Question of the Month #13: How Can Thymic Regeneration Combat Age-Related Autoimmunity?

Posted by Michael Rae on February 19, 2016 | Chief Science Officer's Team

Q: You’ve explained the rejuvenation biotechnologies that will be required to restore the aging immune system’s ability to fight off infection via ablating dysfunctional T-cell clones and tissue engineering new thymus gland grafts. But what can be done to prevent or reverse one of the other dysfunctions of the aging immune system: rising autoimmunity?

A: We tend to focus on rejuvenating the aging immune system’s specific immunity to pathogens because the loss of this ability is more often acutely life-threatening, as can be seen in the terrifying rise of influenza-associated pneumonia hospitalization and death rates beginning around age 65. But there is also a substantial rise in autoimmunity with age, leading to greater incidence of specific autoimmune diseases such as rheumatoid arthritis and lupus, along with a less specific rise in autoimmune reactivity in the aging immune system, which is seen in the rising frequency of autoantibodies even in people with no overt autoimmune disorder. Particularly common are elevated antibodies targeting the body’s own phospholipids (which drive an increase in blood clotting), proteins in the cell nucleus, and the body’s own antibodies (rheumatoid factor (RF), which causes the immune complexes associated with rheumatoid arthritis). These may be linked to the rising inflammatory tone with age, and possibly to the increase in cancer, atherosclerosis, and neurodegeneration with age.

While their effects are incomplete and not without side-effects, existing models of slow aging already show us that the age-related rise in autoimmunity is modifiable. Both laboratory rodents subjected to Calorie restriction (a strong model of slow aging, at least in mice and rats) and human centenarians enjoy rates of autoimmune antibodies and disease that resemble those of controls with much lower calendar ages.

One key to rejuvenating the aging immune system and eliminating the autoimmunity of aging is engineering biologically young thymus tissue to supplement or supplant the shrunken and structurally-damaged (“involuted”) aging thymus. The young, healthy thymus prevents autoimmunity in two ways. First, it screens newly-matured T-cells and eliminates any that target “self” proteins in a process known as negative selection. Recently, researchers created mice whose thymuses decayed more rapidly than normal with age by gradually eliminating a gene (FoxN1) that is involved in maturing and maintaining the organ. This accelerated thymic involution resulted in the release of high numbers of autoreactive T-cells from the thymus, which rapidly became activated and began attacking body tissues, leading to increased inflammation. The scientists traced this back to an impairment of the activity of a protein involved in negative selection, and the involuted thymus tissue’s inability to recruit the innate immune cells needed to present the thymus with the tissue-specific self-antigens needed to screen out the harmful self-reactive cells.1,2 Engineered young thymic tissue grafts would restore the youthful thymus’ strong capacity for negative selection.

Additionally, aging people suffer a loss of regulatory T cells (Tregs), also known as suppressor T cells, which help to enforce tolerance to “self” antigens. One possible cause of this is the sheer failure of the involuted thymus to generate sufficient total numbers of T-cells, a subset of which go on to become Tregs. If so, then engineered youthful thymic tissue will reverse that deficit.

But an additional, non-exclusive cause of the loss of Tregs with age is that they may be crowded out by rising clones of dysfunctional T-cells with age. If so, then rejuvenation biotechnology to ablate these “anergic” T-cells might make room to allow the body to restore their numbers, just as it is expected to do for killer T-cells directed at new pathogens.

And, finally, the technology required to eliminate such cells (such as a mature version of the prototype “T-cell scrubber” developed by researchers with SENS Research Foundation3 and now being adapted as part of Foundation-funded work to rejuvenate the aging systemic environment) could potentially also be turned directly on the self-reactive T-cell clones themselves, purging them from the body even as other aspects of immune aging are reversed by other rejuvenation biotechnologies. Very similar technology could also be applied to clearing out autoreactive B-cell clones, which are essential for autoantibody production and for perpetuation of the autoimmune response.4 There is, indeed, already proof-of-concept work in ablating aged B-cell clones as rejuvenation biotechnology for humoral immunity. Depending on the full fruits of other rejuvenation therapies, these techniques might need to be periodically reapplied, and could also potentially be used to suppress hereditary and other non-age-related causes of autoimmunity.4

 

References

[1] Coder BD, Wang H, Ruan L, Su DM. Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation. J Immunol. 2015 Jun 15;194(12):5825-37. doi: 10.4049/jimmunol.1500082. Epub 2015 May 8. PubMed PMID: 25957168; PubMed Central PMCID: PMC4458423.

[2] Xia J, Wang H, Guo J, Zhang Z, Coder B, Su DM. Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection. Aging Dis. 2012 Jun;3(3):248-59. Epub 2012 May 1. PubMed PMID: 22724083; PubMed Central PMCID: PMC3375081.

[3] Rebo J, Causey K, Zealley B, Webb T, Hamalainen M, Cook B, Schloendorn J. Whole-animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles. Rejuvenation Res. 2010 Apr-Jun;13(2-3):298-300. PubMed PMID: 20426617.

[4] Bollmann FM. Rheumatic autoimmune diseases: proposed elimination of autoreactive B-cells with magnetic nanoparticle-linked antigens. Med Hypotheses. 2012 Apr;78(4):479-81. doi: 10.1016/j.mehy.2012.01.010. Epub 2012 Jan 30. PubMed PMID: 22285628.