MICA: Investigating the pathogenic role of T follicular helper cells and their therapeutic targeting in primary Sjogren's syndrome
Lead Research Organisation:
Queen Mary University of London
Department Name: William Harvey Research Institute
Abstract
Sjögren's syndrome (SS) is the second most common rheumatic autoimmune disease with a prevalence affecting between 100,000-250,000 in UK and a predominance in women (female to male ratio is 9:1). SS is characterised by immune cell infiltration in the salivary and lacrimal glands leading to dry mouth and dry eyes. However, SS is a highly heterogeneous disease with 30/40% of SS patients developing moderate to severe extraglandular manifestations and 5% developing a form of cancer (lymphoma) which arise from B cells, a type of white blood cells. Currently, the treatment of SS is unsatisfactory with no effective therapies available.
Studies from our and other groups have identified a subset (30-40%%) of SS patients which present B cell clusters in the salivary glands called germinal centres. These patients have a more active disease and have a 16-fold higher risk of developing lymphoma than the remaining patients without germinal centres.
Previous work has demonstrated that another subset of very specialised white blood cells, called T follicular helper (Tfh) cell, play a critical role in supporting the survival and activation of B cell in germinal centres. While the role of Tfh is well established in germinal centres which arise in lymphoid organs (i.e. the spleen, tonsils or lymph glands) their role in aberrant germinal centres which form during chronic inflammatory disease is unknown.
Thus, in this application, which is a Partnership between 3 UK Universities and MedImmune, a pharmaceutical company, we aim 1) to investigate the role of Tfh in promoting the disease in a series of studies involving human samples and animal models; 2) to address whether blocking Tfh in preclinical studies with novel pharmaceutical compounds will impact on various features of the disease, such as the activation of B cell in the salivary glands and the amelioration of salivary flow and 3) to identify key factors which will allow us to understand which SS patients are more likely to respond to novel treatment targeting Tfh in SS.
This proposal have the objective to have immediate clinical impact as MedImmune and the Academic partners of this application are working closely together to bring novel treatments in the clinic for the benefit of patients with SS (pilot clinical studies planned for late 2015 and in 2016 in UK). It is envisaged that, if successful, this work will also impact on other medical conditions which might benefit from targeting Tfh cells. Specifically, we anticipate that this proposal will bring new knowledge and will identify key factors which will allow us to measure the level of activation of Tfh in different patients. This work will be essential because will inform on which SS patients are more likely to respond to the new treatments that we are developing and will be tested in upcoming clinical trials in SS. These trials will be based on the concept of "target validation", whereby the work done in this project will put us in the position to stratify patients based on the level of Tfh present in their salivary glands (or in their blood). We hope that this approach on one side will increase the response rate and on the other side will prevent SS patients who are unlikely to respond from being exposed to the potential side effects of the novel treatments.
Studies from our and other groups have identified a subset (30-40%%) of SS patients which present B cell clusters in the salivary glands called germinal centres. These patients have a more active disease and have a 16-fold higher risk of developing lymphoma than the remaining patients without germinal centres.
Previous work has demonstrated that another subset of very specialised white blood cells, called T follicular helper (Tfh) cell, play a critical role in supporting the survival and activation of B cell in germinal centres. While the role of Tfh is well established in germinal centres which arise in lymphoid organs (i.e. the spleen, tonsils or lymph glands) their role in aberrant germinal centres which form during chronic inflammatory disease is unknown.
Thus, in this application, which is a Partnership between 3 UK Universities and MedImmune, a pharmaceutical company, we aim 1) to investigate the role of Tfh in promoting the disease in a series of studies involving human samples and animal models; 2) to address whether blocking Tfh in preclinical studies with novel pharmaceutical compounds will impact on various features of the disease, such as the activation of B cell in the salivary glands and the amelioration of salivary flow and 3) to identify key factors which will allow us to understand which SS patients are more likely to respond to novel treatment targeting Tfh in SS.
