clarify the features of reciprocal interaction among ligands and receptors, in the attempt to understand the rules regulating the IL-1 system and its effectiveness, a deep analysis of the relationship between structure and function in the proteins of the IL-1 family becomes of key importance. Information on this line has been provided by several groups mainly with studies of mutagenesis of IL-1alpha, IL-1beta and IL-1ra in parallel with biological assays of activity. In this review, a survey of the available data is provided, in order to construct a hypothetical model of the functional structure of IL-1 proteins as a basis for future therapeutic interventions based on genetic and protein engineering.

Caspase 1↗
PubMed1994

Functional distinctions between MRL-lpr and MRL-gld lymphocytes. Normal cells reverse the gld but not lpr immunoregulatory defect.

Homozygosity for either of the autosomal recessive mutations, lpr or gld, confers an autoimmune syndrome characterized by massive lymphoid hyperplasia and extensive autoantibody production. Despite the similarities in disease progression, functional distinctions in these genetic defects have been observed in bone marrow transplantation studies. To elucidate the mechanisms responsible for the aberrant immune phenotype of these strains, we analyzed interactions between normal T cells and T cells from the two autoimmune strains with regard to their in vitro responses to autologous and allogeneic stimuli and in an in vivo bone marrow transplantation model. Despite similar propensities for lpr and gld T cells to spontaneously proliferate in vitro in response to autologous class II Ag, a dramatic difference in their immunoregulatory properties was found when mixtures of normal and autoimmune CD4+ responder cells were challenged with an allogeneic stimulus. T cells from the lpr, but not gld, mice blocked the normal T cell component of the response. In vivo, the ability of lpr stem cells to trigger a wasting syndrome when transplanted into normal irradiated recipients could not be prevented by including normal stem cells in the inoculum; however, the ability of gld stem cells to transfer the gld-lymphoproliferative syndrome to normal recipients could be prevented with the addition of normal stem cells. These results support a model whereby the lpr and gld strains are defective in reciprocal components of a down-regulatory signaling pathway; failure to express either the functional receptor or ligand leads to a dysregulated immune system resulting in systemic autoimmunity. Based on the linkage between the lpr locus and Fas Ag expression, we propose that the failure of lpr mice to express Fas results in overproduction of Fas-ligand, whereas gld mice fail to make either the Fas-ligand or a functionally related protein, presumably belonging to the TNF family.

Animals↗
PubMed1993

Mature CD4+ T lymphocytes from MRL/lpr mice are resistant to receptor-mediated tolerance and apoptosis.

The goal of this study was to examine the functional responses and tolerance susceptibility of T lymphocytes from mice of the autoimmune strain, MRL/lpr. A population of autoreactive CD4+ T cells can be readily expanded from the lymphoid tissues of young lpr mice. Lines of IL-2-producing autoreactive and alloreactive lpr and alloreactive +/+ T cells were developed to study their responses to tolerance-inducing stimuli. Culture of +/+ T cells with high concentrations of immobilized anti-CD3 antibody induces both functional anergy and apoptosis. By contrast, lpr-derived T cell lines are relatively resistant to anergy and apoptosis. The implications of these findings for the development of autoimmunity, and the possible role of the Fas Ag in determining resistance or susceptibility to tolerance, are discussed.

Animals↗
PubMed1992

T cell surface molecules regulating noncognate B lymphocyte activation. Role of CD2 and LFA-1.

A central event in humoral responses is the Ag-mediated interaction of Th cells and B cells. This interaction leads to the activation of both cell types and results in cytokine secretion by the T cells and proliferation and secretion of Ig by the B cells. The proliferative and differentiative responses of B cells are dependent on contact-mediated signals and cytokines provided by the activated Th cells. Although the role of cytokines in B cell activation and differentiation is understood, the nature of the signals delivered by the activated Th cells and the molecules involved in this process are not known. In this study we have examined Ag-mediated "cognate" T-B cell interactions as well as B cell activation induced by contact with preactivated and fixed Th lymphocytes. Our results indicate that both the T cell surface molecules lymphocyte function associated Ag-1 and CD2 are important in the activation of T cells by Ag presented by B lymphocytes. This indicates that B cells have similar characteristics as other APC. However, once the T cells are activated, contact-mediated stimulation of resting B lymphocytes (the noncognate phase) is dependent on CD2 but not lymphocyte function associated Ag-1. Two lines of evidence indicate this; first, it is inhibited by blocking of CD2 on the T cells and, second, such stimulation is not efficiently mediated by a CD2- Th cell line. Thus, CD2 plays an obligatory role at several discrete stages of T cell-mediated activation of resting B lymphocytes.

