Publisher Summary Despite the great progress that has been achieved in recent years in the diagno... more Publisher Summary Despite the great progress that has been achieved in recent years in the diagnosis and treatment of Hodgkin's lymphoma, the etiopathogenesis of this disease still remains obscure. Definite proof that Hodgkin's disease (HD) is a malignant neoplasm, albeit a remarkably atypical one, has been provided during the past two decades by a number of cytogenetic, immunological, and molecular biology studies. Several fundamental issues, however, still remain open. They include the genesis of the immune deficiency, the nature of the normal counterpart of the neoplastic cells, and the role of other tumor-infiltrating lymphocytes. This chapter describes the immunological alterations found in untreated HD patients, mainly focusing on those involving the T and B cell compartments. The chapter also discusses the hypotheses on the origin of Reed–Sternberg (RS) cells and describes the role of the cells surrounding them in involved lymphoid organs.
1. PZ Zipfel, S. G. Irving, K. Kelly, U. Siebenlist, Mol. Cell. Biol. 9,1041 (1989). 2. J. Maguir... more 1. PZ Zipfel, S. G. Irving, K. Kelly, U. Siebenlist, Mol. Cell. Biol. 9,1041 (1989). 2. J. Maguire and K. Kelly,unpublished data. 3. C. Reynet and C. R. Kahn, Science 262, 1441 (1993). 4. EF Pai et al., EMBO J. 9, 2351 (1990). 5. HR Bourne, DA Sanders, F. McCormick, Nature 349, ...
Background & Aims Activation of Kupffer cells and recruitment of monocytes are key events in ... more Background & Aims Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs. Methods Macrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK+/CD206+/CD163+/CD209- macrophages. The role of MerTK was assessed by pharmacologic and genetic inhibition. HSC migration was determined in Boyden chambers, viability was measured by the MTT assay, and proliferation was evaluated by the BrdU incorporation assay. Results Gas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK+/CD206+/CD163+/CD209- macrophages exhibited activation of STAT3, ERK1/2, p38 and increased expression of VEGF-A. Activation of MerTK in THP-1 macrophages induced a secretome which promoted a significant increase in migration, proliferation, viability and expression of profibrogenic factors in HSCs. Similarly, conditioned medium from MerTK+ macrophages induced a significant increase in cell migration, proliferation, STAT3 and p38 phosphorylation and upregulation of IL-8 expression in HSCs. Moreover, conditioned medium from Gas-6-stimulated Kupffer cells induced a significant increase in HSC proliferation. These effects were specifically related to MerTK expression and activity in macrophages, as indicated by pharmacologic inhibition and knockdown experiments. Conclusions MerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis. Lay summary Fibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue.
Paternal HLA-C antigens expressed by trophoblast, which liken the trophoblast to a semiallograft,... more Paternal HLA-C antigens expressed by trophoblast, which liken the trophoblast to a semiallograft, could be presented by the maternal APCs to the specific maternal CD4 + T helper cells, which could release various cytokines in response to these alloantigens. On the basis of the cytokines produced the effector CD4 + T helper lymphocytes can be classified in Th1, Th2 and Th17 cells. We focused here the possible role of these 3 human effector CD4 + T helper subpopulations, known to be involved either in allograft rejection (Th1 and Th17 cells) or in allograft tolerance (Th2 cells). Th1 and Th17 cells may compromise pregnancy and be responsible for miscarriage and Th2 cells may be responsible for the success and maintenance of pregnancy. Interestingly, our recent findings showed a beneficial role of Th17 cells, whose major role is the protection against extracellular bacteria and thus may promote adequately the response required to protect the mother against dangerous extracellular patho...
Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune syst... more Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly andviamediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine productionin vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and ...
Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19.... more Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71–93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and t...
Chemotherapy protocol can destroy the reproductive potential of young cancer patients. Doxorubici... more Chemotherapy protocol can destroy the reproductive potential of young cancer patients. Doxorubicin (DOX) is a potent anthracycline commonly used in the treatment of numerous malignancies. The purpose of the study was to evaluate the ovarian toxicity of DOX via inflammation and the possible protective effect of the green tea polyphenol epigallocatechin-3-gallate (EGCG). Ovarian tissue of three patients was cultured with 1 µg/ml DOX and/or 10 µg/ml EGCG for 24 and 48 h. Levels of inflammatory factors were determined by quantitative Real-Time PCR, western blot, zimography, and multiplex bead-based immunoassay. Morphological evaluation, damaged follicle count and TUNEL assay were also performed. DOX influenced inflammatory responses by inducing a significant increase in the expression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and cyclooxigenase-2 (COX-2), of inflammatory interleukins (IL), such as interleukin-6 (IL-6) and interleukin-8 (IL-8), and the inflam...
In recent years it has become clear that the type of an antigen-specific immune response is deter... more In recent years it has become clear that the type of an antigen-specific immune response is determined by the selective or preferential activation of CD4+ T-cell subsets secreting different patterns of cytokines that lead to strikingly different T-cell functions. Two very distinct cytokine secretion patterns were originally defined among a panel of mouse CD4+ T-cell clones (Mosmann et al, 1986). Th1, but not Th2, cells produce interleukin (IL)-2, gamma-interferon (IFN-γ) and tumor necrosis factor (TNF)-β, whereas Th2, but not Th1, cells express IL-4, IL-5, IL-6 and IL-10 (Mosmann and Moore, 1991). Other cytokines are produced by both T-cell subpopulations. More recent data on the cytokine secretion patterns of T-cell clones and normal T cells have revealed the existence of other phenotypes. Among both mouse and human T-cell clones, a pattern of IL-2, IL-4, IL-5 and IFN-γ (ThO) has been described by several laboratories and in some cases these clones have been shown to produce all cytokines tested, including IL-3, IL-10 and granulocyte macrophage-colony stimulatory factor (GM-CSF) (Maggi et al., 1988; Paliard et al., 1988; Mosmann and Moore, 1991).
Proceedings of the National Academy of Sciences, 1991
Human bone marrow (BM) cells lacking T- and B-cell markers expressed RNA encoding interleukin (IL... more Human bone marrow (BM) cells lacking T- and B-cell markers expressed RNA encoding interleukin (IL) 4 and secreted detectable amounts of IL-4 in supernatants in response to Fc epsilon or Fc gamma receptor (Fc epsilon R or Fc gamma R) cross-linking. In some experiments, IL-5 RNA expression in response to Fc epsilon R cross-linkage could also be detected. In contrast, RNA transcripts for, and secretion of, IL-2, IL-6, and interferon gamma were never observed. The presence of IL-3 in the cultures was essential for IL-4 production by non-B, non-T BM cells in response to Fc gamma R cross-linking and enhanced IL-4 RNA expression in response to Fc epsilon R cross-linking. Under the same experimental conditions, BM T and B lymphocytes, as well as peripheral blood T, B, and non-B, non-T cells, did not express IL-4 RNA. Prolonged incubation of non-B, non-T cells in IgE-free medium followed by extensive washing did not inhibit IL-4 production induced by anti-IgE antibodies, suggesting that the ...
Publisher Summary Despite the great progress that has been achieved in recent years in the diagno... more Publisher Summary Despite the great progress that has been achieved in recent years in the diagnosis and treatment of Hodgkin's lymphoma, the etiopathogenesis of this disease still remains obscure. Definite proof that Hodgkin's disease (HD) is a malignant neoplasm, albeit a remarkably atypical one, has been provided during the past two decades by a number of cytogenetic, immunological, and molecular biology studies. Several fundamental issues, however, still remain open. They include the genesis of the immune deficiency, the nature of the normal counterpart of the neoplastic cells, and the role of other tumor-infiltrating lymphocytes. This chapter describes the immunological alterations found in untreated HD patients, mainly focusing on those involving the T and B cell compartments. The chapter also discusses the hypotheses on the origin of Reed–Sternberg (RS) cells and describes the role of the cells surrounding them in involved lymphoid organs.
1. PZ Zipfel, S. G. Irving, K. Kelly, U. Siebenlist, Mol. Cell. Biol. 9,1041 (1989). 2. J. Maguir... more 1. PZ Zipfel, S. G. Irving, K. Kelly, U. Siebenlist, Mol. Cell. Biol. 9,1041 (1989). 2. J. Maguire and K. Kelly,unpublished data. 3. C. Reynet and C. R. Kahn, Science 262, 1441 (1993). 4. EF Pai et al., EMBO J. 9, 2351 (1990). 5. HR Bourne, DA Sanders, F. McCormick, Nature 349, ...
Background & Aims Activation of Kupffer cells and recruitment of monocytes are key events in ... more Background & Aims Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs. Methods Macrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK+/CD206+/CD163+/CD209- macrophages. The role of MerTK was assessed by pharmacologic and genetic inhibition. HSC migration was determined in Boyden chambers, viability was measured by the MTT assay, and proliferation was evaluated by the BrdU incorporation assay. Results Gas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK+/CD206+/CD163+/CD209- macrophages exhibited activation of STAT3, ERK1/2, p38 and increased expression of VEGF-A. Activation of MerTK in THP-1 macrophages induced a secretome which promoted a significant increase in migration, proliferation, viability and expression of profibrogenic factors in HSCs. Similarly, conditioned medium from MerTK+ macrophages induced a significant increase in cell migration, proliferation, STAT3 and p38 phosphorylation and upregulation of IL-8 expression in HSCs. Moreover, conditioned medium from Gas-6-stimulated Kupffer cells induced a significant increase in HSC proliferation. These effects were specifically related to MerTK expression and activity in macrophages, as indicated by pharmacologic inhibition and knockdown experiments. Conclusions MerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis. Lay summary Fibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue.
