Showing items 1 - 20 of 28

Your selections:

An NZW-derived interval on chromosome 7 moderates sialadenitis, but not insulitis in congenic nonobese diabetic mice

- Burt, Rachel, Watkins, Laura, Tan, Iris, Wang, Nancy, Quirk, Fiona, Mackin, Leanne, Morgan, Phillip, Zhang, Jian-Guo, Berzins, Stuart, Morahan, Grant, Brodnicki, Thomas

  • Authors: Burt, Rachel , Watkins, Laura , Tan, Iris , Wang, Nancy , Quirk, Fiona , Mackin, Leanne , Morgan, Phillip , Zhang, Jian-Guo , Berzins, Stuart , Morahan, Grant , Brodnicki, Thomas
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Journal of Immunology Vol. 184, no. 2 (January 2010 2010), p. 859-868
  • Full Text: false
  • Reviewed:
  • Description: Autoimmune lymphocytic infiltration of the salivary glands, termed sialadenitis, is a pathologic feature of Sjögren’s syndrome (SjS) that is also prominent in nonobese diabetic (NOD) mice. Genetic factors regulate sialadenitis, and a previous (NOD × NZW)F2 study detected linkage to murine chromosome (Chr) 7. The locus, subsequently annotated as Ssial3, maps to the distal end of Chr7 and overlaps a region associated with type 1 diabetes susceptibility in NOD mice. To examine whether Ssial3 could contribute to both diseases, or was specific for SjS, we generated a congenic mouse strain that harbored an NZW-derived Chr7 interval on the NOD genetic background. This congenic strain exhibited reduced sialadenitis compared with NOD mice and confirmed Ssial3. This reduction, however, did not ameliorate saliva abnormalities associated with SjS-like disease in NOD mice, nor were congenic mice protected against insulitis (lymphocytic infiltration of the pancreatic islets) or diabetes onset. Thus, the Ssial3 locus appears to have a tissue-specific effect for which the NZW allele is unable to prevent other autoimmune traits in the NOD mouse. Anomalous increases for antinuclear Ab production and frequency of marginal-zone B cells were also identified in congenic mice, indicating that the NZW-derived Chr7 interval has a complex effect on the NOD immune system.
  • Description: C1

The role of NFkB in T-lymphocyte development and function

- Valle, Elisha de, Lie, Laurensius, Gugasyan, Raffi, Berzins, Stuart

Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family

- Chan, Angela, Serwecinska, Liliana, Cochrane, Andrew, Harrison, Leonard, Godfrey, Dale, Berzins, Stuart

  • Authors: Chan, Angela , Serwecinska, Liliana , Cochrane, Andrew , Harrison, Leonard , Godfrey, Dale , Berzins, Stuart
  • Date: 2009
  • Type: Text , Journal article
  • Relation: Clinical and Experimental Immunology Vol. 156, no. 2 (May 2009 2009), p. 238-245
  • Full Text: false
  • Reviewed:
  • Description: Natural killer T cells (NKT) are a regulatory subset of T lymphocytes whose frequency in peripheral blood is highly variable within the human population. Lower than normal NKT frequencies are associated with increased predisposition to a number of diseases, including type 1 diabetes and some forms of cancer, raising the possibility that an increased frequency may be protective. However, there is little or no understanding of how high NKT frequencies arise or, most importantly, whether the potential exists to boost and maintain NKT levels for therapeutic advantage. Here, we provide a detailed functional and phenotypic characterization of the NKT compartment of a human donor with NKT levels approximately 50 times greater than normal, including an analysis of NKT in her immediate family members. The study focuses upon the characteristics of this donor and her family, but demonstrates more broadly that the size and flexibility of the NKT niche is far greater than envisioned previously. This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit.
  • Description: C1

Experimental and human evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin NGAL ) in the development of cardiac hypertrophy and heart failure

- Marques, Francine, Prestes, Priscilla, Byars, Sean, Ritchie, Scott, Wurtz, Peter, Patel, Sheila, Booth, Scott, Rana, Indrajeetsinh, Minoda, Yosuke, Berzins, Stuart, Curl, Claire, Bell, James, Wai, Bryan, Srivastava, Piyush, Kangas, Antti, Soininen, Pasi, Ruohonen, Saku, Kahonen, Mika, Lehtimaki, Terho, Raitoharju, Emma, Havulinna, Aki, Perola, Markus, Raitakari, Olli, Salomaa, Veikko, Ala-Korpela, Mika, Kettunen, Johannes, McGlynn, Maree, Kelly, Jason, Wlodek, Mary, Lewandowski, Paul, Delbridge, Lea, Burrell, Louise, Inouye, Michael, Harrap, Stephen, Charchar, Fadi

Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy

- Chan, Angela, Neeson, Paul, Leeansyah, Edwin, Tainton, K., Quach, Hang, Prince, Henry, Harrison, S.J., Godfrey, Dale, Ritchie, David, Berzins, Stuart

  • Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Harrison, S.J. , Godfrey, Dale , Ritchie, David , Berzins, Stuart
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Clinical and Experimental Immunology Vol. 175, no. 1 (2014), p. 49-58
  • Full Text: false
  • Reviewed:
  • Description: The causes of multiple myeloma (MM) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with MM, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with MM and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for MM, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive MM had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation.

Temporal regulation of natural Killer T cell interferon gamma responses by β-catenin-dependent and -independent Wnt signaling

- Kling, Jessica, Jordan, Margaret, Pitt, Lauren, Meiners, Jana, Thanh-Tran, Thao, Tran, Le Son, Nguyen, Tam, Mittal, Deepak, Villani, Rehan, Steptoe, Raymond, Khosrotehrani, Kiarash, Berzins, Stuart, Baxter, Alan, Godrey, Dale, Blumental, Antje

  • Authors: Kling, Jessica , Jordan, Margaret , Pitt, Lauren , Meiners, Jana , Thanh-Tran, Thao , Tran, Le Son , Nguyen, Tam , Mittal, Deepak , Villani, Rehan , Steptoe, Raymond , Khosrotehrani, Kiarash , Berzins, Stuart , Baxter, Alan , Godrey, Dale , Blumental, Antje
  • Date: 2018
  • Type: Text , Journal article
  • Relation: Frontiers in Immunology Vol. 9, no. (2018), p. 1-13
  • Full Text:
  • Reviewed:
  • Description: Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-γ) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator β-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-γ production. β-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and β-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, α-galactosylceramide (α-GalCer) using a mouse model. Pharmacologic targeting of β-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-γ responses. By contrast, within several hours of α-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired α-GalCer-induced IFN-γ responses, independent of β-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/β-catenin signaling that curbs IFN-γ responses, but that, subsequently, Wnt ligands sustain IFN-γ expression independent of β-catenin activity. Our analyses in ICG001-treated mice confirmed a role for β-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to α-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.
  • Description: Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-

A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage

- Koay, Hui-Fern, Gherardin, Nicholas, Enders, Anselm, Loh, Liyen, Mackay, Laura, Almeida, Catarina, Russ, Brendan, Nold-Petry, Claudia, Nold, Marcel, Bedoui, Sammy, Chen, Zhenjun, Corbett, Alexandra, Eckle, Sidonia, Meehan, Bronwyn, d'Udekem, Yves, Konstantinov, Igor, Lappas, Martha, Liu, Ligong, Goodnow, Chris, Fairlie, David, Rossjohn, Jamie, Chong, Mark, Kedzierska, Katherine, Berzins, Stuart, Belz, Gabrielle, McCluskey, James, Uldrich, Adam, Godfrey, Dale, Pellicci, Daniel

A potentially important role for T cells and regulatory T cells in Langerhans cell histiocytosis

- Mitchell, Jenne, Berzins, Stuart, Kannourakis, George

  • Authors: Mitchell, Jenne , Berzins, Stuart , Kannourakis, George
  • Date: 2018
  • Type: Text , Journal article , Review
  • Relation: Clinical Immunology Vol. 194, no. (2018), p. 19-25
  • Full Text: false
  • Reviewed:
  • Description: Langerhans cell histiocytosis is characterized by lesions containing inflammatory immune cells, including myeloid cells and T cells. Patient mortality remains unacceptably high and new treatment options are required. Several LCH studies have identified aberrant frequencies of T cell subsets with potential immune regulatory properties. High numbers of Foxp3+ regulatory T cells and gamma-delta T cells have been reported in patients with LCH, although, the cause of their presence or their significance is not yet clear. This review describes the current understanding of how LCH develops and progresses, focusing on the growing evidence that regulatory T cell subsets may be important and discussing the exciting potential for harnessing these cells to treat LCH using immune based therapies.

Altered populations of unconventional T Cell lineages in patients with Langerhans Cell Histiocytosis

- Mitchell, Jenée, Kvedaraite, Egle, von Bahr Greenwood, Tatiana, Henter, Jan-Inge, Pellicci, Daniel, Berzins, Stuart, Kannourakis, George

  • Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Henter, Jan-Inge , Pellicci, Daniel , Berzins, Stuart , Kannourakis, George
  • Date: 2018
  • Type: Text , Journal article
  • Relation: Scientific Reports Vol. 8, no. 1 (2018), p. 1-13
  • Full Text:
  • Reviewed:
  • Description: Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of γδ T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies.

An NZW-derived interval on chromosome 7 moderates sialadenitis, but not insulitis in congenic nonobese diabetic mice

- Burt, Rachel, Watkins, Laura, Tan, Iris, Wang, Nancy, Quirk, Fiona, Mackin, Leanne, Morgan, Phillip, Zhang, Jian-Guo, Berzins, Stuart, Morahan, Grant, Brodnicki, Thomas

  • Authors: Burt, Rachel , Watkins, Laura , Tan, Iris , Wang, Nancy , Quirk, Fiona , Mackin, Leanne , Morgan, Phillip , Zhang, Jian-Guo , Berzins, Stuart , Morahan, Grant , Brodnicki, Thomas
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Journal of Immunology Vol. 184, no. 2 (2010), p. 859-868
  • Full Text: false
  • Reviewed:
  • Description: Autoimmune lymphocytic infiltration of the salivary glands, termed sialadenitis, is a pathologic feature of Sjögren's syndrome (SjS) that is also prominent in nonobese diabetic (NOD) mice. Genetic factors regulate sialadenitis, and a previous (NOD x NZW)F2 study detected linkage to murine chromosome (Chr) 7. The locus, subsequently annotated as Ssial3, maps to the distal end of Chr7 and overlaps a region associated with type 1 diabetes susceptibility in NOD mice. To examine whether Ssial3 could contribute to both diseases, or was specific for SjS, we generated a congenic mouse strain that harbored an NZW-derived Chr7 interval on the NOD genetic background. This congenic strain exhibited reduced sialadenitis compared with NOD mice and confirmed Ssial3. This reduction, however, did not ameliorate saliva abnormalities associated with SjS-like disease in NOD mice, nor were congenic mice protected against insulitis (lymphocytic infiltration of the pancreatic islets) or diabetes onset. Thus, the Ssial3 locus appears to have a tissue-specific effect for which the NZW allele is unable to prevent other autoimmune traits in the NOD mouse. Anomalous increases for antinuclear Ab production and frequency of marginal-zone B cells were also identified in congenic mice, indicating that theNZW-derived Chr7 interval has a complex effect on the NOD immune system. Copyright © 2010 by The American Association of Immunologists, Inc.

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

- Chan, Angela, Neeson, Paul, Leeansyah, Edwin, Tainton, K., Quach, Hang, Prince, Henry, Godfrey, Dale, Ritchie, David, Berzins, Stuart

  • Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Godfrey, Dale , Ritchie, David , Berzins, Stuart
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Leukemia Vol. 24, no. 3 (2010), p. 592
  • Full Text: false
  • Reviewed:
  • Description: Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function.

Ex-vivo analysis of human Natural Killer T cells demonstrates heterogeneity between tissues and within established CD4+ and CD4- subsets

- Chan, Angela, Leeansyah, Edwin, Cochrane, Andrew, d'Udekem, Yves, Mittag, Diana, Harrison, Leonard, Godfrey, Dale, Berzins, Stuart

  • Authors: Chan, Angela , Leeansyah, Edwin , Cochrane, Andrew , d'Udekem, Yves , Mittag, Diana , Harrison, Leonard , Godfrey, Dale , Berzins, Stuart
  • Date: 2013
  • Type: Text , Journal article
  • Relation: Clinical and Experimental Immunology Vol. 172, no. 1 (2013), p. 129-137
  • Full Text: false
  • Reviewed:
  • Description: Summary: Our understanding of human type 1 natural killer T (NKT) cells has been heavily dependent on studies of cells from peripheral blood. These have identified two functionally distinct subsets defined by expression of CD4, although it is widely believed that this underestimates the true number of subsets. Two recent studies supporting this view have provided more detail about diversity of the human NKT cells, but relied on analysis of NKT cells from human blood that had been expanded in vitro prior to analysis. In this study we extend those findings by assessing the heterogeneity of CD4+ and CD4- human NKT cell subsets from peripheral blood, cord blood, thymus and spleen without prior expansion ex vivo, and identifying for the first time cytokines expressed by human NKT cells from spleen and thymus. Our comparative analysis reveals highly heterogeneous expression of surface antigens by CD4+ and CD4- NKT cell subsets and identifies several antigens whose differential expression correlates with the cytokine response. Collectively, our findings reveal that the common classification of NKT cells into CD4+ and CD4- subsets fails to reflect the diversity of this lineage, and that more studies are needed to establish the functional significance of the antigen expression patterns and tissue residency of human NKT cells. © 2012 British Society for Immunology.
  • Description: 2003010856

Divergent SATB1 expression across human life span and tissue compartments

- Nüssing, Simone, Koay, Hui-Fern, Sant, Sneha, Loudovaris, Thomas, Mannering, Stuart, Lappas, Martha, d′Udekem, Yves, Konstantinov, Igor, Berzins, Stuart, Rimmelzwaan, Guus, Turner, Stephen, Clemens, Bridie, Godfrey, Dale, Nguyen, Thi, Kedzierska, Katherine

  • Authors: Nüssing, Simone , Koay, Hui-Fern , Sant, Sneha , Loudovaris, Thomas , Mannering, Stuart , Lappas, Martha , d′Udekem, Yves , Konstantinov, Igor , Berzins, Stuart , Rimmelzwaan, Guus , Turner, Stephen , Clemens, Bridie , Godfrey, Dale , Nguyen, Thi , Kedzierska, Katherine
  • Date: 2019
  • Type: Text , Journal article
  • Relation: Immunology and Cell Biology Vol. 97, no. (2019), p. 498-511
  • Full Text:
  • Reviewed:
  • Description: Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T-cell development, with SATB1-knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T-cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD-1). Thus, SATB1 expression in T-cell subsets across different tissue compartments in humans is of potential importance for targeting PD-1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD-1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen-specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T-cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine-tuned expression dynamics, which appear to be tissue- and antigen-dependent. Furthermore, SATB1 expression negatively correlates with PD-1 expression in virus-specific CD8 + T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD-1 in T cells, highly relevant to human malignancies or chronic viral infections.

Natural killer T cells: Drivers or passengers in preventing human disease?

- Berzins, Stuart, Richie, David

  • Authors: Berzins, Stuart , Richie, David
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Nature Reviews Immunology Vol. 14, no. 9 (2014), p. 640-646
  • Full Text: false
  • Reviewed:
  • Description: Natural killer T (NKT) cells are credited with regulatory roles in immunity against cancers, autoimmune diseases, allergies, and bacterial and viral infections. Studies in mice and observational research in patient groups have suggested that NKT cell-based therapies could be used to prevent or treat these diseases, yet the translation into clinical settings has been disappointing. We support the view that NKT cells have regulatory characteristics that could be exploited in clinical settings, but there are doubts about the natural roles of NKT cells in vivo and whether NKT cell defects are fundamental drivers of disease in humans. In this Opinion article, we discuss the uncertainties and opportunities regarding NKT cells in humans, and the potential for NKT cells to be manipulated to prevent or treat disease. © 2014 Macmillan Publishers Limited.

Lessons learned from an unusual presentation of CD3+, CD56- T-Cell large granular lymphocyte leukemia

- Berzins, Stuart, Harrison, S.J., Lee, Robert, Ritz, Nicole, Chan, Andrew, Came, Neil, Curtis, Nigel, Lim, Andrew

  • Authors: Berzins, Stuart , Harrison, S.J. , Lee, Robert , Ritz, Nicole , Chan, Andrew , Came, Neil , Curtis, Nigel , Lim, Andrew
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Journal of Clinical Oncology Vol. 28, no. 28 (2010), p. e498- e502
  • Full Text: false
  • Reviewed:
  • Description: The WHO classification subdivides large granular lymphocytic leukemias (LGLLs) into two subtypes, T and natural killer (NK) LGLLs, with distinct immunophenotypes and clinical presentations.1 Although arising from a common progenitor cell, NK cells are bone marrow–derived innate immune cells capable of cytokine production and cytotoxicity, and T cells are thymic-derived, antigen-specific lymphocytes that express a T-cell receptor (TCR).2 Natural killer T (NKT) cells, a subset of T cells, express NK-associated antigens such as CD16, CD56, and CD57, in addition to a CD1d-restricted, semi-invariant TCR.3 The point at which NKT cells branch from other TCR rearranged cells is not clearly defined. However, this is believed to be mediated through CD1d thymic-dependant signaling in CD4 CD8 double-positive thymocyte precursors.4,5 NK LGLL has a CD3−, CD8+, CD16+, CD56+ phenotype, with variable expression of CD57. It presents in teenagers and young adults with “B” symptoms, lymphadenopathy, hepatosplenomegaly, lymphocytosis, anemia, and thrombocytopenia and typically follows an aggressive clinical course.6 T-cell LGLLs are CD3+, CD8+, CD16+ with a clonal TCR rearrangement and defective Fas (CD95) -mediated apoptosis.7,8 Median age of onset is 55 years, presenting with splenomegaly, neutropenia, and recurrent infections. It is associated with rheumatoid arthritis and follows an indolent and protracted clinical course.9 We describe the case of a teenage patient with T-cell LGLL, who despite having a CD56 immunophenotype, initially showed an aggressive clinical course more in keeping with an NKT leukemia. We discuss the reasoning behind his conservative management and the observed changes in lymphocyte count and serum cytokine/chemokine levels over an 18-month period. There have been no reported cases of an initially aggressive presentation with subsequent spontaneous regression.

Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy

- Chan, Angela, Neeson, Paul, Leeansyah, Edwin, Tainton, K., Quach, Hang, Prince, Henry, Harrison, S.J., Godfrey, Dale, Ritchie, David, Berzins, Stuart

  • Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Harrison, S.J. , Godfrey, Dale , Ritchie, David , Berzins, Stuart
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Clinical & Experimental Immunology Vol. 175, no. 1 (2014), p.
  • Full Text: false
  • Reviewed:
  • Description: The causes of multiple myeloma (MM) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with MM, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with MM and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for MM, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive MM had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation.

Human blood MAIT cell subsets defined using MR1 tetramers

- Gherardin, Nicholas, Souter, Michael, Koay, Hui-Fern, Mangas, Kirstie, Seemann, Torsten, Stinear, Timothy, Eckle, Sidonia, Berzins, Stuart, d'Udekem, Yves, Konstantinov, Igor, Fairlie, David, Ritchie, David, Neeson, Paul, Pellicci, Daniel, Uldrich, Adam, McCluskey, James, Godfrey, Dale

NKT cell development in the absence of the autoimmune regulator gene (Aire)

- Pitt, Lauren, Hubert, Francois-Xavier, Scott, Hamish, Godfrey, Dale, Berzins, Stuart

  • Authors: Pitt, Lauren , Hubert, Francois-Xavier , Scott, Hamish , Godfrey, Dale , Berzins, Stuart
  • Date: 2008
  • Type: Text , Journal article
  • Relation: European Journal of Immunology Vol. 38, no. 10 (2008), p. 2689-2696
  • Full Text: false
  • Reviewed:
  • Description: Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP31 Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence self-tolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.
  • Description: C1

Acute exercise leads to regulation of Telomere-Associated genes and MicroRNA expression in immune Cells

- Chilton, Warrick, Marques, Francine, West, Jenny, Kannourakis, George, Berzins, Stuart, O'Brien, Brendan, Charchar, Fadi

  • Authors: Chilton, Warrick , Marques, Francine , West, Jenny , Kannourakis, George , Berzins, Stuart , O'Brien, Brendan , Charchar, Fadi
  • Date: 2014
  • Type: Text , Journal article
  • Relation: PloS One Vol. 9, no. 4 (2014), p. e92088
  • Full Text:
  • Reviewed:
  • Description: Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. Funding NHMRC

An emerging role for immune regulatory subsets in chronic lymphocytic leukaemia

- Wallace, Morgan, Alcantara, Marice, Minoda, Yosuke, Kannourakis, George, Berzins, Stuart

  • Authors: Wallace, Morgan , Alcantara, Marice , Minoda, Yosuke , Kannourakis, George , Berzins, Stuart
  • Date: 2015
  • Type: Text , Journal article
  • Relation: International Immunopharmacology Vol. 28, no. 2 (2015), p. 897-900
  • Full Text: false
  • Reviewed:
  • Description: The last few years has seen the burgeoning of a new category of therapeutics for cancer targeting immune regulatory pathways. Antibodies that block the PD-1/PD-L1 interaction are perhaps the most prominent of these new anti-cancer therapies, but several other inhibitory receptor ligand interactions have also shown promise as targets in clinical trials, including CTLA-4/CD80 and Lag-3/MHC class II. Related to this is a rapidly improving knowledge of 'regulatory' lymphocyte lineages, including NKT cells, MATT cells, B regulatory cells and others. These cells have potent cytokine responses that can influence the functioning of other immune cells and many researchers believe that they could be effective targets for therapies designed to enhance immune responses to cancer. This review will outline our current understanding of FOXP3 + 'Tregs', NKT cells, MAIT cells and B regulatory cells immune regulatory cell populations in cancer, with a particular focus on chronic lymphocytic leukaemia (CLL). We will discuss evidence linking CLL with immune regulatory dysfunction and the potential for new therapies targeting regulatory cells. (C) 2015 Elsevier B.V. All rights reserved.