This proposal have the objective to have immediate clinical impact as MedImmune and the Academic partners of this application are working closely together to bring novel treatments in the clinic for the benefit of patients with SS (pilot clinical studies planned for late 2015 and in 2016 in UK). It is envisaged that, if successful, this work will also impact on other medical conditions which might benefit from targeting Tfh cells. Specifically, we anticipate that this proposal will bring new knowledge and will identify key factors which will allow us to measure the level of activation of Tfh in different patients. This work will be essential because will inform on which SS patients are more likely to respond to the new treatments that we are developing and will be tested in upcoming clinical trials in SS. These trials will be based on the concept of "target validation", whereby the work done in this project will put us in the position to stratify patients based on the level of Tfh present in their salivary glands (or in their blood). We hope that this approach on one side will increase the response rate and on the other side will prevent SS patients who are unlikely to respond from being exposed to the potential side effects of the novel treatments.
Technical Summary
In this proposal we will test the hypothesis that T follicular helper (Tfh) cells fuel autoreactive B cell activation and autoimmunity in Sjogren's syndrome (SS), in particular in patients with germinal centres (GC) in the salivary glands (SG). Moreover, we aim to pursue with our industrial partner a translational program to develop Tfh blocking agents for clinical use in SS and to understand how Tfh-based patient stratification may inform randomised clinical trial (RCT) design. We will proceed following 3 progressive steps:
1) To investigate the presence of Tfh and their products in the circulation and SG of SS and characterise their functional role in promoting autoreactive B cell activation.
We will access the deeply phenotyped EMR SS Biobank with over 150 SG biopsies with matching histology, RNA and peripheral blood. To identify Tfh-related signatures and stratify samples according to the degree of lymphoid organization, we will use:
i) multicolour confocal microscopy
ii) Fluidigm microfluidic chips
iii) multicolour FACS analysis
iv) in vitro organ cultures
2) To test in vivo the efficacy of pharmacological blockade of Tfh in modulating sialoadenitis, autoimmunity and exocrine dysfunction in murine models of SS.
We will block key factors involved in Tfh function, such as the ICOS/ICOSL and the IL-21/IL21R pathways, in order to ameliorate disease in 2 animal models of SS:
i) spontaneous NOD.H2h4 mice
ii) novel human SS/SCID xeno-grafts
3) To define the contribution of Tfh to SG pathobiology and disease outcome through the analysis of biopsies pre- and post-treatment in order to inform Tfh-based patient stratification.
We will use matching SG biopsies and peripheral blood collected as part of the UK multicentre RCT of Rituximab in SS. Using the techniques summarised in Aim 1, we will investigate whether:
i) Tfh signatures are influenced by B cell depletion
ii) persistency of Tfh allows the escape of autoreactive B cells in the SG
1) To investigate the presence of Tfh and their products in the circulation and SG of SS and characterise their functional role in promoting autoreactive B cell activation.
We will access the deeply phenotyped EMR SS Biobank with over 150 SG biopsies with matching histology, RNA and peripheral blood. To identify Tfh-related signatures and stratify samples according to the degree of lymphoid organization, we will use:
i) multicolour confocal microscopy
ii) Fluidigm microfluidic chips
iii) multicolour FACS analysis
iv) in vitro organ cultures
2) To test in vivo the efficacy of pharmacological blockade of Tfh in modulating sialoadenitis, autoimmunity and exocrine dysfunction in murine models of SS.
We will block key factors involved in Tfh function, such as the ICOS/ICOSL and the IL-21/IL21R pathways, in order to ameliorate disease in 2 animal models of SS:
i) spontaneous NOD.H2h4 mice
ii) novel human SS/SCID xeno-grafts
3) To define the contribution of Tfh to SG pathobiology and disease outcome through the analysis of biopsies pre- and post-treatment in order to inform Tfh-based patient stratification.
We will use matching SG biopsies and peripheral blood collected as part of the UK multicentre RCT of Rituximab in SS. Using the techniques summarised in Aim 1, we will investigate whether:
i) Tfh signatures are influenced by B cell depletion
ii) persistency of Tfh allows the escape of autoreactive B cells in the SG
Planned Impact
The project will have a significant impact both on basic research and applied translational science.