Paternal HLA-C antigens expressed by trophoblast, which liken the trophoblast to a semiallograft,... more Paternal HLA-C antigens expressed by trophoblast, which liken the trophoblast to a semiallograft, could be presented by the maternal APCs to the specific maternal CD4 + T helper cells, which could release various cytokines in response to these alloantigens. On the basis of the cytokines produced the effector CD4 + T helper lymphocytes can be classified in Th1, Th2 and Th17 cells. We focused here the possible role of these 3 human effector CD4 + T helper subpopulations, known to be involved either in allograft rejection (Th1 and Th17 cells) or in allograft tolerance (Th2 cells). Th1 and Th17 cells may compromise pregnancy and be responsible for miscarriage and Th2 cells may be responsible for the success and maintenance of pregnancy. Interestingly, our recent findings showed a beneficial role of Th17 cells, whose major role is the protection against extracellular bacteria and thus may promote adequately the response required to protect the mother against dangerous extracellular patho...
Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune syst... more Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly andviamediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine productionin vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and ...
Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19.... more Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71–93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and t...
Chemotherapy protocol can destroy the reproductive potential of young cancer patients. Doxorubici... more Chemotherapy protocol can destroy the reproductive potential of young cancer patients. Doxorubicin (DOX) is a potent anthracycline commonly used in the treatment of numerous malignancies. The purpose of the study was to evaluate the ovarian toxicity of DOX via inflammation and the possible protective effect of the green tea polyphenol epigallocatechin-3-gallate (EGCG). Ovarian tissue of three patients was cultured with 1 µg/ml DOX and/or 10 µg/ml EGCG for 24 and 48 h. Levels of inflammatory factors were determined by quantitative Real-Time PCR, western blot, zimography, and multiplex bead-based immunoassay. Morphological evaluation, damaged follicle count and TUNEL assay were also performed. DOX influenced inflammatory responses by inducing a significant increase in the expression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and cyclooxigenase-2 (COX-2), of inflammatory interleukins (IL), such as interleukin-6 (IL-6) and interleukin-8 (IL-8), and the inflam...
In recent years it has become clear that the type of an antigen-specific immune response is deter... more In recent years it has become clear that the type of an antigen-specific immune response is determined by the selective or preferential activation of CD4+ T-cell subsets secreting different patterns of cytokines that lead to strikingly different T-cell functions. Two very distinct cytokine secretion patterns were originally defined among a panel of mouse CD4+ T-cell clones (Mosmann et al, 1986). Th1, but not Th2, cells produce interleukin (IL)-2, gamma-interferon (IFN-γ) and tumor necrosis factor (TNF)-β, whereas Th2, but not Th1, cells express IL-4, IL-5, IL-6 and IL-10 (Mosmann and Moore, 1991). Other cytokines are produced by both T-cell subpopulations. More recent data on the cytokine secretion patterns of T-cell clones and normal T cells have revealed the existence of other phenotypes. Among both mouse and human T-cell clones, a pattern of IL-2, IL-4, IL-5 and IFN-γ (ThO) has been described by several laboratories and in some cases these clones have been shown to produce all cytokines tested, including IL-3, IL-10 and granulocyte macrophage-colony stimulatory factor (GM-CSF) (Maggi et al., 1988; Paliard et al., 1988; Mosmann and Moore, 1991).
Proceedings of the National Academy of Sciences, 1991
Human bone marrow (BM) cells lacking T- and B-cell markers expressed RNA encoding interleukin (IL... more Human bone marrow (BM) cells lacking T- and B-cell markers expressed RNA encoding interleukin (IL) 4 and secreted detectable amounts of IL-4 in supernatants in response to Fc epsilon or Fc gamma receptor (Fc epsilon R or Fc gamma R) cross-linking. In some experiments, IL-5 RNA expression in response to Fc epsilon R cross-linkage could also be detected. In contrast, RNA transcripts for, and secretion of, IL-2, IL-6, and interferon gamma were never observed. The presence of IL-3 in the cultures was essential for IL-4 production by non-B, non-T BM cells in response to Fc gamma R cross-linking and enhanced IL-4 RNA expression in response to Fc epsilon R cross-linking. Under the same experimental conditions, BM T and B lymphocytes, as well as peripheral blood T, B, and non-B, non-T cells, did not express IL-4 RNA. Prolonged incubation of non-B, non-T cells in IgE-free medium followed by extensive washing did not inhibit IL-4 production induced by anti-IgE antibodies, suggesting that the ...
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