|Hand of a rheumatoid arthritis patient|
The author and dramatist Friedrich Dürrenmatt wrote that “Without tolerance, our world turns into hell”. Nothing could be truer for sufferers of autoimmune conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn’s disease (an inflammatory bowel condition) and Type 1 diabetes, where faults in one or more of the mechanisms that normally prevent the immune system from attacking the body (“immune tolerance”) result in chronic tissue and damage.
A strength and weakness of the immune system is that, for speed and breadth of recognition of foreign antigens, the white blood cells responsible for antibody production (B cells) and those active in cell-mediated responses (T cells) express a broad repertoire of randomly-generated surface receptors. Probability dictates that a number of T and B cell clones will possess receptors that recognize “self” molecules (“autoantigens”).
Policing of the immune system to weed out or otherwise inactivate self-reactive T and B cell occurs in the thymus gland and bone marrow, respectively, and in peripheral sites including the lymph nodes. Not all bad actors are recognised and dealt with: escapee self-recognising T cells are held in check by another subset of T cells (regulatory T cells- “Treg”). Through quirks in genetics and a contribution from environmental factors, one more of the mechanisms involved in self-tolerance fail in some individuals, leading to autoimmune disease.
Current therapies for autoimmune conditions are aimed at reducing inflammation using steroids or inducing remission through “disease modifying” drugs (DMARDs), either biologics which neutralise the signalling molecules (“cytokines”) involved in the inflammatory cascade or with small molecules such as methotrexate and, more recently, Janus kinase inhibitors. All result in some degree of immune suppression and may not result in satisfactory disease control: up to a quarter of those receiving DMARDs for rheumatoid arthritis fail to obtain sustained benefit.
The therapeutic potential of restoring self-tolerance has been actively pursued for close to two decades. Purging the immune system of mature T and B cells through aggressive chemotherapy, followed by its restoration through stem cell transplantation has had some success in multiple sclerosis and Crohn’s disease patients, but comes with high risk of mortality.
More viable approaches applicable across a range of autoimmune conditions involve the targeting of autoantigen-recognising T cells or the generation of Treg cells to restore self-tolerance.Paradoxically, tolerance can be restored by presentation of the offending autoantigen(s) in the form of a “tolerizing vaccine” containing whole proteins or peptides, or DNA or mRNA encoding the autoantigen of choice.
Tolerization through presentation of insulin or other autoantigens recognised in Type 1 diabetes (caused by the autoimmune destruction of insulin-producing beta cell in the pancreas) has the potential to preserve insulin levels but clinical studies have been largely disappointing, as has been the case in multiple sclerosis and rheumatoid arthritis studies.
Cellular immunotherapies that more effectively present autoantigens or increase numbers of Treg cells have great promise in severe or refractory autoimmune diseases. Dendritic cells (DCs) are specialised at presenting antigens to the immune system, a property exploited in cancer vaccine development, [Dendritic cell vaccines: back to the future] but are also effective at inducing Treg cells. Some degree of clinical benefit has been observed in studies involving local administration of autoantigen-loaded and non-antigen specific “tolerogenic” DCs (tolDC) into the knee joints of subjects with rheumatoid arthritis. Other studies with tolDC therapy are ongoing in subjects with Type 1 diabetes and Crohn’s disease and in preventing rejection in solid organ transplantation.
Other cellular immunotherapy strategies in active development involve the isolation, expansion and (re)infusion of Treg cells or mesenchymal stem cells which have multiple effects on the immune system, including Treg induction. In another twist, Treg cells may be genetically engineered to express autoantigen-recognising receptors and early-stage development of this approach is underway in the prevention of transplant rejection. An advantage of mesenchymal stem cell immunotherapy is that cells can be readily obtained and expanded from donated cord blood or fatty tissue (“allogenic” therapy).
While relatively complex and expensive, and currently at a very early stage of development, cellular immunotherapies may eventually become established as a means of managing severe or refractory autoimmune conditions without requiring constant medication or continual switching of drug regimens. The quality of life and economic implications for effective treatment are significant: in the developed economies, around 1% of adults develop rheumatoid arthritis, with the majority being first diagnosed while still of working age. Multiple sclerosis and Crohn’s disease patients are generally diagnosed while still in their early 30s.
Photo credit: Bernd Brägelmann Braegel Mit freundlicher Genehmigung von Dr. Martin Steinhoff