Animals↗
PubMed1991

Binding of IL-1 beta to IL-1R type II at single cell level.

To gain information on the possible biologic role of IL-1R type II (IL-1RII), expression of the 68-kDa IL-1 binding protein on human lymphoblastoid B cells was investigated at single cell level. Binding of iodinated IL-1 beta was evaluated by autoradiography on cytosmears of IL-1RII positive B cell lines RAJI, the RAJI clone 1H7, and STS 25. Results obtained suggest an heterogeneity of IL-1RII expression within the B cell population, with only 5 to 16% of the cells able to bind IL-1 beta. Up-regulation of IL-1RII expression by dexamethasone, evident in conventional binding assays, was achieved through both increase in the number of IL-1 binding cells (14-30%) and augmentation of receptor density on positive cells, By combining autoradiography with immunocytochemical staining, it could be shown that about 80% of IL-1RII + cells were negative for Ki67, a nuclear antigen expressed from late G1 to M phase. Cell cycle dependent expression of IL-1RII was confirmed on cells enriched in different phases of the cell cycle by counterflow centrifugal elutriation. It is thus proposed that IL-1RII is associated to the cell cycle.

Antigens, CD↗
PubMed1991

Quantitation of biologically active IL-1 by a sensitive assay based on immobilized human IL-1 receptor type II (IL-1RII).

A rapid and sensitive solid-phase radioassay is described for the quantitative detection of human interleukin-1 (IL-1) based on its capability to bind the nitrocellulose-immobilized IL-1 receptor solubilized from plasma membranes of a subclone of the human B cell lymphoma Raji. The assay can detect human IL-1 beta levels as low as 1 X 10(-11) M, both in physiological buffers and in human plasma. Much lower sensitivity was observed for human IL-1 alpha (3.7 X 10(-9) M) and murine IL-1 beta (2 X 10(-9) M). This assay has the advantage to specifically detect only the correctly folded biologically active IL-1. Simple pretreatment procedure that selectively removes IL-1 beta from samples has been devised so that the ratio of the two IL-1s isoforms in the sample can be precisely determined. This assay represents a fast method for the simultaneous-testing of large numbers of biological samples.

Filtration↗
PubMed1988

In vivo restoration of T cell functions by human IL-1 beta or its 163-171 nonapeptide in immunodepressed mice.

The immunorestorative capacities of human (hu) IL-1 beta or its synthetic fragment 163-171 (VQGEESNDK) were assessed in vivo in mice immunodepressed by aging, sublethal irradiation, or both. Subcutaneous administration of hu rIL-1 beta into immunodepressed animals immediately after carrier (horse red blood cells, HRBC) priming could restore to normal levels Th cell activity. This was measured as the ability of spleen cells from HRBC-primed mice to induce a hapten-specific antibody response in spleen cells from nonimmune mice in vitro stimulated with the hapten-carrier conjugate TNP-HRBC. In parallel, the ability of spleen cells from hu rIL-1 beta-treated immunodepressed animals to produce T cell growth factor activity upon in vitro mitogen stimulation was also increased significantly as compared to that of untreated mice and approached that of immunocompetent controls. The immunorestorative activity of hu rIL-1 beta on Th cell activity and T cell growth factor production could be mimicked by the synthetic nonapeptide 163-171 which, at the doses used, produced in most instances even greater effects than the whole protein. Although the optimal immunorestorative doses of the 163-171 peptide were several orders of magnitude higher than those of hu rIL-1 beta, the complete lack of IL-1-like inflammatory and toxic effects suggests that the synthetic hu IL-1 beta fragment may be successfully used as immunomodulating agent in the therapy of T cell immunodeficiencies.

Adjuvants, Immunologic↗