1. Impact on basic research and knowledge acquisition within and beyond the field of SS and rheumatology.
Tfh cells play a fundamental role in the regulation of adaptive immune responses, specifically on B cell activation and germinal centres in secondary lymphoid organs. Our proposal aims to investigate Tfh within ectopic germinal centres forming in the salivary glands of patients with SS. Thus, at the basic science level a better understanding of the role of key pathways involved in Tfh function, such as the ICOS/ICOSL and IL-21/IL-21R will broadly benefit the scientific community with considerable advance in knowledge not only in the specific field of SS but also other autoimmune diseases, characterized by ectopic germinal centres (i.e. rheumatoid syndrome, lupus nephritis, inflammatory bowel diseases, multiple sclerosis, autoimmune thyroiditis etc).
2. Impact on translational and clinical research
- Moving towards new therapeutics in SS: Demonstration that blocking Tfh cells ameliorate sialoadenitis, autoimmunity and exocrine dysfunction will provide supporting evidence that targeting Tfh-related pathways is a potential therapeutic strategy in SS. The opportunity to dissect the molecular functions in vitro and in vivo (SCID/SS chimeras) using human tissues will provide invaluable data for the translational relevance of this pathway to the disease. Our aim is to impact on clinical trial design by identifying biomarkers that could be used to stratify patients prior to inclusion in clinical studies. MedImmune, the Industrial partner of this application, has invested significant resources to bring preclinical compounds towards early phase clinical trials. The PI and Academic co-applicants of this application are working closely with MedImmune within the NIHR NOCRI translational research partnership to develop RCTs in SS. This project will impact in defining inclusion criteria and clinical and biological endpoints in view of starting patient recruitment in late 2015 (anti-ICOS) and from 2016 (anti-IL-21).
- Broader impact on translational and clinical science through the development of Tfh blocking agents for clinical use: MedImmune is a world player in antibody therapeutics with significant expertise in the development of novel therapeutics in autoimmune diseases. SS as a first indication is highly ranked in the translational pipeline. The opportunity to develop unique reagents in partnership with MedImmune will further accelerate the developmental programme to bring Tfh targeted therapies for clinical use not only in patients with SS, but also in other autoimmune conditions characterized by autoreactive B cell activation.
3- Commercial impact on the public and private sector. A defined developmental programme described in this application coupled with a strong Academic Industry partnership will maximise the opportunity to translate novel scientific and clinical observation into commercially valuable assets such as diagnostic or therapeutic agents. The equitable Head of Terms agreed between QMUL and MedImmune will also ensure that economic benefits will profit both private and public partners.
4- Impact on patient health. It is hoped that the ultimate beneficiaries of this research will be patients with SS, a disease with prevalence in UK between 0.2-0.5% (100,000-250,000 patients) which currently lacks disease modifying drugs. This application will impact directly on patient health as the pathways that we intend to study in this proposal will be targeted in early phase clinical trials during the proposed tenure of this application. The definition of Tfh-related tissue and/or peripheral biomarkers of disease activity as well as response (or lack thereof) to B cell depletion will make immediate impact on SS through patients stratification guiding "intelligent" clinical trial design.
1. Impact on basic research and knowledge acquisition within and beyond the field of SS and rheumatology.
Tfh cells play a fundamental role in the regulation of adaptive immune responses, specifically on B cell activation and germinal centres in secondary lymphoid organs. Our proposal aims to investigate Tfh within ectopic germinal centres forming in the salivary glands of patients with SS. Thus, at the basic science level a better understanding of the role of key pathways involved in Tfh function, such as the ICOS/ICOSL and IL-21/IL-21R will broadly benefit the scientific community with considerable advance in knowledge not only in the specific field of SS but also other autoimmune diseases, characterized by ectopic germinal centres (i.e. rheumatoid syndrome, lupus nephritis, inflammatory bowel diseases, multiple sclerosis, autoimmune thyroiditis etc).
