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Biomedical subjects

Sudhir Gupta

Publications and source records attributed to Sudhir Gupta.

At least 19 recordsLinked to original sources
PubMed2007

Arsenic trioxide induces apoptosis via the mitochondrial pathway by upregulating the expression of Bax and Bim in human B cells.

Arsenic trioxide (As2O3) has been approved for the treatment of acute promyelocytic leukemia (APML) and it is a promising candidate for the treatment of patients with lymphoproliferative disorders, such as relapsed or refractory multiple myeloma and myelodysplastic syndromes. The effects of As2O3 on B cells, specifically which do not express Bcl-2, have not been studied. In this study, we have demonstrated that As2O3, at clinically achievable therapeutic concentrations, induces apoptosis in Bcl-2 negative human B cell line Ramos. As2O3-induced apoptosis is associated with reduced mitochondrial transmembrane potential (delta psi), enhanced generation of intracellular reactive oxygen species (ROS), release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into cytoplasm, activation of caspases, and upregulation of Bax and Bim expression. Exogenous glutathione (GSH) reverses the As2O3-induced apoptosis in a dose-dependent manner. Altogether, these data indicate that As2O3 induces apoptosis in B cells, regardless of Bcl-2 expression, via the mitochondrial pathway by enhancing oxidative stress.

Antineoplastic Agents↗
PubMed2006

Dendritic cells in human aging.

Dendritic cells (DCs) play a critical role in linking innate and adaptive immunity. A role of DCs in immunosenescence and chronic inflammation associated with aging has not been investigated in detail. In this article, we will briefly review DCs biology and changes associated with human aging.

Aging↗
PubMed2006

Thimerosal induces TH2 responses via influencing cytokine secretion by human dendritic cells.

Thimerosal is an organic mercury compound that is used as a preservative in vaccines and pharmaceutical products. Recent studies have shown a TH2-skewing effect of mercury, although the underlying mechanisms have not been identified. In this study, we investigated whether thimerosal can exercise a TH2-promoting effect through modulation of functions of dendritic cells (DC). Thimerosal, in a concentration-dependent manner, inhibited the secretion of LPS-induced proinflammatory cytokines TNF-alpha, IL-6, and IL-12p70 from human monocyte-derived DC. However, the secretion of IL-10 from DC was not affected. These thimerosal-exposed DC induced increased TH2 (IL-5 and IL-13) and decreased TH1 (IFN-gamma) cytokine secretion from the T cells in the absence of additional thimerosal added to the coculture. Thimerosal exposure of DC led to the depletion of intracellular glutathione (GSH), and addition of exogenous GSH to DC abolished the TH2-promoting effect of thimerosal-treated DC, restoring secretion of TNF-alpha, IL-6, and IL-12p70 by DC and IFN-gamma secretion by T cells. These data suggest that modulation of TH2 responses by mercury and thimerosal, in particular, is through depletion of GSH in DC.

Cell Survival↗
PubMed2006

Differential sensitivity of naïve and memory subsets of human CD8+ T cells to TNF-alpha-induced apoptosis.

In this investigation, we have examined the relative sensitivity of human naïve, central memory (T(CM)), and two types of effector memory CD8+ T cells (T(EM) and T(EMRA)) to TNF-alpha-induced apoptosis. Our data show that naïve and T(CM) CD8+ T cells were sensitive, whereas T(EM) and T(EMRA) CD8+ T cells were relatively resistant to TNF-alpha-induced apoptosis. The apoptosis profile correlated with the activation of caspase-8 and caspase-3. However, no correlation was observed between relative sensitivity of four CD8+ T cell subsets to apoptosis and the expression of TNFR-I or TNFR-II. T(EM) and T(EMRA) CD8+ T cells displayed increased phosphorylation of IKKalpha/beta and IkappaB and increased NF-kappaB activity as compared to naïve and T(CM) CD8+ T cells. Bcl-2, Bcl-x(L) and FLIP(L) expression was higher and Bax expression was lower in T(EM) and T(EMRA) CD8+ T cells as compared to naïve and T(CM) CD8+ T cells. These data suggest that signaling molecules downstream of TNFRs may be responsible for differential sensitivity among subsets of CD8+ T cells to TNF-alpha-induced apoptosis.

Adult↗
PubMed2006

A paradox of immunodeficiency and inflammation in human aging: lessons learned from apoptosis.

Aging is associated with a paradox of immunodeficiency and inflammation (an evidence of hyperactive immune system). Apoptosis is associated with cellular depletion and suppression of inflammatory response. In this brief review, we will present evidence for the role of increased apoptosis in immunodeficiency and paradoxical increased inflammation associated with human aging. In particular, a role of apoptotic cells in failure to generate anti-inflammatory responses and directly activating inflammatory responses will be discussed.

Journal Article↗
PubMed2006

Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home.

