We have recently shown that cyclosporin A (CsA) reverses pleiotropic drug resistance in human acu... more We have recently shown that cyclosporin A (CsA) reverses pleiotropic drug resistance in human acute lymphatic leukemia in vitro and daunorubicin resistance in Ehrlich ascites tumor in vivo. In the present study we examined the mechanisms by which CsA might reverse pleiotropic drug resistance relative to changes in cellular plasma membrane potentials and intracellular calcium ([Ca2+]i). Membrane potentials were measured with DIOC5 dye flow-cytometrically and [Ca2+]i levels with Quin 2 dye spectrofluorimetrically. All pleiotropic (PDR) drug-resistant tumor sublines had decreased membrane potentials (membrane depolarized) compared with their corresponding drug-sensitive parental tumors. In comparison, the membrane potentials of a control antimetabolite-resistant acute leukemia cell line were unchanged. The basal levels of [Ca2+]i in the PDR sublines were variable compared with those of parental drug-sensitive cell lines. Incubation of all PDR tumor sublines with CsA or verapamil resulted in the restoration of membrane potentials to that characteristic of the corresponding drug-sensitive parental tumor. Cyclosporin A produced variable changes in the levels of [Ca2+]i. These data suggest that alteration of membrane potentials is one of the mechanisms responsible for pleiotropic drug resistance in malignancy and show that this alteration is corrected by CsA and verapamil.
Thirty-nine children with ALL who had completed three years of chemotherapy were randomized to re... more Thirty-nine children with ALL who had completed three years of chemotherapy were randomized to receive oral BCG for immunotherapy or no treatment as controls. There was not a significant difference between the two groups in the relapse rate. Among the immune parameters, only in vitro blastogenic responses to PHA and PPD rose significantly in the BCG group compared with the controls. Skin testing also revealed evidence of tuberculin sensitization. The group as a whole was studied for the kinetic recovery of immune functions after the cessation of chemotherapy, which revealed a dissociation in both cellular and humoral systems. At three weeks after therapy, only peripheral blood lymphocyte count, non T-cells, and serum IgM showed a significant abnormality. There was a rise in these parameters in the subsequent weeks, and the non-T-cell count reached normal levels sooner than the other two parameters. Children who were less than 5 years of age at the time of diagnosis showed a lesser degree of immunosuppression after long-term chemotherapy compared with those who were greater than or equal to 5 years of age. The analysis of the data indicated a relationship between the low serum immunoglobulins (IgG, IgA) and disease status.
Aging in humans is associated with progressive decline in T cell function, hyperimmunoglobulinemi... more 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.
Apoptosis is mediated via death receptor, the mitochondrial, and the endoplasmic reticulum pathwa... more Apoptosis is mediated via death receptor, the mitochondrial, and the endoplasmic reticulum pathway. Following activation of naïve T cells with antigens, different subsets of memory T cells are generated. In this review we have discussed relative sensitivity/resistance of naïve and different subsets of memory T cells to apoptosis via different signaling pathways. Molecular basis for differential sensitivity to apoptosis is discussed.
Based upon their migrating properties and effector functions, CD8(+) T cells have been further cl... more Based upon their migrating properties and effector functions, CD8(+) T cells have been further classified into central memory (T(CM)) and two types of effector memory (T(EM) and T(EMRA)) cells. These memory cells display distinct replicative characteristics. Because apoptosis plays an important role in cellular homeostasis, we have examined the relative sensitivity of naïve (T(N)) and different memory CD8(+) T cells to apoptosis. We show that both T(EM) and T(EMRA) CD8(+) T cells are resistant to apoptosis, whereas T(N) and T(CM) CD8(+) T cells are sensitive to apoptosis.
Upon activation by antigen, naive T cell subsets undergo proliferation and differentiation into e... more 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.
Peripheral blood and bone marrow cells of 38 patients with malignant lymphoma in the leukemic pha... more Peripheral blood and bone marrow cells of 38 patients with malignant lymphoma in the leukemic phase were defined by multiple immunologic markers and determination of the enzyme terminal deoxynucleotidyl transferase (TdT). Despite shared B cell markers (surface ...
... Role of Protein Kinase C-ß Isozyme in Activation of Latent Human Immunodeficiency Virus Type ... more ... Role of Protein Kinase C-ß Isozyme in Activation of Latent Human Immunodeficiency Virus Type 1 in Promonocytic Ul Cells by Phorbol-12-Myristate Acetate CHOONG H. KIM, SASTRY GOLLAPUDI, ALEX KIM, TOM LEE, and SUDHIR GUPTA ABSTRACT ...