2. Impact on translational and clinical research
- Moving towards new therapeutics in SS: Demonstration that blocking Tfh cells ameliorate sialoadenitis, autoimmunity and exocrine dysfunction will provide supporting evidence that targeting Tfh-related pathways is a potential therapeutic strategy in SS. The opportunity to dissect the molecular functions in vitro and in vivo (SCID/SS chimeras) using human tissues will provide invaluable data for the translational relevance of this pathway to the disease. Our aim is to impact on clinical trial design by identifying biomarkers that could be used to stratify patients prior to inclusion in clinical studies. MedImmune, the Industrial partner of this application, has invested significant resources to bring preclinical compounds towards early phase clinical trials. The PI and Academic co-applicants of this application are working closely with MedImmune within the NIHR NOCRI translational research partnership to develop RCTs in SS. This project will impact in defining inclusion criteria and clinical and biological endpoints in view of starting patient recruitment in late 2015 (anti-ICOS) and from 2016 (anti-IL-21).
- Broader impact on translational and clinical science through the development of Tfh blocking agents for clinical use: MedImmune is a world player in antibody therapeutics with significant expertise in the development of novel therapeutics in autoimmune diseases. SS as a first indication is highly ranked in the translational pipeline. The opportunity to develop unique reagents in partnership with MedImmune will further accelerate the developmental programme to bring Tfh targeted therapies for clinical use not only in patients with SS, but also in other autoimmune conditions characterized by autoreactive B cell activation.
3- Commercial impact on the public and private sector. A defined developmental programme described in this application coupled with a strong Academic Industry partnership will maximise the opportunity to translate novel scientific and clinical observation into commercially valuable assets such as diagnostic or therapeutic agents. The equitable Head of Terms agreed between QMUL and MedImmune will also ensure that economic benefits will profit both private and public partners.
4- Impact on patient health. It is hoped that the ultimate beneficiaries of this research will be patients with SS, a disease with prevalence in UK between 0.2-0.5% (100,000-250,000 patients) which currently lacks disease modifying drugs. This application will impact directly on patient health as the pathways that we intend to study in this proposal will be targeted in early phase clinical trials during the proposed tenure of this application. The definition of Tfh-related tissue and/or peripheral biomarkers of disease activity as well as response (or lack thereof) to B cell depletion will make immediate impact on SS through patients stratification guiding "intelligent" clinical trial design.
Organisations
- Queen Mary University of London (Lead Research Organisation)
- Cardiff University (Collaboration)
- Stanford University (Collaboration)
- Servier Laboratories (Collaboration)
- University of Paris (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- University Medical Center Gronigen (Collaboration)
- AstraZeneca (United States) (Project Partner)
Publications
Pontarini E.
(2018)
T follicular-helper cells (TFH) enrichment and follicular T regulatory cells (TFR) exclusion from ectopic germinal centers in salivary glands of Sjogren's Syndrome patients
in CLINICAL AND EXPERIMENTAL RHEUMATOLOGY
Price E
(2021)
The management of Sjögren's syndrome: British Society for Rheumatology guideline scope.
in Rheumatology (Oxford, England)
Price E
(2022)
Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren's syndrome: a randomized, phase 2, double-blind, placebo-controlled study.
in Rheumatology (Oxford, England)
Price EJ
(2017)
The British Society for Rheumatology guideline for the management of adults with primary Sjögren's Syndrome.
in Rheumatology (Oxford, England)
Price EJ
(2017)
The British Society for Rheumatology guideline for the management of adults with primary Sjögren's Syndrome.
in Rheumatology (Oxford, England)
Pucino V
(2019)
Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring.
in Cell metabolism
Pucino V
(2017)
Lactate at the crossroads of metabolism, inflammation, and autoimmunity.
in European journal of immunology
Retamozo S
(2021)
Influence of the age at diagnosis in the disease expression of primary Sjögren syndrome. Analysis of 12,753 patients from the Sjögren Big Data Consortium
in Clinical and Experimental Rheumatology
Seror R
(2022)
Development and preliminary validation of the Sjögren's Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren's syndrome.
