Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common cytokine receptor gamma chain (gammac), a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. The cytoplasmic domain of gammac consists of 85 aa, in which the carboxyl-terminal 48 aa are essential for its interaction with and activation of the Janus kinase, Jak3. Evidence has been provided that Jak3-independent signals might be transmitted via the residual membrane-proximal region; however, its role in vivo remains totally unknown. In the present study, we expressed mutant forms of gammac, which lack either most of the cytoplasmic domain or only the membrane-distal Jak3-binding region, on a gammac null background. We demonstrate that, unlike gammac or Jak3 null mice, expression of the latter, but not the former mutant, restores T lymphopoiesis in vivo, accompanied by strong expression of Bcl-2. On the other hand, the in vitro functions of the restored T cells still remained impaired. These results not only reveal the hitherto unknown role of the gammac membrane-proximal region, but also suggest the differential requirement of the cytoplasmic subregions of gammac in T cell development and function.
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PMID:Differential requirement of the cytoplasmic subregions of gamma c chain in T cell development and function. 1096 26

Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private alpha-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor beta- and gamma-chains. The gamma-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the gamma-chain is called the common gamma or gamma-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the gamma-c expression. Decreased gamma-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.
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PMID:IL-15 and IL-2: a matter of life and death for T cells in vivo. 1113 25

Combined antiretroviral treatment in some human immunodeficiency virus-infected persons does not lead to a rapid increase in CD4 cell counts, and these patients may remain susceptible to opportunistic infections. A group of 13 patients with CD4 cell counts <200 cells/mm3 after > or =9 months of combined antiretroviral treatment received interleukin (IL)-2 immunotherapy (4.5x106 IU twice daily for 5 days every 6 weeks). After only 3 cycles, their CD4 cell counts increased from 123 cells/mm3 (range, 104-134 cells/mm3) to 229 cells/mm3 (range, 176-244 cells/mm3). A marked increase was noted in the naive CD45RA subpopulation of CD4 T lymphocytes. Furthermore, the magnitude of the CD4 cell count response correlated with the baseline expression levels of the antiapoptotic molecule Bcl-2. This study demonstrates that IL-2 immunotherapy can accelerate the recovery of CD4 lymphocytes in persons whose CD4 cell counts fail to increase rapidly in response to combined antiretroviral treatment.
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PMID:Rapid effect of interleukin-2 therapy in human immunodeficiency virus-infected patients whose CD4 cell counts increase only slightly in response to combined antiretroviral treatment. 1118 Nov 49

A recent clinical trial of gene therapy for X-linked severe combined immunodeficiency (XSCID) has shown that retroviral-mediated gene correction of bone marrow stem cells can lead to the development of normal immune function. These exciting results have been preceded by successful immune reconstitution in several XSCID mouse models, all carrying null mutations of the common gamma chain (gamma(c)). One question not formally addressed by these previous studies is that of possible dominant-negative effects of the endogenous mutant gamma(c) protein on the activity of the wild-type transferred gene product. The present work was therefore undertaken to study whether corrective gene transfer was applicable to an XSCID murine model with preserved expression of a truncated gammac molecule (Deltagamma(c+)-XSCID). Gene correction of Deltagamma(c+)-XSCID mice resulted in the reconstitution of lymphoid development, and preferential repopulation of lymphoid organs by gene-corrected cells demonstrated the selective advantage of gamma(c)-expressing cells in vivo. Newly developed B cells showed normalization of lipopolysaccharide-mediated proliferation and interleukin-4 (IL-4)-induced immunoglobulin G1 isotype switching. Splenic T cells and thymocytes of treated animals proliferated normally to mitogens and responded to the addition of IL-2, IL-4, and IL-7, indicating functional reconstitution of gammac-sharing receptors. Repopulated thymi showed a clear increase of CD4-/CD8- and CD8+ fractions, both dramatically reduced in untreated Deltagamma(c+)-XSCID mice. These improvements were associated with the restoration of Bcl-2 expression levels and enhanced cell survival. These data indicate that residual expression of the endogenous truncated gamma(c) did not lead to dominant-negative effects in this murine model and suggest that patient selection may not be strictly necessary for gene therapy of XSCID.
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PMID:Lack of dominant-negative effects of a truncated gamma(c) on retroviral-mediated gene correction of immunodeficient mice. 1123

Transgenic mice were created in which a sheep keratin promoter directed the expression of IL-2 into the dermis. These KIL-2 transgenic mice were used to investigate the effects of localized IL-2 dysregulation on immune responses. Peripheral tolerance to skin antigens was not broken by in situ IL-2 expression because syngeneic KIL-2 skin grafts were not rejected. However, MHC Class I-disparate skin grafts from KIL-2 donors were rejected faster (median survival time (MST) 12 days) than grafts of non-transgenic littermate skin (MST 18 days). In contrast, the kinetics of KIL-2 H-Y-disparate skin graft rejection (MST 14 days) did not differ significantly from controls (MST 16 days), suggesting that upregulation of IL-2 at the effector site could affect CD4+ T cell- independent, but not CD4+ T cell-dependent, responses. No effect on rejection kinetics was observed when wild type allogeneic skin was grafted onto transgenic mice that expressed bcl2 constitutively in their lymphocytes (MST of 14 days, both sets), indicating that this was not simply due to increased longevity of T cells within the IL-2 expressing graft. We therefore suggest that aberrant expression of IL-2 can accelerate helper-independent CD8+ T cell responses by increasing proliferation and/or differentiation of cytolytic T cells at the effector site.
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PMID:Effect of localized cytokine dysregulation: accelerated rejection of IL-2-expressing skin grafts. 1126 5

Both faulty regulation of apoptosis and the inappropriate expression of several interleukins have been considered important defects of lymphocytes in the human autoimmune disease systemic lupus erythematosus (SLE). We therefore tested the in vitro effect of recombinant interleukin (IL-)-2, 4, 7, and 15 on peripheral blood mononuclear cells from patients with SLE and from healthy volunteers. Intracellular Bcl-2 and Bax expression was measured by fluorocytometry and the rate of apoptosis was determined by the TUNEL technique and propidium iodide staining. IL-2, IL-4, IL-7 and IL-15 led to a significant increase in Bcl-2 and a reduction in cell death rates, which was even more pronounced in SLE. Bax levels remained unchanged. Interestingly, the high ex vivo Bcl-2 content of lymphocytes from some SLE patients was maintained after growth factor withdrawal. Anti-apoptotic cytokine signaling may significantly influence the deregulation of cell death in SLE lymphocytes.
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PMID:Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus. 1127 43

The treatment of sepsis and septic shock remains a clinical conundrum, and recent prospective trials with biological response modifiers aimed at the inflammatory response have shown only modest clinical benefit. Recently, interest has shifted toward therapies aimed at reversing the accompanying periods of immune suppression. Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy, and organ system dysfunction. During sepsis syndromes, lymphocyte apoptosis can be triggered by the absence of IL-2 or by the release of glucocorticoids, granzymes, or the so-called 'death' cytokines: tumor necrosis factor alpha or Fas ligand. Apoptosis proceeds via auto-activation of cytosolic and/or mitochondrial caspases, which can be influenced by the pro- and anti-apoptotic members of the Bcl-2 family. In experimental animals, not only can treatment with inhibitors of apoptosis prevent lymphoid cell apoptosis; it may also improve outcome. Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of lymphocyte apoptosis represents an attractive therapeutic target for the septic patient.
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PMID:Apoptosis in sepsis: a new target for therapeutic exploration. 1129 47

Anergic/suppressive CD4(+)CD25(+) T cells exist in animal models but their presence has not yet been demonstrated in humans. We have identified and characterized a human CD4(+)CD25(+) T cell subset, which constitutes 7-10 % of CD4(+) T cells in peripheral blood and tonsil. These cells are a CD45RO(+)CD45RB(low) highly differentiated primed T cell population that is anergic to stimulation. Depletion of this small subset from CD4(+) T cells significantly enhances proliferation by threefold in the remaining CD4(+)CD25(-) T cells, while the addition of isolated CD4(+)CD25(+) T cells to CD4(+)CD25(-) T cells significantly inhibits proliferative activity. Blocking experiments suggest that suppression is not mediated via IL-4, IL-10 or TGF-beta and is cell-contact dependent. Isolated CD4(+)CD25(+) T cells are susceptible to apoptosis that is associated with low Bcl-2 expression, but this death can be prevented by IL-2 or fibroblast-secreted IFN-beta. However, the anergic/suppressive state of these cells is maintained after cytokine rescue. These human regulatory cells are therefore a naturally occurring, highly suppressive, apoptosis-prone population which are at a late stage of differentiation. Further studies into their role in normal and pathological situations in humans are clearly essential.
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PMID:Human anergic/suppressive CD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population. 1129 37

B-cell chronic lymphocytic leukemia (CLL) is characterized by profound immune dysfunction and a marked resistance to apoptosis. Understanding the cellular biology of immune effector cells from CLL patients as well as leukemic target cells is essential to developing immune mediated therapeutic strategies for CLL. In this study, an immortal CLL cell line called WSU-CLL has been used to study the characteristics of B-cell CLL as a tumor target for natural killer (NK), activated natural killer, and lymphokine activated killer (LAK) cells. The WSU-CLL cells were significantly less (p<0.001) susceptible to NK cell mediated cytotoxicity compared to K562, a standard tumor target cell line. In vitro activation of effector cells with either short term, low dose IL-2 or long term, high dose IL-2 significantly increased the susceptibility of CLL cells for cell mediated killing. The addition of CD1a+/CD3-/CD4+/CD80+/CD83+ dendritic cells derived from human umbilical cord blood increased the cytotoxicity of LAK cells against WSU-CLL. There is an increased expression of Bcl-2 and decreased expression of Fas on WSU-CLL cells as determined by RT-PCR techniques indicating possible roles for these genes in exerting resistance to immune cell mediated lysis. When Bcl-2 expression was downregulated in WSU-CLL cells using gene specific antisense oligonucleotides, the susceptibility of WSU-CLL cells to the cytotoxicity of chemotherapeutic agent Fludarabine was increased. Thus, our results suggest that in vitro activation with cytokines, addition of accessory cell populations such as dendritic cells and/or manipulation of key gene expression i.e. down regulation of Bcl-2 might be potential strategies to increase the antitumor cytotoxicity against CLL cells.
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PMID:Increased cytotoxicity against B-chronic lymphocytic leukemia by cellular manipulations: potentials for therapeutic use. 1134 40

We transferred naive alloreactive CD8 T cells from TCR transgenic mice to irradiated recipients expressing a partial (H-2Kbm8) or a full (H-2Kb) agonist alloantigen (alloAg). The consequences were strikingly distinct, resulting in acceleration of host lymphopoiesis in the former group, but in strong graft-vs-host reaction, preventing host lymphocyte reconstitution in the latter group. This was correlated, respectively, with long-term persistence and with rapid disappearance of the transferred CD8 T cells. Analysis of transferred T cells showed that initial T cell expansion and modulation of expression of activation markers CD44 and CD62L, as well as induction of cytotoxic function, were similar in both groups. However, IL-2 production and subsequent up-regulation of CD25, early perforin-independent cytolysis, and early down-regulation of Bcl-2 expression were detected only in T cells transferred in hosts expressing full agonist alloAg. Expansion of transferred CD8 T cells was not dependent on either IL-2 or CD25 expression. This expansion could lead to either accelerated host reconstitution or to strong graft-vs-host, depending on the nature of the alloAg. Thus, the extent of Ag stimulation may be a crucial parameter in protocols of alloreactive T cell immunotherapy.
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PMID:Differential survival of transferred CD8 T cells and host reconstitution depending on TCR avidity for host-expressed alloantigen. 1139 Apr 68


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