We have recently shown that cyclosporin A (CsA) reverses pleiotropic drug resistance in human acu... more We have recently shown that cyclosporin A (CsA) reverses pleiotropic drug resistance in human acute lymphatic leukemia in vitro and daunorubicin resistance in Ehrlich ascites tumor in vivo. In the present study we examined the mechanisms by which CsA might reverse pleiotropic drug resistance relative to changes in cellular plasma membrane potentials and intracellular calcium ([Ca2+]i). Membrane potentials were measured with DIOC5 dye flow-cytometrically and [Ca2+]i levels with Quin 2 dye spectrofluorimetrically. All pleiotropic (PDR) drug-resistant tumor sublines had decreased membrane potentials (membrane depolarized) compared with their corresponding drug-sensitive parental tumors. In comparison, the membrane potentials of a control antimetabolite-resistant acute leukemia cell line were unchanged. The basal levels of [Ca2+]i in the PDR sublines were variable compared with those of parental drug-sensitive cell lines. Incubation of all PDR tumor sublines with CsA or verapamil resulted in the restoration of membrane potentials to that characteristic of the corresponding drug-sensitive parental tumor. Cyclosporin A produced variable changes in the levels of [Ca2+]i. These data suggest that alteration of membrane potentials is one of the mechanisms responsible for pleiotropic drug resistance in malignancy and show that this alteration is corrected by CsA and verapamil.
Thirty-nine children with ALL who had completed three years of chemotherapy were randomized to re... more Thirty-nine children with ALL who had completed three years of chemotherapy were randomized to receive oral BCG for immunotherapy or no treatment as controls. There was not a significant difference between the two groups in the relapse rate. Among the immune parameters, only in vitro blastogenic responses to PHA and PPD rose significantly in the BCG group compared with the controls. Skin testing also revealed evidence of tuberculin sensitization. The group as a whole was studied for the kinetic recovery of immune functions after the cessation of chemotherapy, which revealed a dissociation in both cellular and humoral systems. At three weeks after therapy, only peripheral blood lymphocyte count, non T-cells, and serum IgM showed a significant abnormality. There was a rise in these parameters in the subsequent weeks, and the non-T-cell count reached normal levels sooner than the other two parameters. Children who were less than 5 years of age at the time of diagnosis showed a lesser degree of immunosuppression after long-term chemotherapy compared with those who were greater than or equal to 5 years of age. The analysis of the data indicated a relationship between the low serum immunoglobulins (IgG, IgA) and disease status.
Aging in humans is associated with progressive decline in T cell function, hyperimmunoglobulinemi... more 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.
Apoptosis is mediated via death receptor, the mitochondrial, and the endoplasmic reticulum pathwa... more Apoptosis is mediated via death receptor, the mitochondrial, and the endoplasmic reticulum pathway. Following activation of naïve T cells with antigens, different subsets of memory T cells are generated. In this review we have discussed relative sensitivity/resistance of naïve and different subsets of memory T cells to apoptosis via different signaling pathways. Molecular basis for differential sensitivity to apoptosis is discussed.
Based upon their migrating properties and effector functions, CD8(+) T cells have been further cl... more Based upon their migrating properties and effector functions, CD8(+) T cells have been further classified into central memory (T(CM)) and two types of effector memory (T(EM) and T(EMRA)) cells. These memory cells display distinct replicative characteristics. Because apoptosis plays an important role in cellular homeostasis, we have examined the relative sensitivity of naïve (T(N)) and different memory CD8(+) T cells to apoptosis. We show that both T(EM) and T(EMRA) CD8(+) T cells are resistant to apoptosis, whereas T(N) and T(CM) CD8(+) T cells are sensitive to apoptosis.
Upon activation by antigen, naive T cell subsets undergo proliferation and differentiation into e... more 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.
Peripheral blood and bone marrow cells of 38 patients with malignant lymphoma in the leukemic pha... more Peripheral blood and bone marrow cells of 38 patients with malignant lymphoma in the leukemic phase were defined by multiple immunologic markers and determination of the enzyme terminal deoxynucleotidyl transferase (TdT). Despite shared B cell markers (surface ...
... Role of Protein Kinase C-ß Isozyme in Activation of Latent Human Immunodeficiency Virus Type ... more ... Role of Protein Kinase C-ß Isozyme in Activation of Latent Human Immunodeficiency Virus Type 1 in Promonocytic Ul Cells by Phorbol-12-Myristate Acetate CHOONG H. KIM, SASTRY GOLLAPUDI, ALEX KIM, TOM LEE, and SUDHIR GUPTA ABSTRACT ...
Uploads
Papers by Sudhir Gupta