in Annals of the rheumatic diseases
Weller ML
(2016)
Hepatitis Delta Virus Detected in Salivary Glands of Sjögren's Syndrome Patients and Recapitulates a Sjögren's Syndrome-Like Phenotype in Vivo.
in Pathogens & immunity
Yildirim D
(2021)
Composite endpoints for Sjögren's Syndrome
in The Lancet Rheumatology
Description | BSR and BHPR Guideline for the Management of Adults with Primary Sjögren's Syndrome |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
URL | http://www.rheumatology.org.uk/includes/documents/cm_docs/2016/f/full_guidline_open_cons_sjogrens.do... |
Description | FOREUM stratified medicine award scheme |
Amount | € 600,000 (EUR) |
Organisation | Foreum |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 07/2018 |
End | 07/2021 |
Description | Horizon 2020 funding for the HarmonicSS project on the harmonization of Sjogren's patients cohorts to change policy at european level |
Amount | € 10,000,000 (EUR) |
Funding ID | 731944 |
Organisation | European Commission |
Department | Horizon 2020 |
Sector | Public |
Country | European Union (EU) |
Start | 01/2017 |
End | 07/2020 |
Description | Investigating lactate as an inflammatory early signal in ectopic lymphoid neogenesis and its translational impact in patients with autoimmune diseases |
Amount | £581,947 (GBP) |
Funding ID | MR/T031980/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2020 |
End | 02/2023 |
Description | NECESSITY - New clinical endpoints in primary Sjögren's Syndrome: an interventional trial based on stratifying patients |
Amount | € 8,000,000 (EUR) |
Funding ID | 282540 |
Organisation | European Commission H2020 |
Sector | Public |
Country | Belgium |
Start | 01/2020 |
End | 12/2024 |
Title | Salivary gland organ cultures as preclinical models for therapeutic intervention |
Description | Salivary gland organ cultures have been set up from labial salivary gland biopsies from patients with Sjogren's syndrome. Each gland is divided in 2 and equally assigned to active compound or appropriate experimental control. Incubation time can vary from few hours to several days in culture (up to 7 days). Outcome include modulation of immunoglobulines and autoantibody production, cytokine release, FACS on egressed or digested cells, transcriptomic profile of whole RNA extracted from the tissue or from isolated cells. |
Type Of Material | Model of mechanisms or symptoms - human |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | This tool was presented at EULAR 2017 (Madrid, Spain) and International symposium on Sjogren's syndrome (Washington, USA, 2018) as a useful preclinical model to measure the biological effect of human-specific preclinical therapeutics prior to use in clinical trials in human. |
Title | Dataset related to article "NK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation." |
Description | Salivary glands (SGs) represent a permissive site for several sialotropic viruses whose persistence is linked to the development of autoimmunity. Natural Killer (NK) cells play a key role in viral clearance but their involvement in viral infection control and in tertiary lymphoid structures (TLS) development within SGs is unknown. By using an inducible model of TLS in the SGs of wild-type C57BL/6 mice, induced by the local delivery of a replication-defective adenovirus (AdV), we demonstrated that circulating NK cells are rapidly recruited to SGs and highly enrich the early inflammatory infiltrate prior to TLS development. NK cells migrating to SGs in response to AdV infection up-regulate NKp46, undergo proliferation, acquire cytotoxic potential, produce Granzyme-B and IFN-?, and reduce viral load in the acute phase of the infection. Nonetheless, the selective depletion of both circulating and infiltrating NK cells in AdV-infected mice neither affect the development and frequency of TLS nor the onset of autoimmunity. These data demonstrate that, upon local viral delivery of AdV, peripheral NK cells homing to SGs can exert an early control of the viral infection but are dispensable for the formation of TLS and breach of immunologic tolerance. This research used pzf and ets file form extensions, we attach pdfs information about |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
URL | https://zenodo.org/record/3712120 |
Title | NGS sequencing data of infiltrating B cells obtained from pSS patient salivary glands |
