ACR 2017 | Daily Highlights
Induction of Immune Tolerance through an Epitope-Specific Vaccine Induces Clinical Amelioration in Patients with Rheumatoid Arthritis
Authors: Jin Hui Sherlynn Chan1, Theodorus van den Broek2, Jing Yao Leong1, Maura Rossetti3, Roberto Spreafico4 and Salvatore Albani1,5, 1SingHealth Translational Immunology and Inflammation Centre (STIIC), Duke-NUS Medical School, Singapore, Singapore, 2University Medical Center of Utrecht, Utrecht, Netherlands, 3University of California, Los Angeles, Los Angeles, CA, 4Synthetic Genomics, La Jolla, CA, 5KK Women's and Children's Hospital, Singapore, Singapore
The manipulation of immune tolerance using immune checkpoints such as PD-1 is gaining progressive attraction in diseases such cancer where such manipulation would be clinically relevant. In our previous studies, we have identified an antigenic epitope which contributes to autoimmune inflammation in rheumatoid arthritis. Using dnaJP1, a peptide derived from the pro-inflammatory dnaJ proteins, we have concluded Phase I and II clinical trials1,2 in which clinical amelioration was associated with the induction of immune tolerance to dnaJP1. Here, we hypothesize that clinical amelioration relies on immunomodulatory mechanisms of immune tolerance involving the reactivation of immune checkpoints.
PBMCs obtained at the end of the Phase II trial (Day168), from clinical responders treated with dnaJP1 (n=6) and clinical non-responders treated with placebo (n=10) were studied for gene expression by quantitative PCR and multi-coloured flow cytometry with antibody panels designed to investigate the T cell immunomes. Flow cytometry results were analysed by clustering with Multi-Dimensional Automated Reduction and Visualization (MARVis), an in-house customised machine learning software.
Analysis of PBMCs with the MARVis software employed in this study allowed for the identification of immune subsets and the dissection of complex interactions between immune cell populations at a level which was unachievable before. Examination of the T cell immunomes of dnaJP1 responders and placebo non-responders revealed that clinical amelioration is an outcome of an active process of tolerization. More specifically, the induction of immune tolerance appears to depend on the generation of a population of CD4+FoxP3+ regulatory T (Treg) cells in which PD-1 plays an active role in enhancing the production of anti-inflammatory cytokines such as TGFβ. This vital observation is complemented by the reshaping of the effector T (Teff) cell compartment which is accompanied by a significant decline in the expression of pro-inflammatory cytokines such as IL-17A and IFNγ between the start and the end of epitope-specific immunotherapy. In parallel, epitope-specific immunotherapy also elicited a subset of antigen-experienced memory T cells (CD4+CD45RO+CD69+TGFβ+) which are reliant on tolerogenic pathways.
We have taken a holistic approach in identifying the mechanisms dictating the induction of immune tolerance. Our data paves the way for a vaccine-like approach for epitope-specific immunotherapy in rheumatoid arthritis. This novel approach relies on the restoration of the balance amongst various immune checkpoints and will contribute significantly to the development of clinically effective therapies in RA.
1 Prakken et al., 2004, PNAS
2 Koffeman et al., 2009, Arthritis & Rheumatism
Additional Disclosure: S. Albani is the inventor of patents owned by Singhealth & UCSD
J. H. S. Chan, None; T. van den Broek, None; J. Y. Leong, None; M. Rossetti, None; R. Spreafico, None; S. Albani, None.
In Phase I and II clinical trials of dnaJP1, a peptide derived from the pro-inflammatory dnaJ proteins, clinical amelioration was associated with the induction of immune tolerance to dnaJP1. In responders, the immunization was associated with the generation of a population of Treg cells in which PD-1 actively role enhances the production of anti-inflammatory cytokines such as TGFβ and a significant decline in the expression of pro-inflammatory IL-17A and IFNγ. In parallel, epitope-specific immunotherapy elicited a subset of antigen-experienced memory T cells reliant on tolerogenic pathways.
Data from this and other advanced approaches suggest that non-pharmaceutical methods bear the potential for meaningful modulation of autoimmune disease – an exciting prospect for our future.
Prof. Dr. Paul Hasler