Genetically engineering regulatory T cells to treat SLE

Clinical trials are testing whether increasing the number of regulatory T cells helps people with lupus. One treatment approach being explored involves giving patients large doses of these cells.  But Dr. Ooi and his lab colleagues believe that they can make more effective regulatory T cells that protect specific cells. In lupus, harmful immune cells hone in on certain molecules and attack cells that carry them. One of the immune cells’ main targets is a portion of the cell nucleus referred to as the Smith antigen. Regulatory T cells that recognize the Smith antigen might be able to shut down these harmful immune cells. Their work will identify which parts of the Smith antigen that immune cells respond to. Once they know that, they will be able to genetically engineer regulatory T cells to protect cells carrying the Smith antigen in mice. If these cells reduce lupus symptoms in the animals, they plan to create regulatory T cells for treating patients with lupus.

What this study means for people with lupus

Researchers are studying regulatory T cells – cells that keep our immune system under control — as a therapy for lupus. Dr. Ooi’s project aims to genetically engineer regulatory T cells that are better at shielding the body’s cells from immune system attack. After evaluating the cells in mice, he and his team hope to test them in people with the disease.

Autoreactivity to the Smith (Sm) antigen is pathognomonic of SLE. Here, we propose to determine the molecular mechanism for anti-Sm autoimmunity, potentially leading to a novel way to develop Sm antigen specific regulatory T cells (Tregs) to treat patients with SLE. Autoantibodies specific for the Sm antigen are strongly associated with disease severity in SLE. Furthermore, experimentally, immunization with Sm polypeptides induce SLE-like features. Sm specific T cells play an important role in class switching anti-Sm autoantibodies and participate as disease effectors, and anti-Sm autoreactivity is strongly associated with the human leukocyte antigen (HLA)-DR15. Though only present in 30-40% of SLE patients, compared to less specific autoantibody targets, Sm represents the best opportunity for antigen-specific immune regulation in SLE. We have shown, in a Nature 2017 publication, focussing on an antigen-specific autoimmune disease (Goodpasture’s, anti-GBM), the structure-function relationship between disease-associated MHC and antigen-specific immunity; this follows earlier work demonstrating the structure-function association of HLA-DR4 and anti-CCP in RA (J Exp Med, 2013). Moreover, we showed that antigen specific Tregs are of much greater potency than polyclonal expanded Tregs, suppress autoimmune disease in an antigen specific manner, and, importantly, block the expansion of antigen specific T follicular helper cells, the key T cell subset for the development of autoantibodies. Now, we propose a novel method, using the latest technologies, to determine the structure/function relationship between HLA-DR15 and anti-Sm autoimmunity in SLE, and generate Sm antigen specific Tregs. In Aim 1, we will define the dominant pathogenic Sm T cell epitopes by immunizing HLA-DR15 transgenic mice with overlapping peptides encompassing all nine Sm proteins, and determine if these epitopes are naturally presented by peptide elution MALDI-TOF mass spectrometry experiments. In Aim 2, we will generate HLA-DR15 recombinant molecules covalently linked to the dominant Sm T cell epitopes. Using these molecules, we will solve the crystal structure to elucidate the molecular conformation that drives the anti-Sm T cell response, and generate HLA-DR15 tetramers to determine the frequency, phenotype of anti-Sm specific T cells as well as obtain clonally expanded paired Valpha and Vbeta T cell receptor (TCR) sequences from SLE patients with active disease. In Aim 3, we will retrovirally transduce Sm-specific TCR sequences onto polyclonally expanded Tregs ex vivo and investigate the efficacy of these Sm antigen specific Tregs compared to polyclonal Tregs in suppressing pro-inflammatory Sm specific autoreactivity.
This work will define the Sm T cell epitopes in the most clinically relevant HLA II in SLE, provide information including HLA II-epitope molecular structure and phenotype of Sm specific T cells, and push towards an antigen-specific therapeutic option for SLE.