Description | We are in the process of uploading on Arrayexpress the 454-NGS sequencing data of infiltrating B cells obtained from 8 salivary gland biopsies of SS patients in preparation of the submission of a manuscript to a high impact factor journal. |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | We are in the process of uploading on Arrayexpress the 454-NGS sequencing data of infiltrating B cells obtained from 4 pSS patients as part of the process of submitting a manuscript to a high impact factor journal. |
Title | RNA-seq data of labial salivary gland biopsies of Sjogren vs sicca patients |
Description | Bulk RNA-seq data of labial salivary gland biopsies of Sjogren vs sicca patients |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | Available for additional analysis by other investigators as publicly available with no restriction to access Deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-10517. |
URL | http://www.ebi.ac.uk/arrayexpress |
Description | IMI-2 NECESSITY partnership WP3-WP4-WP5 |
Organisation | Servier Laboratories |
Department | International Research Institute Servier |
Country | France |
Sector | Private |
PI Contribution | I am leading as PI of QMUL on several projects related to WP3 (histopathology biomarker validation) and WP4 (peripheral blood biomarker validation) of the IMI2-NECESSITY partnership. I am also involved in WP5 (definition of new activity criteria for clinical trials) including the validation of the new CRESS score in the TRACTISS trial. |
Collaborator Contribution | University of Paris (PI Prof Xavier Mariette) coordinates the IMI-2 Necessity partnership. University Medical Center Gronigen co-lead with me (Prof Frans Kroese) the histopathology biomarker validation (WP3) and the development of the CRESS score (Prof Hendrika Bootsma) in WP5. Servier will be running RNASeq from whole blood RNA from the TRACTISS trial (baseline, Week 16 and week 48). |
Impact | IMI-2 Necessity WP3, WP4 and WP5 are still ongoing and it is estimated that will lead to formal outcomes by 2022. |
Start Year | 2020 |
Description | IMI-2 NECESSITY partnership WP3-WP4-WP5 |
Organisation | University Medical Center Gronigen |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | I am leading as PI of QMUL on several projects related to WP3 (histopathology biomarker validation) and WP4 (peripheral blood biomarker validation) of the IMI2-NECESSITY partnership. I am also involved in WP5 (definition of new activity criteria for clinical trials) including the validation of the new CRESS score in the TRACTISS trial. |
Collaborator Contribution | University of Paris (PI Prof Xavier Mariette) coordinates the IMI-2 Necessity partnership. University Medical Center Gronigen co-lead with me (Prof Frans Kroese) the histopathology biomarker validation (WP3) and the development of the CRESS score (Prof Hendrika Bootsma) in WP5. Servier will be running RNASeq from whole blood RNA from the TRACTISS trial (baseline, Week 16 and week 48). |
Impact | IMI-2 Necessity WP3, WP4 and WP5 are still ongoing and it is estimated that will lead to formal outcomes by 2022. |
Start Year | 2020 |
Description | IMI-2 NECESSITY partnership WP3-WP4-WP5 |
Organisation | University of Paris |
Country | France |
Sector | Academic/University |
PI Contribution | I am leading as PI of QMUL on several projects related to WP3 (histopathology biomarker validation) and WP4 (peripheral blood biomarker validation) of the IMI2-NECESSITY partnership. I am also involved in WP5 (definition of new activity criteria for clinical trials) including the validation of the new CRESS score in the TRACTISS trial. |
Collaborator Contribution | University of Paris (PI Prof Xavier Mariette) coordinates the IMI-2 Necessity partnership. University Medical Center Gronigen co-lead with me (Prof Frans Kroese) the histopathology biomarker validation (WP3) and the development of the CRESS score (Prof Hendrika Bootsma) in WP5. Servier will be running RNASeq from whole blood RNA from the TRACTISS trial (baseline, Week 16 and week 48). |
Impact | IMI-2 Necessity WP3, WP4 and WP5 are still ongoing and it is estimated that will lead to formal outcomes by 2022. |
Start Year | 2020 |
Description | Recombinant monoclonal antibodies from single lesional B cells isolated from the salivary glands of patients with Sjogren's syndrome |
Organisation | Stanford University |
Country | United States |
Sector | Academic/University |
