Reviewing the 5th International Therapeutic Tolerance Workshop (#TTW2022)

From June 28th to July 1st, 2022, Newcastle-upon-Tyne played host to the 5th International Therapeutic Tolerance Workshop (#TTW2022), traditionally held every four years, with a one-year hiatus due to Covid-19. The workshop took place at the university’s brand new 24-acre science district: The Helix, previously home to the brewery that produced the regions famous “Newcastle Brown Ale”. Each successive workshop has tracked the progress and evolution of therapeutic tolerance research, from “Myth or Reality?” (2005) to “Lessons Learned” (2022). In the award-winning Catalyst building, Professor John Isaacs (Newcastle University, UK) welcomed 170 attendees from a variety of scientific backgrounds and career stages to celebrate, explore and discuss the latest advances.

Speakers and topics covered 
Cellular mediators in the breach of immune tolerance were the primary focus of the opening session; René Toes (Leiden University Medical Centre, Leiden) discussed the potential of using glycosylation state of anti-citrullinated peptide antibodies (ACPA) as a biomarker to improve the prediction model of developing rheumatoid arthritis (RA). He described how the presence of variable domain glycans in healthy individuals with ACPAs is associated towards the transition to RA.

Timothy Tree (King’s College London, UK) then spoke about the current lack of consistency in type 1 diabetes mellitus (T1DM) trials and how an initiative, INNODIA, aimed to improve this. One aim of INNODIA was to harmonise five high dimensional flow cytometry panels to allow monitoring of over 140 cell populations across sites around Europe. In addition to this, Timothy spoke about functional assays he has developed, including a micro-suppression assay, which uses a cell sorter to vastly reduce the cell number needed.

Joanne Jones from Cambridge University, UK, described how CD8 regulatory T cells (Tregs) are currently understudied, but in her hands showed equal suppressive action to CD4 Tregs. Low frequencies of CD8 Tregs were found in human umbilical cord blood but showed expression of CD103, a receptor involved in tissue homing. Looking across human tissues, Joanne found significant levels of these CD103⁺ CD8 Tregs, implying an important homeostatic role.

There were also opportunities for PhD students and early career researchers to present. Bruno Raposo from Karolinska Institute (Stockholm, Sweden) spoke about how past mouse models of RA lack a true anti-citrullinated peptide T-cell response. He identified clinically relevant T-cell receptors (TCRs) from RA patients and re-expressed these in a novel mouse model. These mice could develop RA in a citrullinated-antigen dependent manner. 

Wednesday morning started with an inspiring keynote session by Shimon Sakaguchi (Osaka University, Japan). The father of Tregs presented ‘developing therapies to target the immune system’, specifically covering the differentiation of antigen specific effector/memory T-cells to functionally stable FoxP3⁺ Tregs, to induce and maintain self-tolerance and potentially provide Treg cell therapy for autoimmune and inflammatory diseases.

The first theme of the morning was ‘human tolerance trials - the story so far’. James Hutchinson (University Hospital Regensburg, Germany) and Fadi Issa (University of Oxford, UK) of the ONE study consortium spoke about this large-scale international transplantation study. Their aim is to produce feasible regulatory cell-based therapies whilst avoiding unwanted immune suppression, in order to move towards immune-regulated allograft acceptance. They conducted a study where they collected clinical and immunological outcomes from phase I/II trial datasets conducted in Europe and the USA, involving different regulatory cell-based therapies, namely T-regs, tolerogenic dendritic cells (tolDCs) or regulatory macrophages (Mregs). They then compared this to a “reference group trial”, comprised of a standard-of-care cohort receiving basiliximab, tapering steroids, mycophenolate mofetil (MMF) and tacrolimus. They demonstrated that regulatory cell-based therapies can be practicable and safe in living-donor kidney transplant recipients. 

The topic of the late morning was centred around delivery of therapies to patients. Eva Martínez-Cáceres (Barcelona Clinical Hospital, Spain) demonstrated safe, well tolerated tolerogenic DC (tolDC) intranodal and intradermal injection options in multiple sclerosis (MS). This was followed by Piotr Trzonkowski’s (Medical University of Gdansk, Poland) successful work in developing Treg delivery systems in established diabetes, with future studies aimed at identifying and treating pre-symptomatic patients. 

Wednesday afternoon was dedicated to the role of co-stimulation blockade in tolerance. Natalie Edner (University College London, UK) presented her work on the mechanism of abatacept action in T1DM, demonstrating follicular helper T-cells to be predictive of clinical response. Sticking with the theme of abatacept, Georg Schett (Universitätsklinikum Erlangen, Germany) discussed the results of the ARIAA trial, in which abatacept appears to successfully delay progression to established RA amongst at risk individuals. A further round of oral presentations followed later in the afternoon, with talks ranging from early proof of concept work on novel therapeutic strategies such as CRISPR modified Tregs (Ibo Janssens, Antwerp, Belgium), to the results of Ranjeny Thomas’ (University of Queensland Diamantina Institute, Brisbane, Australia) early phase clinical trial of den 181, a novel tolerogenic nanoparticle.

The closing session was the first of the meeting’s great debates, with Ranjeny Thomas debating against Sir Robert Lechler (King's College London, UK) for the motion ‘this house believes that tolerance isn’t tolerance without biomarkers’. Whilst Sir Robert stressed the point that one does not need a biomarker to be deemed healthy, common ground was at least shared on the notion that prediction of complications, be that transplant rejection or relapse of autoimmunity, was a major goal of tolerance research. With no post-debate vote, the only clear winner was the audience!

