Ewch i’r prif gynnwys
Bernhard Moser

Yr Athro Bernhard Moser

Athro

Yr Ysgol Meddygaeth

Email
MoserB@caerdydd.ac.uk
Telephone
+44 29206 87058
Campuses
Adeilad Henry Wellcome ar gyfer Ymchwil Biofeddygol, Ystafell 3F08, Ysbyty Athrofaol Cymru, Parc y Mynydd Bychan, Caerdydd, CF14 4XN

Trosolwyg

CHEMOKINES (CHEMOtactic cytoKINES) are master regulators of cell migration. Together with adhesion molecules, chemokines orchestrate the localisation and relocation of the highly sophisticated immune cell network throughout our body. Our own review articles listed in the side panel give a flavour about the complexity of this migration system, which in humans is composed of 48 individual chemokines encoded by separate genes and 18 separate chemokine receptors that bind either a single chemokine or a large number of individual chemokines.

The above picture represents the structure of human CXCL14, the last chemokine whose receptor is not yet known.

Hallmark features of chemokines include

  • Ø Activity in health (homeostasis/immune surveillance) and disease (inflammation)
  • Ø Inappropriate production may cause chronic disease (excess chemokines) or immune suppression (insufficient chemokines)
  • Ø Functional redundancy (most notably among inflammatory chemokines)
  • Ø Structural similarity and cross-species sequence conservation
  • Ø Dual functional motives: extracellular anchorage and receptor binding domains (except for membrane-bound forms)

The complex system of chemokines and their receptors expressed on immune cells is thought to reflect the exquisite complexity of immune cells that include a variety of precursor cells that undergo differentiation in primary lymphoid tissues, mature immune cells that inspect all tissues in our body and effector cells of both the innate and adaptive immune system that are mobilised in response to acute infections. The combination of chemokine receptors on immune cells represents an address code that guides individual immune cells to the tissue location where the corresponding chemokines are produced.

The unquestionable importance of chemokines in all aspects of immunity (haematopoiesis, immune surveillance, infection/disease) prompted an intensive, worldwide search for drugs that inhibit their function. At this point two chemokine receptor-specific drugs are approved for clinical use (Maraviroc for the treatment of HIV-1 patients, and AMD3100 for bone marrow stem cell mobilisation) but many more are in the pipeline.

Professor Bernhard Moser holds the Chair of Infection and Immunity at Cardiff University. He studied at the Federal Institute of Technology, Zürich (Diploma in Biochemistry, 1981) and at the University of British Columbia, Vancouver (PhD in Microbiology and Immunology, 1988). He was promoted to Privatdozent (PD in Medicine and Natural Sciences, 1995) and to Professor (2006) at the University of Bern. He spent his sabbatical leave in the laboratory of Prof. M. Brenner (Havard University, 1997-98). Distinctions include the Pfizer Research Award (1997, jointly with Dr. P. Lötscher), the Prof. Dr. Max. Clöetta Price (2003) and the Royal Society-Wolfson Research Merit Award (2007). He is a member of many academic societies, including the Henry Kunkel Society. Research of Prof. Moser’s group centers on human chemokines and their receptors expressed by immune cells. Initial work focused on the identification of chemokine receptors (starting with the IL-8 receptors, CXCR1 and CXCR2), followed by their biochemical and functional characterization. His group was first in identifying the human chemokine receptors CXCR3, CXCR4, CXCR5, CXCR6, CCR3 and CCR8. These findings enabled them to investigate (i) the role of CXCR4 in HIV infection, (ii), chemokine receptor antagonists, (iii) control of T cell migration (discovery of follicular B helper T (TFH) cells), and (iv) role of homeostatic chemokines in tissue homeostasis and immune defence. Finally, his group identified gdT-APCs, human gdT cells with professional antigen presentation functions, and this discovery is now being translated into the clinics (cellular immunotherapy of cancer patients). Long-standing collaborators included Prof. C. Mackay (Monash University, Melbourne). Prof. F. Arenzana-Seisdedos (Pasteur Institute, Paris) and Prof. I. Clark-Lewis (UBC, Vancouver). Several of these findings led to patents, and Prof. Moser is frequently asked for advice by major pharmaceutical companies.

