Chapter 131
Controlling Our Immune System — 8
Overall, T cell engineering will likely be more challenging than B cells because their depletion will not be tolerated as well. Nevertheless, a proof of concept was achieved with marked success and without untoward effects in a patient with ankylosing spondylitis with a selective T cell depletion antibody targeting an autoantigen (TRBV9+). This antigen may well be useful for restoring tolerance in psoriatic arthritis, uveitis, and inflammatory bowel disease.
It would not be at all surprising to see genome editing of engineered T cells for facilitating tolerance, as has been done for boosting the immune response against cancer. For all these uses the living drug property of engineered cells must be kept in mind, with the potential for cytokine release syndrome and the downstream consequences of interfering with the immune response over time. That’s why antiaging strategies are being developed for these cells before they’re administered to patients. Nonetheless, the cell engineering approaches are collectively showing much promise for promoting tolerance.
But what about some tools from closer to home? We already can successfully transplant a patient’s own hematopoietic (blood) stem cells (after depleting lymphocytes [AHSCT]) in the treatment of autoimmune conditions, such as multiple sclerosis, Crohn’s disease, lupus, and systemic sclerosis. However, it is a complex strategy that requires two hospital-based stages, the first to mobilize the stem cells over multiple successive days, and the second requiring hospital admission with chemotherapy and immunotherapy to ablate all the lymphocytes (B and T cells), followed by reinfusion of the person’s collected blood stem cells. Unlike most of the previous approaches reviewed, it lacks specificity, carries substantial up-front risk from the cell ablation therapies, and is unsuitable for a prevention strategy, but, again, it has been associated with some cures. AHSCT is the subject of multiple randomized trials, particularly multiple sclerosis. The potential to engineer blood stem cells within the body, instead of having to remove them and ablate cells, may offer a more practical, lower-risk alternative in the future.
We come to the last on my list of extremely promising approaches to restoring tolerance and curing autoimmune diseases—and it is far from the least. After all, the gut microbiome, with approximately forty trillion microorganisms, is center stage for coordination of our immune response. The gut-associated lymphoid tissue (GALT) is considered the largest immune organ in the body, with the greatest number and diversity of immune compartments and immune cells. Just one cellular component, the intestinal intraepithelial lymphocytes (IELs), one of the largest populations of T cells in the body, has been shown to have a metabolic role affecting GLP-1 levels after eating. The multiple compartments include Peyer’s patches in the small intestine, especially in ileum; extensive lymphoid tissue in the appendix; and many lymphoid follicles throughout the small and large intestine. These patches and follicles are in intimate contact with the inside space (lumen) of the gut and have the array of B (naive, memory), T (naive, CD4+, CD8+, Treg), and dendritic cells. Gut cells have been demonstrated to produce complement proteins, and when blocked in an experimental model, they improved outcomes. The microorganisms produce metabolites, especially short-chain fatty acids, that modulate the function and differentiation of these immune cells. A pro-inflammatory effect, with production of cytokines, can disrupt the intestinal barrier and leak microbes and substances into the blood. There is also the bidirectional gut-brain axis, with the embedded gut (called enteric) nervous system (nicknamed the “second brain”) that communicates with the central nervous system through neurotransmitters, the vagus nerve, and ganglia. Reflecting how impactful this axis is is the recent finding that it even regulates our motivation to exercise!