Ellie Kroeger is a writer and researcher currently studying the vaginal microbiome and vaginal microbiota transplants. She holds a B.Sc. in human biology from the University of Southern California. You can connect with her via her website (https://www.elliekroeger.com/).
T cell with CARs, courtesy of Pixaby
It is estimated that tens of millions of North Americans suffer from some form of an autoimmune disease – an overreaction of the immune system to its own healthy tissues, which causes severe, systemic symptoms. Could regenerative medicine be the solution? How can stem cell therapies reprogram a dysregulated immune system?
What is autoimmunity?
Autoimmunity is when your body begins attacking itself. When you are diagnosed with an autoimmune disease, your immune system has lost the ability to differentiate between foreign invaders (like pathogenic bacteria and viruses) and healthy cells and tissues, leading to an indiscriminate attack on both. This results in severe inflammation (as measured by high levels of CRP and inflammatory cytokines) and a wide array of frustrating symptoms — from non-specific fatigue and brain fog to loss of nerve function (multiple sclerosis) or even an inability to synthesize insulin (type 1 diabetes), as tissues are destroyed by your own immune system.
Considered a chronic disease, autoimmunity usually progresses over time, and this progression can be gradual or rapid. Throughout the course of the disease, there can also be cyclic flare-ups followed by periods of remission. Due to the non-specific symptoms and fluctuations in severity, autoimmune diseases are often diagnosed years after the onset of symptoms. Although the exact cause(s) of autoimmunity are unknown, it is likely multi-factorial and an unfortunate combination of genetic susceptibility and environmental factors. Autoimmunity is strongly associated with gut dysbiosis, stress, exposure to chemicals, infections (like EBV), and inflammatory diets, but these factors have not been proven to be causal.
There might be as many as 150 autoimmune diseases, and although their presentations can be quite different, they are all rooted in an auto-reactive immune system that is attacking its own healthy cells. This shared auto-reactivity is what causes the overlapping and non-specific symptoms of fatigue and inflammation.
What therapies does regenerative medicine offer for autoimmune diseases?
- Hematopoietic Stem Cell Transplantation (HSCT)
HSCT, often referred to as a bone marrow transplant, is a serious and high-risk medical procedure. Its goal is to essentially “reset” the immune system. It involves the ablation (or destruction) of the existing auto-reactive immune system via high-dose chemotherapy and/or immunosuppressive drugs, followed by a re-infusion of the patient’s own HSCs to rebuild a new immune system. This is called autologous HSCT, because the stem cells were collected from the patient’s own blood or bone marrow prior to the ablation. Using a donor’s stem cells (allogeneic HSCT) is much riskier as the chance of rejection and graft vs host disease is high.
Ideally, the new immune system that is rebuilt via the HSCs will not become auto-reactive. This new immune system is considered naïve when transplanted, and it will hopefully develop the ability to properly differentiate between self- and non-self-antigens and thus mount an appropriate immune response. The microbiome assists in the “training” and development of the new immune system, and because greater microbial diversity is associated with better HSCT outcomes, fecal microbiota transplants and probiotics could be a part of a post-operative care plan. After the procedure, the immune system is vulnerable to infections for weeks to months as neutrophils (a type of white blood cell), followed by T and B cells, gradually recover. The long and stressful recovery may be worth it, though: some studies have shown up to 90 per cent long-term remission for patients with multiple sclerosis.
- Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs), which are primarily derived from bone marrow, adipose tissue, and umbilical cord tissue, can modulate the immune system and repair tissues via paracrine signaling. They are known to target sites of inflammation, where they secrete healing molecules that promote regulatory T cells, reduce inflammatory cytokines, and increase anti-inflammatory cytokines, in addition to nudging the immune system into a more tolerogenic phenotype (capable of producing immunological tolerance). By increasing immuno-tolerance, MSCs calm the over-reactivity that is characteristic of autoimmunity. Although this is not a cure, it can reduce symptoms and even induce remission; however, further research is needed.
- CAR Treg Therapy
The role of regulatory T cells (Tregs) is to suppress excessive immune responses and prevent autoimmunity. They maintain immune tolerance, which is decreased in autoimmunity as a result of self-reactive T cells. By engineering Tregs to go to a specific antigen or tissue via a chimeric antigen receptor (CAR), they can act precisely at the site of inflammation, releasing immunosuppressive cytokines and disrupting other immune cells, such as self-reactive T cells.
How is this different from CAR T-cell therapy for cancer?
When someone has cancer, malignant cells have found a way to bypass and hide from the immune system. That way, the malignant cells can grow unchecked by T cells. CAR T-cell therapy engineers T cells to recognize these malignant cells and attack them. The goal is to teach the immune system to kill the cancer and be more aggressive.
CAR-Treg therapy also aims to retrain the immune system at a localized site, but with the opposite goal. The goal is to make the immune system less aggressive. Regulatory T cells will dampen the immune response and promote immune tolerance.
Both treatments are part of a branch of medicine known as immunotherapy. Immunotherapies modulate the immune system so that it can better fight off disease, whether by up-regulation or down-regulation of its defences. In cancer, the immune system is under-reacting to an actual threat and needs to be upregulated. In autoimmunity, the immune system is overreacting to a false threat and needs to be downregulated. Correcting a dysregulated immune system is a more permanent solution than the long-term use of symptom-suppressing drugs.
What does this mean for those currently suffering from autoimmunity?
Many stem cell therapies are currently being studied in clinical trials and are not yet approved or regulated for use. HSCT is available, but eligibility is strict. The regulation of MSCs varies internationally, but in Canada they are only legally available in approved clinical trials. As for CAR Treg therapy, it is also only legally available in international clinical trials. Although pre-clinical trials for CAR-Tregs have been incredibly promising, human trials can take years.
In the meantime, those suffering from autoimmunity can participate in clinical trials and look forward to the advancing research. Of course, the best treatment for any disease is prevention. But as the rates of autoimmunity rise drastically in our industrialized world — whether due to microbiome disruption, chemical exposure, over-sanitization, epigenetics, or ultra-processed food — we must find ways to rebalance the immune system. Regenerative immunotherapy may be the answer.
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