Cyhoeddiad

2024

2023

2022

2021

2020

2018

2017

2016

2015

2014

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

2003

2001

2000

Erthyglau

Ymchwil

Below is are samples of past and current research activites (in chronological order) of the Moser lab:

1        Moser, B., I. Clark-Lewis, R. Zwahlen, and M. Baggiolini. 1990. Neutrophil-activating properties of the melanoma growth-stimulatory activity. J. Exp. Med. 171:1797-1802. (PMID: 2185333)

Functional rebranding of the tumour growth cytokine MGSA as a potent neutrophil chemoattractant (today known as CXCL1).

2        Moser, B., C. Schumacher, V. von Tscharner, I. Clark-Lewis, and M. Baggiolini. 1991. Neutrophil-activating peptide 2 and gro/melanoma growth-stimulatory activity interact with neutrophil-activating peptide 1/interleukin 8 receptors on human neutrophils. J. Biol. Chem. 266:10666-10671. (PMID:2037605)

First biochemical demonstration that human neutrophils express two types of IL-8 receptors, CXCR1 and CXCR2; the corresponding cDNAs were reported subsequently in the same year by the groups of P.M. Murphy (NIH) and W.I. Wood (Genentech).

3        Moser, B., B. Dewald, L. Barella, C. Schumacher, M. Baggiolini, and I. Clark-Lewis. 1993. Interleukin-8 antagonists generated by N-terminal modification. J. Biol. Chem. 268:7125-7128. (PMID: 8463247)

Demonstration that potent inhibitors of IL-8 receptors can be generated by IL-8 structure variation.

4        Loetscher, M., B. Gerber, P. Loetscher, S. A. Jones, L. Piali, I. Clark-Lewis, M. Baggiolini, and B. Moser. 1996. Chemokine receptor specific for IP10 and Mig: Structure, function and expression in activated T lymphocytes. J. Exp. Med. 184:963-969. (PMID: 9064356)

Discovery of first T cell-specific chemokine receptor (CXCR3), shifting research interests from innate to adaptive immune cells. (>790 citations)

5        Oberlin E., Amara A., Bachelerie F., Bessia C., Virelizier J.L., Arenzana-Seisdedos F., Schwartz O., Heard J.M., Clark-Lewis I., Legler D.F., Loetscher M., Baggiolini M., Moser B. 1996. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature., 382: 833-835. (PMID: 8752281)

Discovery of SDF-1 (now termed CXCL12) as the specific chemokine ligand for LESTR (now termed CXCR4) and its potent suppressive activity for X4-HIV-11 (back-to-back publication with T.A. Springer's group, Harvard Medical School). (>1,200 citations)

6        Arenzana-Seisdedos, F., Virelizier, J.-L., Rousset, D., Clark-Lewis, I., Loetscher, P., Moser, B. and Baggiolini, M. 1996. HIV blocked by chemokine antagonist. Nature 383: 400.  (PMID: 8837769)

This report demonstrates the potent inhibition of R5-HIV-1 infection by a novel class of RANTES/CCL5-based CCR5 antagonist.

7        Stuber Roos, R., M. Loetscher, D.F. Legler, I. Clark-Lewis, M. Baggiolini, and B. Moser. 1997. Identification of CCR8, the receptor for the human CC chemokine I‑309. J. Biol. Chem., 272:17251-17254. (PMID: 9211859)

Discovery of CCR8 as the specific receptor for the chemokine I-309 (now termed CCL1); this finding formed the basis of our current investigations into human skin-specific memory T cells (see also refs 13 and 20)

8        Legler, D.F., M. Loetscher, R.S. Roos, I. Clark-Lewis, M. Baggiolini, and B. Moser. 1998. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J. Exp. Med., 187:655-660. (PMID: 9463416)

Discovery of BCA-1 (now termed CXCL13) as a potent B cell chemoattractant with selectivity for MDR15/BLR1 (now termed CXCR5). (>400 citations)

9        Loetscher, P., M. Uguccioni, L.Bordoli, M. Baggiolini, B. Moser, C. Chizzolini, J.M. Dayer. 1998. CCR5 is characteristic of Th1 lymphocytes. Nature, 391:344-345. (PMID: 9450748)

Demonstration that CCR5 is preferentially expressed on Th1 cells, giving a rationale for the depletion of peripheral blood Th1 cells during primary infection with R5-HIV-1. (>690 citations)

10      Arenzana-Seisdedos, F., A. Amara, D. Thomas, J.-L. Virelizier, F. Baleux, I. Clark-Lewis, D.F. Legler, B. Moser, and M. Baggiolini. 1998. b-chemokine MDC and HIV‑1 infection. Science, 281:487a.

Technical comment in response to a Science report by R. Gallo's group (Baltimore). Demonstration that R. Gallo’s report is wrong, saying that MDC (now termed CCL22) and its selective receptor CCR4 act as HIV-1 suppressor and HIV-1 co-receptor, respectively. Merger of the two fields, chemokines and HIV infection, created a substantial number of controversial reports.

11      Schaerli, P., K. Willimann, A.L. Lang, M. Lipp, P. Loetscher, and B. Moser. 2000. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med., 192:1553-1562. (PMID: 11104798)

Demonstration that CXCR5 is characteristic for a subset of human CD4+ T cells with B cell helper activities. Together with a back-to-back report by M. Lipp’s group (Berlin), these findings led to the definition of a novel Thelper subset, which we have termed follicular B helper T cells (TFH cells). (>370 citations)

12      Kurth, I., K. Willimann, P. Schaerli, T. Hunziker, I. Clark-Lewis, and B. Moser. 2001. Monocyte selectivity and tissue localization suggests a role for breast and kidney–expressed chemokine (BRAK) in macrophage development. J. Exp. Med. 194:855-862. (PMID: 11561000)

Demonstration of the epithelial tissue localisation of the novel chemokine BRAK (now termed CXCL14) and its selectivity for monocytes. The finding initiated our interest in immune surveillance of peripheral tissues.

13      Schaerli, P., L. Ebert, K. Willimann, A. Blaser, R. Stuber Roos, P. Loetscher, and B. Moser. 2004. A skin-selective homing mechanism for human immune surveillance T cells. J. Exp. Med., 199:1265-1275.  (PMID: 15125746)

First report of a selective accumulation of CCR8+ T cells in healthy human skin, which led to current research into the mechanisms underlying the generation/maintenance of steady-state immunity (immune surveillance) in healthy peripheral tissues.

14      Brandes, M., K. Willimann, and B. Moser. 2005. Professional antigen-presentation function by human gd T cells. Science, 309:264-268. (PMID: 15933162)

Discovery of gdT-APC (VgVd-TCR gdT cell-derived antigen-presenting cells). These findings formed the basis for current translational initiatives directed at using gdT-APC vaccines for immunotherapy of cancer patients.  (>230 citations)

15      Schaerli, P., K. Willimann, L.M. Ebert, A. Walz, and B. Moser. 2005. Cutaneous CXCL14 targets blood precursors to epidermal niches for Langerhans cell differentiation. Immunity, 23:331-342. (PMID: 16169505)

In an extension to ref 12, this report provides evidence for a role of CXCL14 in the generation of cutaneous dendritic cells under steady-state conditions. First demonstration of the importance of tissue factors in “shaping” immune surveillance cells.

