Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.79 (granzyme B)
 3,301 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allogeneic haematopoietic stem cell transplantation (SCT) has emerged as a curative therapeutic option. However, the role of graft-versus-host disease in lung injury after SCT has yet to be determined. In the present study, primary bronchial epithelial cells and the bronchial epithelial cell line BEAS-2B were used to investigate immune responses of allogeneic CD8+ T-cells directed against respiratory epithelial cells. Following stimulation with irradiated bronchial epithelial cells, CD8+ T-cells produced significant amounts of interferon-gamma, upregulated alloantigen activation markers and proliferated highly compared with T-cells stimulated with interleukin-2 alone. Furthermore, cytotoxicity assays demonstrated that bronchial epithelial cell-specific and granzyme B-mediated cytolytic activity was induced in CD8+ T-cells. Generation of natural killer (NK) T-cells, NK-like T-cells, cytokine-induced killer cells or lymphokine-activated killer cells could be excluded by phenotyping, culture conditions and neglectable lytic activity following stimulation with interleukin-2 alone. Inhibition experiments showed that lysis of bronchial epithelial cells was not major histocompatibility complex-I restricted, but depended on NK group 2 member D signalling; a stimulatory receptor initially shown to be expressed on NK cells. The present data imply that the respiratory epithelium has an antigen presenting function and directly alloactivates cytotoxic CD8+ T-cells that show nonclassical effector function.
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PMID:NKG2D-dependent effector function of bronchial epithelium-activated alloreactive T-cells. 1841 14

Chemokines and their receptors play an important role in the development of allograft rejection through directing mononuclear cell invasion of the graft. To study whether chemokine assays in the urine could prove to be predictive of acute rejection, we measured the urinary excretion of several chemokines, including fractalkine, chemokine monokine induced by interferon-gamma, interferon-gamma-inducible protein 10, macrophage inflammatory protein-3 alpha, granzyme B, and perforin in 215 allograft recipients and in 80 healthy control subjects. The 67 patients with acute rejection had significantly higher levels of all urinary chemokines compared to the healthy controls or patients having chronic allograft nephropathy but with stable renal function. Only changes in urinary fractalkine differentiated patients with acute rejection from those with acute tubular necrosis. The 7 patients who lost their grafts had greater urinary fractalkine, interferon-gamma, and macrophage inflammatory protein-3 alpha concentrations than those patients with reversible acute rejection. The area under the receiver operating characteristic curve for fractalkine was the best indicator among all of the markers differentiating 39 patients diagnosed with steroid-resistant from the 28 patients with steroid-sensitive acute rejection and in predicting graft loss. Our study shows that measuring urinary fractalkine levels is a noninvasive approach for detecting acute rejection where high levels were associated with steroid-resistance and poor outcome.
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PMID:Urinary fractalkine is a marker of acute rejection. 1880 27

One major limitation of UCBT is the lack of donor cells available for posttransplantation donor leukocyte infusions (DLI) to boost immunity or induce graft-versus-leukemia (GVL) activity. Starting from a approximately 5% fraction of a UCB graft, we report the feasibility and biological characteristics of ex vivo expansion of frozen/thawed CB T cells by anti-CD3 and anti-CD28 antibody-coated Dynal beads in the presence of interleukin (IL)-2. We postulated that while undergoing expansion, UCB T cells may mature toward a Th1/Tc1 phenotype and acquire the potential for cytotoxicity. Whereas an almost 2-log expansion also led to the acquisition of IL-12Ralpha and an increase in Th1 characteristics, postexpansion lymphocytes produced less interferon-gamma, tumor necrosis factor-alpha, and granzyme B; stored almost no perforin; and lacked cytotoxicity against allogeneic targets. Collectively, these suggest relative safety from acute/hyperacute graft-versus-host disease. CD8(+) T cells expanded preferentially, whereas a higher rate of apoptosis in CD4(+) T cells also promoted an inverted CD4/CD8 ratio. Most expanded T cells retained expression of CD27, CD28, and L-selectin but down-regulated CCR-7. In summary, UCB T cell proliferation sustained by CD3/CD28 co-stimulatory beads and IL-2 can lead to clinically relevant doses of DLI from a very small fraction of the UCB graft, although future strategies to reduce apoptosis may enhance their clinical potential.
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PMID:Ex vivo expansion and Th1/Tc1 maturation of umbilical cord blood T cells by CD3/CD28 costimulation. 1880 50

