Chapter 135
Controlling Our Immune System — 12
This can be seen as a beginning of the work toward restoring tolerance for more definitive treatment, and ultimately prevention. Tolerogenic vaccines, such as one with citrullinated peptides, or one that targets antigen-specific T cells, have very encouraging preclinical data.
As with type 1 diabetes, immune tolerance and preventive strategies for rheumatoid arthritis are being actively pursued, and an autoantibody can be used to identify high-risk individuals. Poor gum health can trigger anti-citrullinated autoantibodies, contributing to disease development in susceptible individuals.
Lupus research has joined the health span revolution. Besides the impressive clinical results for lupus using engineered T cells directed against CD-19, the use of Treg cells with the Smith-specific autoantigen of lupus nephritis stopped disease progression in the experimental model of this severe manifestation of the disease. This could be a launchpad for using Treg cell infusions targeting specific autoantigens playing a role for several autoimmune conditions. Much work has been done to identify causative genes of lupus, such as toll-like receptor-7 (TLR7), and single-cell sequencing to find specific CD8+ (GZMH+) T cells has been markedly expanded in some patients with lupus. Another toll-like receptor (TLR9) found in B cells was shown to impair central B cell tolerance, a novel pathway that could be suppressed.
Again and again, we see one line of research having implications that open up multiple others. A discovery in inflammatory bowel disease of intraepithelial lymphocytes with specific T cell receptor antigens tied to loss of self-recognition is one path to developing immune tolerance in the future. People with celiac disease are stuck with a gluten-free diet for life, which is exceedingly difficult to maintain. Given the central disease-causing role of CD4+ T cells specific for gluten, multiple companies are in clinical trials with modified gluten proteins as antigen-specific therapy. A major genetic discovery underpinning inflammatory bowel disease and likely other autoimmune diseases was the finding of a disease-causing pathway that drives inflammation and appears to be druggable. This could yield a preferred, more focused approach compared with the way we use broad immunosuppression treatments today. Many more therapies are in the pipeline, including Tregs, microbiome intervention, and use of the liver, as previously discussed. While it’s just in the mouse model so far, a single infusion of CAR-T cells provided durable protection against asthma attacks, potentially quashing an autoimmune form of this common disease.
The antibody-drug conjugate strategy we discussed in the cancer chapter is now being tested in clinical trials for autoimmune diseases combining TNF-blocking antibodies with a glucocorticoid (like cortisone) receptor to maximize efficacy. So are bispecific T cell engagers in patients with refractory rheumatoid arthritis.