The lifelong IgG replacement therapy for patients with primary immunedeficiencies (PIDD) may be provided by intravenous (IVIG) or by subcutaneous IgG (SCIG) infusions. We investigated the impact of weekly SCIG self-infusions at home on the health-related quality of life, treatment satisfaction, and preferences in patients treated with IVIG at the hospital/doctor's office (Group A) or at home (Group B) before the study started. Forty-four adult North American PIDD patients were included in the study, 28 patients in Group A and 16 in Group B. Patients in Group A reported significantly less limitations with their work/daily activities, a significantly improved vitality, and better general health. Treatment satisfaction was significantly improved in Group A. The preference for the subcutaneous route and for home therapy was respectively 81% and 90% in Group A. In Group B, 69% preferred the subcutaneous route and 92% home therapy.

Adult↗
PubMed2006

Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases.

Intravenous immunoglobulin (IVIg) infusions at 3-4 week intervals are currently standard therapy in the United States for patients with primary immune deficiency diseases (PIDD). To evaluate alternative modes of immunoglobulin administration we have designed an open-label study to investigate the efficacy and safety of a subcutaneously administered immunoglobulin preparation (16% IgG) in patients with PIDD. After their final IVIg infusion, 65 patients entered a 3-month, wash-in/wash-out phase, designed to bring patients to steady-state with subcutaneously administered immunoglobulin. This was followed by 12 months of weekly SCIg infusions, at a dose determined in a pharmacokinetic substudy to provide noninferior intravascular exposure. This resulted in a mean weekly dose of 158 mg/kg, calculated to equal 137% of the previous intravenous dose. Two patients (4%) each reported 1 serious bacterial infection (pneumonia), an annual rate of 0.04 per patient-year. There were 4.43 infections of any type per patient-year. Mean trough serum IgG levels increased from 786 to 1040 mg/dL during the study, a mean increase of 39%. The most frequent treatment-related adverse event was infusion-site reaction, reported by 91% of patients; this was predominantly mild or moderate, and the incidence decreased over time. No treatment-related serious adverse events were reported. We conclude that subcutaneous administration of 16% SCIg is a safe and effective alternative to IVIg for replacement therapy of PIDD.

Adolescent↗
PubMed2005

TNF-alpha-induced apoptosis in human naïve and memory CD8+ T cells in aged humans.

Recently, human CD8+ T cells have been divided into naïve, central memory (T(CM)), and two types of effector memory cells (T(EM) and T(EMRA)), which are phenotypically identified by a set of cell surface molecules. In this investigation, we have compared the relative sensitivity of these subsets to TNF-alpha-induced apoptosis in young and aged humans. Our data show increased sensitivity of naïve and T(CM) CD8+ T cells from aged humans to TNF-alpha-induced apoptosis as compared to young subjects. Both T(EM) and T(EMRA) CD8+ T cells from young and aged subjects were relatively resistant to TNF-alpha-induced apoptosis and no significant difference was observed between young and aged subjects. Increased apoptosis of naïve and T(CM) CD8+ T cells in aged humans was associated with increased activation of caspase-8 and caspase-3 as compared to young subjects. There was no difference in the expression of TNFR-I or TNFR-II on any of the four subpopulations of CD8+ T cells between young and aged subjects. These data suggest that increased TNF-alpha-induced apoptosis of naïve and T(CM) CD8+ T cells may play a role in the deficiency of naïve and T(CM) CD8+ T cells in human aging. However, apoptosis does not appear to play a major role in increased accumulation of effector memory CD8+ T cells during human aging.

Adult↗
PubMed2005

Molecular mechanisms of TNF-alpha-induced apoptosis in naïve and memory T cell subsets.

Aging in humans is associated with progressive decline in T cell function, hyperimmunoglobulinemia, increased prevalence of autoantibodies and decline in naïve CD8(+) T cells and accumulation of memory T cells, which appears to be oligoclonal and display feature of senescence, that is, decreased replication, short telomere length and resistance to apoptosis. Recently memory T cells have been further subdivided into central and effector memory T cells, based upon their migratory and homing properties. They are identified by a number of cell surface makers. In this brief review we will discuss molecular mechanisms of apoptosis in naïve and various types of memory T cells to possibly explain the changes observed in aging, which are very similar to certain autoimmune diseases.

Aging↗
PubMed2005

Life and death of lymphocytes: a role in immunesenescence.

Human aging is associated with progressive decline in immune functions, increased frequency of infections. Among immune functions, a decline in T cell functions during aging predominates. In this review, we will discuss the molecular signaling in two major pathways of apoptosis, namely death receptor pathway and mitochondrial pathway, and their alterations in both T and B lymphocytes in human aging with a special emphasis on naïve and different memory subsets of CD8+ T cells. We will also discuss a possible role of lymphocyte apoptosis in immune senescence.

Journal Article↗
PubMed2005

Axon reactive B cells clonally expanded in the cerebrospinal fluid of patients with multiple sclerosis.