Reactivation of herpes simplex virus type 1 (HSV-1) from neuronal latency is a common and potentially devastating cause of disease worldwide. CD8+ T cells can completely inhibit HSV reactivation in mice, with interferon-gamma affording a portion of this protection. We found that CD8+ T cell lytic granules are also required for the maintenance of neuronal latency both in vivo and in ex vivo ganglia cultures and that their directed release to the junction with neurons in latently infected ganglia did not induce neuronal apoptosis. Here, we describe a nonlethal mechanism of viral inactivation in which the lytic granule component, granzyme B, degrades the HSV-1 immediate early protein, ICP4, which is essential for further viral gene expression.
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PMID:Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. 1884 57

Natural killer (NK) cells play a crucial role in innate immunity as effectors against tumor and pathogen-infected cells. NK-mediated host defense against tumor cells is strongly impaired in patients with head and neck squamous cell carcinoma (HNSCC). Tumor secretion of various immune suppressive mediators contributes to massively compromised immune functions. Herein we demonstrate that NK cell cytotoxicity against tumor cells of HNSCC can be efficiently stimulated by single-stranded immunostimulatory RNA (ss-isRNA). Stimulation with ss-isRNA results in an increased production of interferon-gamma and effector proteins perforin and granzyme B. Our investigations revealed that supernatants of permanent HNSCC cell lines negatively affect the ss-isRNA-triggered stimulation of cytolytic NK cell functions. Stimulation of cytotoxicity requires toll-like receptor 7 (TLR7). Increased expression of NK cell TLR7 was shown in response to ss-isRNA. These results suggest ss-isRNA as a potential immunostimulatory tool of human NK cells against HNSCC.
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PMID:Up-regulation of NK cell function against head and neck cancer in response to ss-isRNA requires TLR7. 1894 62

How CD4-CD8 differentiation is maintained in mature T cells is largely unknown. The present study has examined the role in this process of the zinc finger protein Zbtb7b, a critical factor for the commitment of MHC II-restricted thymocytes to the CD4+ lineage. We showed that Zbtb7b acted in peripheral CD4+ T cells to suppress CD8-lineage gene expression, including that of CD8 and cytotoxic effector genes perforin and Granzyme B, and was important for the proper repression of interferon-gamma (IFN-gamma) during effector differentiation. The inappropriate expression of IFN-gamma by Zbtb7b-deficient CD4+ T cells required the activities of Eomesodermin and Runx transcription factors. Runx activity was needed for Granzyme B expression, indicating that Runx proteins control expression of the cytotoxic program. We conclude that a key function of Zbtb7b in the mature CD4+ T cell compartment is to repress CD8-lineage gene expression.
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PMID:The zinc finger transcription factor Zbtb7b represses CD8-lineage gene expression in peripheral CD4+ T cells. 1906 19

Induction of liver allograft immunological tolerance was performed in rats by intramuscular injection of recombinant adeno-associated virus-human cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin (rAAV-hCTLA4Ig). Dark Agouti and Lewis rats were liver allograft donors and recipients, respectively, in four groups: (A) syngeneic control, (B) blank control, (C) rAAV-enhanced green fluorescent protein negative control, (D) rAAV-hCTLA4Ig. Gene transfers occurred 6 weeks before transplantation. Group D had a significantly longer liver graft survival time (> 100 days) than groups B (11.9 +/- 1.3 days) and C (11.6 +/- 1.1 days). Groups B and C showed severe rejection responses and large amounts of CD4(+) and CD8(+) T-lymphocyte infiltration, while only a mild response and few T-lymphocytes were observed in group D. There were no significant differences in interleukin-2 and interferon-gamma levels in liver grafts between groups D and C, but there were significant decreases in granzyme B and lymphotoxin beta levels in group D compared with group C. It is concluded that immunological tolerance to liver allograft could be achieved by gene transfer of rAAV-hCTLA4Ig through intramuscular injection.
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PMID:Induced liver allograft immunological tolerance in rats by intramuscular injection of recombinant adeno-associated virus-human cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin (rAAV-hCTLA4Ig). 1921 73