16      Brandes, M., K. Willimann, G. Bioley, N. Lévy, M. Eberl, M. Luo, R. Tampé, F. Lévy, P. Romero, and B. Moser. 2009. Cross-Presenting Human gd T Cells Induce Robust CD8+ ab T Effector Cell Responses. Proc. Natl. Acad. Sci. USA 106:2307-2312. (PMID: 19171897)

In an extension to ref 14, this report demonstrates the ability of gdT-APC to cross-present antigens to CD8+ T cells, which is relevant for the initiation of anti-tumour immunity.

17    Eberl, M., G. W. Roberts, S. Meuter, J.D. Williams, N. Topley, and B. Moser. 2009. A rapid crosstalk of human gd T cells and monocytes drives the acute inflammation in bacterial infections. PLoS Pathogens 5:e1000308. (PMID: 19229322)

This report highlights the functional synergy between gdT cells and monocytes, two types of immune cells that are recruited early to sites of microbial infections.

18      Meuter, S., M. Eberl, and B. Moser. 2010. Prolonged antigen survival and cytosolic export in cross-presenting human gd T cells. Proc. Natl. Acad. Sci. USA 107:8730-8735. (PMID: 20413723)

In an extension to refs 14 and 16, this report interrogates mechanisms underlying the exceptional antigen cross-presentation capabilities of gdT-APC, which is of obvious relevance to tumour immunotherapy.

19      Islam, S.A., D.S. Chang, R.C. Colvin, M.H. Byrne, M.L. McCully, B. Moser, S.A. Lira, I.F. Charo, and A.D. Luster. 2010. Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ Th2 cells. Nat. Immunol. 12:167-177. (PMID: 21217759)

This report demonstrates that CCR8 is expressed on a subset of human blood Th2 cells, lending “weight” to the findings in mice of CCR8 expression on Th2 cells in a model of atopic dermatitis. This work pertains directly to current research into human skin T cells.

20      McCully, M.L., K. Ladell, S. Hakobyan, R.E. Mansel, D.A. Price, and B. Moser. 2012. Epidermis instructs skin homing receptor expression in human T cells. Blood 120:4591-98. (PMID:23043070)

Based on novel staining reagents, this report identifies CCR8 as a marker for skin-specific immune surveillance T cells, whose generation is dependent on epidermis-derived T cell differentiation factors. This study forms the basis for current cutaneous CCR8+ T cell research.

Bywgraffiad

08/1981 – 07/1982      Research Associated      Federal Institute of Technology (ETH), Zurich

12/1988 – 08/1994      Research Assistant         Theodor-Kocher Institute, University of Bern, Bern

09/1994 – 12/2004      Group Leader                  Theodor-Kocher Institute, University of Bern, Bern

09/1997 – 07/1998      Visiting Professor            Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston

08/2001 – 12/2003      Director                           Theodor-Kocher Institute (TKI), University of Bern, Bern

01/2004 – 11/2006      Group Leader                  Institute of Cell Biology, University of Bern, Bern

12/2006 – present       Professor                        Chair in Infection & Immunology, Cardiff University, Cardiff

05/2007 – 09/2011      Chair                               Infection, Immunity & Inflammation Interdisciplinary Research Group, Cardiff                                                                                 University, Cardiff

Anrhydeddau a dyfarniadau

1983-85       Terry Fox Cancer Research Foundation Grad. Scholarship (Canada)

1995-2000   Prof. Dr. Max Cloëtta Research Career Development Award (Switzerland)

1997            Pfizer Research Prize (Rheumatology/Immunology) (USA)

2003            Prize Prof. Dr. Max Cloëtta (Switzerland)

2007            Royal Society-Wolfson Research Merit Award (UK)

2008            Henry Kunkel Society (member) (USA)

Gwahaniaethau yng gwaed cleifion â Covid hir

Gwahaniaethau yng gwaed cleifion â Covid hir

04 April 2023