Demyelination and axonal loss have been described as the histological hallmarks of inflammatory lesions of multiple sclerosis (MS) and are the pathological correlates of persistent disability. However, the immune mechanisms underlying axonal damage in MS remain unknown. Here, we report the use of single chain-variable domain fragments (scFv) from clonally expanded cerebrospinal fluid (CSF) B cells to show the role of an anti-axon immune response in the central nervous system (CNS) in MS. The cellular and subcellular distribution of the antigen(s) recognized by these CSF-derived clonal scFv antibodies (CSFC-scFv Abs) was studied by immunochemical staining of brain tissues obtained at autopsy from patients with MS. Immunochemistry showed specific binding of CSFC-scFv Abs to axons in acute MS lesions. The stained axons showed three major types of axonal pathological changes: 1) linear axons, axonal ovoid formation, and axonal transection were seen in the myelinated white matter adjacent to the lesion; 2) accumulation of axonal ovoid formations and Wallerian degeneration were seen at the border between demyelinated lesions and the adjacent white matter; and 3) Wallerian degeneration occurred at the center and edge of acute demyelinated lesions. These findings suggest a B cell axonal specific immune response in the CNS in MS.

Antigens↗
PubMed2005

Molecular mechanisms of TNF-alpha-induced apoptosis in aging human T cell subsets.

TNF-alpha, a pro-inflammatory cytokine, exerts its biological activity by signaling via its two receptors, TNFR-1 and TNFR-2 and by activating NF-kappaB. NF-kappaB is essential for survival of many cell types; however, TNF-alpha also induces cell death. During human aging TNF-alpha production and TNF-alpha-induced apoptosis are increased. In this brief review, we will discuss the TNF-alpha-mediated signaling and various molecular mechanisms underlying increased apoptosis in T cell subsets in aged humans with a special reference to alterations in transcription factor NF-kappaB and Fas-associated death domain (FADD).

Aged↗
PubMed2005

Molecular mechanisms of apoptosis in the cells of the immune system in human aging.

Aging is associated with progressive decline in immune functions and increased frequency of infections, autoimmunity, and cancer. Among immune functions, a decline in T-cell functions during aging predominates. In this review, I discuss the molecular signaling of three distinct pathways of apoptosis, namely the death receptor pathway, the mitochondrial pathway, and the most recently described endoplasmic reticulum stress pathway, and the relative sensitivity of naive, central memory, and effector memory CD8(+) T-cell subsets to apoptosis. In addition, I review apoptosis, especially via death receptor pathway, in naive and various memory subsets of CD4(+) and CD8(+) T cells (with primary emphasis on CD8(+) naive and memory subsets) in human aging and discuss the role of apoptosis in immune senescence.

Aging↗
PubMed2005

Central memory and effector memory subsets of human CD4(+) and CD8(+) T cells display differential sensitivity to TNF-{alpha}-induced apoptosis.

Upon activation by antigen, naive T cell subsets undergo proliferation and differentiation into effector cells, followed by the generation of a pool of memory T cells. Based upon migration pattern and functions, they are classified into central memory (predominantly homing to the lymph nodes) and effector memory (predominantly homing to extralymphoid sites) subsets. These subsets are defined phenotypically by a set of cell surface molecules. In this investigation, we demonstrate that naive and central memory CD4(+) and CD8(+) T cells in humans undergo tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis, whereas effector memory CD4(+) and CD8(+) T cells are relatively resistant to TNF-alpha-induced apoptosis. We also provide evidence for the molecular mechanisms underlying the differential sensitivity of naive and different sets of memory T cells to TNF-alpha-induced apoptosis.

Adolescent↗
PubMed2005

The primary vasculitides: a clinicopathologic correlation.

Primary vasculitis is the inflammation and necrosis of vessel walls not associated with infections, drugs, and autoimmune and lymphoproliferative disorders. It is important to make the correct diagnosis of different types of vasculitis, as their prognosis may be significantly different. Classification of vasculitis based on the size of the vessel is helpful, but there is often an overlap. Whereas the criteria proposed by the American College of Rheumatology are primarily clinical, the definitions set forth by the Chapel Hill Consensus Conference are based only on histologic observations. Correct diagnosis requires appropriate incorporation of the clinical history, laboratory parameters, and the histologic data. Incorporation of antineutrophil cytoplasmic antibodies in defining the pathogenesis of vasculitis has been particularly useful in diagnosing those small vessel vasculitides that are life threatening and need immediate intervention.

Algorithms↗
PubMed2005

Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria.

There is a worldwide increasing concern over the neurological risks of thimerosal (ethylmercury thiosalicylate) which is an organic mercury compound that is commonly used as an antimicrobial preservative. In this study, we show that thimerosal, at nanomolar concentrations, induces neuronal cell death through the mitochondrial pathway. Thimerosal, in a concentration- and time-dependent manner, decreased cell viability as assessed by calcein-ethidium staining and caused apoptosis detected by Hoechst 33258 dye. Thimerosal-induced apoptosis was associated with depolarization of mitochondrial membrane, generation of reactive oxygen species, and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol. Although thimerosal did not affect cellular expression of Bax at the protein level, we observed translocation of Bax from cytosol to mitochondria. Finally, caspase-9 and caspase-3 were activated in the absence of caspase-8 activation. Our data suggest that thimerosal causes apoptosis in neuroblastoma cells by changing the mitochondrial microenvironment.

Animals↗