Pathogenetic mechanisms leading to chronic obstructive pulmonary disease (COPD) remain poorly understood. Because clonogenic T cells (CD4(+)CD28(null)) were shown to be increased in autoimmune diseases we hypothesized that CD4(+)CD28(null) T cells play a role in COPD. Here we describe that enhanced presence of CD4(+)CD28(null) cells is associated with impaired lung function. Sixty-four patients and controls were included. T cell phenotype was analysed using flow cytometry. Enzyme-linked immunosorbent assays were utilized to determine cytokines. Statistical evaluations were performed using non-parametric group comparisons and correlations. A logistic regression model was used to determine predictive values of CD4(+)CD28(null) in the diagnosis of COPD. Populations of CD4(+) T cells lacking surface co-stimulatory CD28 were enlarged significantly in evaluated patients when compared with controls. Natural killer (NK)-like T cell receptors (CD94, 158) and intracellular perforin, granzyme B were increased in CD4(+)CD28(null) cells. Cytokine production after triggering of peripheral blood mononuclear cells (PBMCs) was elevated in patients at early disease stages. Receiver operating characteristic curve plotting revealed that presence of CD4(+)CD28(null) T cells has a diagnostic value. These CD4(+)CD28(null) T cells show increased expression of NK-like T cell receptors (CD94, 158) and intracellular perforin and granzyme B. Furthermore, triggering of PBMCs obtained from patients with mild COPD led to increased interferon-gamma and tumour necrosis factor-alpha production in vitro compared with controls. Our finding of increased CD4(+)CD28(null) T cells in COPD indicates that chronic antigen exposure, e.g. through contents of smoke, leads to loss of CD28 and up-regulation of NK cell receptors expression on T cells in susceptible patients.
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PMID:T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease. 1922 Aug 36

Nonimmediate allergic reactions (NIRs) to drugs, which are the most common reactions induced by specific immunologic mechanisms, can be induced by all commercially available drugs. NIRs can appear hours, days, or even weeks after drug intake. They elicit a spectrum of manifestations, mostly affecting the skin, ranging from maculopapular exanthema and urticaria to other less common but more severe entities such as acute generalized exanthematic pustulosis, drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The main pathologic event involved in NIRs is a T-cell effector response and the wide heterogeneity of clinical symptoms may reflect differences in the underlying immunologic mechanisms. Despite their clinical heterogeneity, NIRs share certain aspects such as the activation of T cells with increased expression of CD25 and HLA-DR. NIRs are classified as type 1 helper (T(H)1) T-cell responses, characterized by the production of interferon-gamma, tumor necrosis factor-alpha, interleukin 2, T-bet, and the cytotoxic markers perforin and granzyme B. Diagnosis is often complicated because of the difficulty of obtaining a reliable clinical history, the important role played by cofactors such as viral diseases, and the low sensitivity of skin tests and in vitro tests. Further studies are thus required in order to improve our understanding of NIRs and refine our diagnostic criteria.
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PMID:Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. 1947 12

Patients with oral squamous cell carcinoma (OSCC) have severe defects in antitumor immune function. Endothelial cells are potential regulators of immune cell function and have therefore been examined to determine their role in tumor-induced immune suppression. The present studies demonstrated that supernatants from endothelial cells exposed to OSCC-conditioned media (endo(OSCC-sup)) exhibited elevated levels of the immune suppressive products prostaglandin E(2) (PGE(2)) and vascular endothelial growth factor (VEGF) compared with supernatants from endothelial cells treated with medium alone (endo(medium)) or with keratinocyte-conditioned medium (endo(ker-sup)). Antibody neutralization of OSCC-derived VEGF prevented tumor-conditioned media from inducing endothelial cells to increase production of PGE(2)and VEGF. Furthermore, treatment of T-cells with supernatants from endo(OSCC-sup) resulted in diminished T-cell proliferation and decreased interferon-gamma (IFN-gamma) production compared with T-cells treated with medium or supernatants from endo(medium) or endo(ker-sup) controls. T-cell levels of granzyme B and perforin were reduced after treatment with supernatant from endo(OSCC-sup) compared with control treatments. The addition of VEGF neutralizing antibody to the OSCC-conditioned medium prevented endothelial cells from being skewed to downregulate T-cell proliferation and production of IFN-gamma, perforin, and granzyme B. Taken together, these studies provide support for the use of VEGF-targeting therapies as an immunotherapeutic agent to block induction of immune suppressive endothelial cells in patients with OSCC.
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PMID:Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions. 1948 Aug 53


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