PI Contribution | This is a collaborative effort with Prof WH Robinson at Stanford University aimed at dissecting the autoantigen specificity of B cells infiltrating and forming ectopic germinal centres in the salivary glands of patients with Sjogren's syndrome. In this collaboration, single B cell subsets (i.e. naive, vs memory vs plasmablasts) will be single cell sorted at our lab. Monoclonal antibodies will be then generated using either 1) traditional single cell PCR for the H and L Ig variable region as already established in my lab or 2) see below |
Collaborator Contribution | 2) in collaboration with Stanford following NGS and barcoding whereby individual IgH V region will be first sequenced and dominant clones established, including analysis of intra-lesional clonal diversification as indication of an antigen-driven response. Selected sequences will be then cloned into expression vectors for antibody expression and characterization of their antigenicity. |
Impact | This collaboration formed the basis for the recent award of an ARUK PhD Scholarship. |
Start Year | 2016 |
Description | Role of IL-27 in regulating TFh |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We entered a formal collaboration to conduct experiments in Cardiff University with a novel model of inducible ectopic lymphoid neogenesis that we previously developed via adenoviral-delivery in murine submandibular glands through retrograde cannulation of the excretory duct. |
Collaborator Contribution | Our collaborator is making available IL-27Ra KO mice to run the cannulation model |
Impact | The collaboration has just been formally set up, further details will be included in the next report period |
Start Year | 2016 |
Description | T cell profiling in Sjogren's syndrome |
Organisation | University of Cambridge |
Department | Department of Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided matched PBMC collected from patients with Sjogren's syndrome before and after treatment with Rituximab as part of the TRACTISS trial. We will be analysing T cell phenotype using a CyTOF panel that have finalised which will be compared with molecular signatures identified by the Cambridge group. |
Collaborator Contribution | Dr Paul Lyons in Cambridge will generate molecular signatures via RNA NGS on CD4 and CD8 populations sorted from PBMC. |
Impact | Analysis is under way |
Start Year | 2015 |
Title | Belimumab/Rituximab combination therapy in pSS |
Description | This study is based on Belimumab/Rituximab combination therapy in pSS and is sponsored by GSK. This study was developed based on contribution from my and other groups who showed that Rituximab is not efficacious in pSS, most likely because of lack of B cell depletion in the salivary gland, a process which is probably related to the high expression levels of BAFF in the salivary glands. Thus, the combination of Rituximab with an anti-BAFF monoclonal antibody (Belimumab) may yield improved clinical efficacy. We are one of only 3 UK sites selected to recruit for this trial and have already met our recruitment target 3 months into the study. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2018 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Results awaited in 2019 |
URL | https://clinicaltrials.gov/show/NCT02631538 |
Title | Clinical Trial in Sjogren's syndrome |
Description | This is a phase 2a clinical trial in primary Sjogren's syndrome using a anti-ICOSL antibody thus targeting interaction between Tfh cells and B cells. It is a co-development between Amgen and MedImmune. I am the CI for the UK and I will be intimately involved in the analysis of salivary gland biopsies taken before and after treatment in order to 1) identify biomarkers able to predict response to treatment and 2) elucidate mechanisms of action of the IP. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2017 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Clinical trial is completing recruitment. Impact will depend on the clinical outcomes. |
URL | https://clinicaltrials.gov/show/NCT02334306 |
Title | Phase II clinical trial in primary Sjogren's syndrome |
Description | This is a phase 2a clinical trial in primary Sjogren's syndrome blocking the CD40/CD40L interaction thus influencing the crosstalk bwtween Tfh cells and B cells. It is sponsored by Novartis and adopted by the NOCRI musculoskeletal translational research partnership (TRP). |
Type | Therapeutic Intervention - Drug |
Year Development Stage Completed | 2017 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Recruitment in progress, impact depending on clinical outcomes. |
URL | https://clinicaltrials.gov/show/NCT02291029 |