The Thursday morning session saw a focus on the latest clinical data for the use of Tregs in autoimmune diseases and transplantation. Sir Robert Lechler illustrated the opportunities for drug free tolerance in liver and kidney transplantation, while Giovanna Lombardi (King’s College London, UK) gave an insight into the outcomes from the ONE, TWO and LIBERATE trials. A recent success of CAR-T therapy was demonstrated by Georg Schett, who used CD19 CAR T-cells targeting B cells, to treat systemic lupus erythematosus. 

Pere Santamaria (University of Calgary, Canada), founder of Parvus Therapeutics, gave an insight into their Navacims™, peptide MHC based nanomedicines as novel therapeutic options for antigen-specific targeting of a broad range of autoimmune diseases, while David Wraith (University of Birmingham, UK) focused on Apitopes (antigen processing independent epitopes) as promising candidates for MS and Graves’ disease.

During the second half of the session Lars Klareskog (Karolinska Institutet, Sweden) discussed the opportunity for early interventions to delay and prevent autoimmune diseases. Lisa Wagar (University of California, USA) presented a novel organoid model generated from tonsil biopsies, with a potential for studying immune responses and molecular mechanisms of disease. Nikhil Jain’s (Institute of Translational Medicine, Zurich, Switzerland) latest data showed that degradation of the nuclear lamina alters cellular morphology and motility, ultimately associated with inflammation. Suppressing this event is an attractive potential option for inhibiting pro-inflammatory responses. James Wason (Newcastle University, UK) closed the session with a talk on innovative protocol designs for clinical trials. 

The afternoon focused on checkpoint inhibitor (CPI)-induced disease, delivered by a “Boston trio” (Massachusetts General Hospital, Boston, MA, USA). Deepak Rao was first to introduce this topic, illustrated through a patient case affected by CPI-induced arthritis. He demonstrated how histology patterns and cellular distributions in the knee synovium can change over time, with a heavier neutrophil infiltrate seen at time zero which later changed into a dense lymphocytic predominance at 6-months. He demonstrated how CPI-induced arthritis is more reflective of a psoriatic picture rather than RA, and characterised specific effector CD8 T-cell subsets (CD38hi CD127-) involved in its mediation. This was neatly followed by talks on CPI-colitis and -myocarditis from colleagues, Molly Thomas and Dan Zlotoff, respectively, who showed raised serum levels of selected immunomodulatory factors such as CXCL-10 and –11, as well as lymphocyte predominance in CPI-induced disease.

The day ended with the second debate ‘This house believes that T-cells are the undisputed therapeutic tolerance target’. Michael Maldonado (University of Pennsylvania, Philadelphia, PA) argued “for”, leading us through the central role of T-cells, whilst Claudia Mauri (University College London, UK) delivered strong counterarguments “against”, with emphasis on why B-cells should be the main tolerance focus. Both defended their sides well despite challenging questions from the audience, providing another workshop highlight. 

The final morning of the workshop began with several fascinating discussions focussed on tolerance inducing cellular therapies in both autoimmunity and solid-organ transplantation. Interestingly, of the highly varied therapies discussed (autologous haematopoietic stem cell transplantation, durable mixed chimerism, and IL-1 inhibition), both regulatory T- and B- cell expansion appeared to correlate largely with tolerance induction. Stuart Forbes (University of Edinburgh, UK) introduced us to the MATCH study, a novel macrophage cell therapy for the treatment of liver cirrhosis. For a disease that would otherwise require liver transplantation, macrophage therapy was shown to be a safe and promising approach. They were also able to demonstrate regression of observable fibrotic scars and macrophage induced matrix metalloproteinase (MMP) upregulation.

Predicting remission was the focus of the next session, where Kenneth Baker (Newcastle University, UK) delivered a captivating presentation on the potential ‘good’ and ‘bad’ guy cell types involved in both disease flare (IgA⁺ plasma cells) and disease remission (regulatory T cells) in RA. Rachel Knevel (Leiden University Medical Center, Leiden) followed with a talk on the importance of stromal cells in RA, showing how a genome-wide association study of the fkbp7 gene in synovial fibroblasts was a potential predictive biomarker for remission in RA. 

The third and final session of the day showcased a breadth of novel and fascinating science in the format of short talks from a diverse range of upcoming researchers comprised of PhD students and early career researchers. The top-prize winning presentation from PhD student, Carl Coyle (King’s College London, UK) showed that the CD8⁺ CD57⁺ NKG2A⁺ KIR^- NK-cell subset was highly associated with stable-remission in RA, further supporting the need for multiple predictive biomarkers.

Sophie Reay and Emma Jackson (Newcastle University, UK) closed the session by demonstrating how excellent scientific collaboration between immunologists and bioengineers can be harnessed to generate novel therapeutics for RA, by presenting work on chitosan based macroparticles for the induction of tolerogenic dendritic cells in vivo. 

Conclusion 
After a stimulating and thought-provoking four days of scientific excellence from 62 speakers representing over 16 countries, the 5th Newcastle International Therapeutic Tolerance Workshop was drawn to a close by John Isaacs. Where tolerance will be in the next four years is not yet known, but one thing that was reinforced by multiple speakers, and explicitly stated by James Hutchinson, is that “international cooperation accelerates scientific achievement”.

The authors would like to thank Dr Fiona Cooke and Professor John Isaacs from our research group for kindly proof-reading the manuscript and Ms Lisa Tait for expertly organising every aspect of the workshop. 

Abbie Degnan, Ioana Nicorescu, James Stanway, Jessica Swift, Kristian Williams and Chung Mun Alice Lin

Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK