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Norma S Kenyon - One of the best experts on this subject based on the ideXlab platform.
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assessment of Cytotoxic Lymphocyte gene expression in the peripheral blood of human islet allograft recipients elevation precedes clinical evidence of rejection
Diabetes, 2004Co-Authors: Dongmei Han, David Baidal, Jenifer Leith, Camillo Ricordi, Rodolfo Alejandro, Norma S KenyonAbstract:Studies in nonhuman primates have demonstrated that elevation of the Cytotoxic Lymphocyte (CL) genes granzyme B, perforin, and Fas ligand in peripheral blood precedes islet allograft rejection. The purpose of this study was to determine whether this approach has utility for prediction of human islet allograft loss. We studied 13 patients who had long-term type 1 diabetes and were treated with steroid-free immunosuppression and given sequential islet cell infusions. All recipients became insulin independent, and eight of them experienced deterioration in glycemic control, followed by reinitiation of insulin therapy. Frequent peripheral blood samples were collected to monitor CL gene mRNA levels with real-time PCR. For the eight back-to-insulin patients, there was a clear elevation of CL gene mRNA levels 25-203 days before the onset of frequent hyperglycemia. Granzyme B was the most reliable indicator of ongoing graft loss. Additional correlations with infection were noted; however, evidence of sensitization in antidonor mixed Lymphocyte reaction was observed in seven of eight patients who experienced partial graft loss, whereas this was not seen when upregulated CL gene expression was associated with infection. The results suggest that, when taken into consideration with other clinical parameters, elevated CL gene levels may enable prediction of islet allograft loss.
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assessment of Cytotoxic Lymphocyte gene expression in the peripheral blood of human islet allograft recipients elevation precedes clinical evidence of rejection
Diabetes, 2004Co-Authors: Xiumin Xu, David Baidal, Jenifer Leith, Camillo Ricordi, Rodolfo Alejandro, Norma S KenyonAbstract:Studies in nonhuman primates have demonstrated that elevation of the Cytotoxic Lymphocyte (CL) genes granzyme B, perforin, and Fas ligand in peripheral blood precedes islet allograft rejection. The purpose of this study was to determine whether this approach has utility for prediction of human islet allograft loss. We studied 13 patients who had long-term type 1 diabetes and were treated with steroid-free immunosuppression and given sequential islet cell infusions. All recipients became insulin independent, and eight of them experienced deterioration in glycemic control, followed by reinitiation of insulin therapy. Frequent peripheral blood samples were collected to monitor CL gene mRNA levels with real-time PCR. For the eight back-to-insulin patients, there was a clear elevation of CL gene mRNA levels 25–203 days before the onset of frequent hyperglycemia. Granzyme B was the most reliable indicator of ongoing graft loss. Additional correlations with infection were noted; however, evidence of sensitization in antidonor mixed Lymphocyte reaction was observed in seven of eight patients who experienced partial graft loss, whereas this was not seen when upregulated CL gene expression was associated with infection. The results suggest that, when taken into consideration with other clinical parameters, elevated CL gene levels may enable prediction of islet allograft loss. Diabetes 53: 2281–2290, 2004
Terry B Strom - One of the best experts on this subject based on the ideXlab platform.
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Cytotoxic Lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts
Transplantation, 1998Co-Authors: L Vasconcellos, Asher D Schachter, X X Zheng, L H Vasconcellos, Michael E Shapiro, William E Harmon, Terry B StromAbstract:BACKGROUND: We have shown previously that heightened expression of the Cytotoxic Lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. METHODS: We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. RESULTS: Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. CONCLUSION: Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection.
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Cytotoxic Lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts
Transplantation, 1998Co-Authors: L Vasconcellos, Asher D Schachter, X X Zheng, L H Vasconcellos, Michael E Shapiro, William E Harmon, Terry B StromAbstract:Background. We have shown previously that heightened expression of the Cytotoxic Lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. Methods. We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. Results. Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. Conclusion. Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection. Despite the growing array of immunosuppressive therapies available to transplant recipients, acute allograft rejection is a common event and is a major factor in determining both short-term and long-term outcomes for the transplant recipient (1). The occurrence of acute rejection is a significant risk factor for hastened development of chronic rejection (2), and therefore prompt diagnosis and treatment of acute rejection episodes is of utmost importance. Currently, acute renal allograft rejection is suspected only when the serum creatinine level rises, after the adverse effect of immunological and inflammatory processes on graft function. Surveillance allograft biopsies may prove to be beneficial in predicting rejection, but clinical application is limited by the invasive nature of this procedure. The early phases of T cell activation and the early immune activation events that precede fixed graft tissue injury can now be detected by quantitative reverse transcription-polymerase chain reaction (RT-PCR*) in preclinical models (3). Using human renal allograft biopsy specimens, we have shown previously that quantitative RT-PCR analysis of intragraft gene expression of the Cytotoxic cell (CL) effector molecules perforin (P), granzyme B (GB), and Fas ligand (FasL) correlates with the pathological diagnosis with extraordinary sensitivity and specificity, particularly when any two of the three genes are simultaneously up-regulated (4). In this study, we are testing the hypotheses that Cytotoxic Lymphocyte (CL) effector genes are coordinately expressed in peripheral blood leukocytes (PBLs) and renal allografts and CL effector molecule gene expression in PBLs correlates with the histological diagnosis.
Guillaume Cartron - One of the best experts on this subject based on the ideXlab platform.
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Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers
EBioMedicine, 2015Co-Authors: Ewelina Krzywinska, Nerea Allende-vega, Amélie Cornillon, Laure Cayrefourcq, Catherine Panabieres, Carlos Vilches, Julie Déchanet-merville, Yosr Hicheri, Jean-françois Rossi, Guillaume CartronAbstract:Natural killer (NK) cells, a Cytotoxic Lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti-tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56 dim CD16 + NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA + RO + phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA + RO − phenotype similar to naïve T cells. In summary, we show that CD45RA + RO + cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hemato-logical neoplasias.
Michael Goldberg - One of the best experts on this subject based on the ideXlab platform.
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decitabine enhances Lymphocyte migration and function and synergizes with ctla 4 blockade in a murine ovarian cancer model
Cancer immunology research, 2015Co-Authors: Lei Wang, Zohreh Amoozgar, Jing Huang, Mohammad H Saleh, Deyin Xing, Sandra Orsulic, Michael GoldbergAbstract:The lack of second-line treatment for relapsed ovarian cancer necessitates the development of improved combination therapies. Targeted therapy and immunotherapy each confer clinical benefit, albeit limited as monotherapies. Ovarian cancer is not particularly responsive to immune checkpoint blockade, so combination with a complementary therapy may be beneficial. Recent studies have revealed that a DNA methyl transferase inhibitor, azacytidine, alters expression of immunoregulatory genes in ovarian cancer. In this study, the antitumor effects of a related DNA methyl transferase inhibitor, decitabine (DAC), were demonstrated in a syngeneic murine ovarian cancer model. Low-dose DAC treatment increases the expression of chemokines that recruit NK cells and CD8(+) T cells, promotes their production of IFNγ and TNFα, and extends the survival of mice bearing subcutaneous or orthotopic tumors. While neither DAC nor immune checkpoint blockade confers durable responses as a monotherapy in this model, the efficacy of anti-CTLA-4 was potentiated by combination with DAC. This combination promotes differentiation of naive T cells into effector T cells and prolongs Cytotoxic Lymphocyte responses as well as mouse survival. These results suggest that this combination therapy may be worthy of further consideration for improved treatment of drug-resistant ovarian cancer.
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decitabine enhances Lymphocyte migration and function and synergizes with ctla 4 blockade in a murine ovarian cancer model
Cancer immunology research, 2015Co-Authors: Lei Wang, Zohreh Amoozgar, Jing Huang, Mohammad H Saleh, Deyin Xing, Sandra Orsulic, Michael GoldbergAbstract:The lack of second-line treatment for relapsed ovarian cancer necessitates the development of improved combination therapies. Targeted therapy and immunotherapy each confer clinical benefit, albeit limited as monotherapies. Ovarian cancer is not particularly responsive to immune checkpoint blockade, so combination with a complementary therapy may be beneficial. Recent studies have revealed that a DNA methyl transferase inhibitor, azacytidine, alters expression of immunoregulatory genes in ovarian cancer. In this study, the antitumor effects of a related DNA methyl transferase inhibitor, decitabine (DAC), were demonstrated in a syngeneic murine ovarian cancer model. Low-dose DAC treatment increases the expression of chemokines that recruit NK cells and CD8+ T cells, promotes their production of IFNγ and TNFα, and extends the survival of mice bearing subcutaneous or orthotopic tumors. While neither DAC nor immune checkpoint blockade confers durable responses as a monotherapy in this model, the efficacy of anti–CTLA-4 was potentiated by combination with DAC. This combination promotes differentiation of naive T cells into effector T cells and prolongs Cytotoxic Lymphocyte responses as well as mouse survival. These results suggest that this combination therapy may be worthy of further consideration for improved treatment of drug-resistant ovarian cancer. Cancer Immunol Res; 3(9); 1030–41. ©2015 AACR .
L Vasconcellos - One of the best experts on this subject based on the ideXlab platform.
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Cytotoxic Lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts
Transplantation, 1998Co-Authors: L Vasconcellos, Asher D Schachter, X X Zheng, L H Vasconcellos, Michael E Shapiro, William E Harmon, Terry B StromAbstract:BACKGROUND: We have shown previously that heightened expression of the Cytotoxic Lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. METHODS: We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. RESULTS: Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. CONCLUSION: Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection.
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Cytotoxic Lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts
Transplantation, 1998Co-Authors: L Vasconcellos, Asher D Schachter, X X Zheng, L H Vasconcellos, Michael E Shapiro, William E Harmon, Terry B StromAbstract:Background. We have shown previously that heightened expression of the Cytotoxic Lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. Methods. We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. Results. Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. Conclusion. Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection. Despite the growing array of immunosuppressive therapies available to transplant recipients, acute allograft rejection is a common event and is a major factor in determining both short-term and long-term outcomes for the transplant recipient (1). The occurrence of acute rejection is a significant risk factor for hastened development of chronic rejection (2), and therefore prompt diagnosis and treatment of acute rejection episodes is of utmost importance. Currently, acute renal allograft rejection is suspected only when the serum creatinine level rises, after the adverse effect of immunological and inflammatory processes on graft function. Surveillance allograft biopsies may prove to be beneficial in predicting rejection, but clinical application is limited by the invasive nature of this procedure. The early phases of T cell activation and the early immune activation events that precede fixed graft tissue injury can now be detected by quantitative reverse transcription-polymerase chain reaction (RT-PCR*) in preclinical models (3). Using human renal allograft biopsy specimens, we have shown previously that quantitative RT-PCR analysis of intragraft gene expression of the Cytotoxic cell (CL) effector molecules perforin (P), granzyme B (GB), and Fas ligand (FasL) correlates with the pathological diagnosis with extraordinary sensitivity and specificity, particularly when any two of the three genes are simultaneously up-regulated (4). In this study, we are testing the hypotheses that Cytotoxic Lymphocyte (CL) effector genes are coordinately expressed in peripheral blood leukocytes (PBLs) and renal allografts and CL effector molecule gene expression in PBLs correlates with the histological diagnosis.
