Delivery of T Cell Progenitor Cells as an Approach to Thymic Regeneration

The thymus is a small organ in which thymocytes generated in the bone marrow mature to become T cells of the adaptive immune system. Unfortunately, the thymus atrophies with age, its active tissue largely replaced by fat in most people by age 50 or so. Thereafter the adaptive immune system declines into immunosenescence and inflammaging, deprived of a sufficiently large supply of reinforcement cells. Given the importance of the immune system to health, in matters including tissue maintenance, resistance to infection, suppression of cancer, and more, regeneration of the thymus must be an important component of any serious effort to rejuvenate the elderly. Numerous approaches have been proposed, shown to work in mice, and some even attempted or demonstrated in humans, but this isn't yet a solved problem.

One important class of approach to thymic regeneration is the delivery of cells that will home to the thymus. These cells can in principle be delivered via simple intravenous injection, rather than requiring a much more invasive introduction into the thymus directly. Once in the thymus they either directly assist in building new tissue, or deliver signals that encourage native stem cells to stop slacking and regenerate the thymus. An example of the type is the delivery of epithelial progenitor cells, demonstrated to produce thymic growth in mice a few years ago. Another example, as outlined in today's open access paper, is to deliver cells that are somewhere in the lineage that starts with thymocytes and ends at T cells, as these will also home to the thymus, and their signaling encourages greater thymic activity. The cross-talk between hematopoietic cells in the bone marrow and the thymus is likely mediated by these cells and their signals.

Thymic Engraftment by in vitro-Derived Progenitor T Cells in Young and Aged Mice

T cells play a critical role in mediating antigen-specific and long-term immunity against viral and bacterial pathogens, and their development relies on the highly specialized thymic microenvironment. T cell immunodeficiency can be acquired in the form of inborn errors, or can result from perturbations to the thymus due to aging or irradiation/chemotherapy required for cancer treatment. Hematopoietic stem cell (HSC) transplant (HSCT) from compatible donors is a cornerstone for the treatment of hematological malignancies and immunodeficiency. Although it can restore a functional immune system, profound impairments exist in recovery of the T cell compartment. T cells remain absent or low in number for many months after HSCT, depending on a variety of factors including the age of the recipient.

While younger patients have a shorter refractory period, the prolonged T cell recovery observed in older patients can lead to a higher risk of opportunistic infections and increased predisposition to relapse. Thus, strategies for enhancing T cell recovery in aged individuals are needed to counter thymic damage induced by radiation and chemotherapy toxicities, in addition to naturally occurring age-related thymic involution.

Preclinical results have shown that robust and rapid long-term thymic reconstitution can be achieved when progenitor T cells, generated in vitro from HSCs, are co-administered during HSCT. Progenitor T cells appear to rely on lymphostromal crosstalk via receptor activator of NF-κB (RANK) and RANK-ligand (RANKL) interactions, creating chemokine-rich niches within the cortex and medulla that likely favor the recruitment of bone marrow-derived thymus seeding progenitors. Here, we employed preclinical mouse models to demonstrate that in vitro-generated progenitor T cells can effectively engraft involuted aged thymuses, which could potentially improve T cell recovery. The utility of progenitor T cells for aged recipients positions them as a promising cellular therapy for immune recovery and intrathymic repair following irradiation and chemotherapy, even in a post-involution thymus.

Comments

If everyone had the immune system of a young teenager we wouldn't be in this coronavirus mess now. Death rates from Covid seem to dovetail with thymus involution: zero under age 10, then rising until 60, then booming after that, and finally killing the majority of 80+ year olds.
Considering how a new immune system could reduce death from infectious diseases as well as the incidence of cancer (likely), this is a line of research that should have billions thrown at it.
Question: is there something else that needs to be regenerated in addition to the thymus for the whole system to function as younger?

Posted by: Barbara T. at October 8th, 2020 4:18 AM

@Reason - Is this the approach that Repair Biotechnologies is taking to Thymus regeneration given that it is seeking to remove damaged cholesterol using macrophages manufactured from iPS cells? How hard would it be to adapt that technology to this treatment?

The lack of need to access the thymus surgically (just an intravenous infusion of T Cell Progenitor Cells) seems advantageous.

I hope someone gets the funding to repeat this study in rhesus monkeys or pet dogs soon.

Posted by: jimofoz at October 8th, 2020 6:42 AM

@Barbara T

>Question: is there something else that needs to be regenerated in addition to the thymus for the whole system to function as younger?

probably have to regenerate "the whole" system to make it equivalent, but with targeted improvements it might not be 100% as good but good enough, like 60%.

I think thymus is only one of many systems to be repaired and reversed. Since the body has multiple feedback loops it is hard to tell how much an improvement we can get of reversing damage of a single system. In the worst case scenario it might be none at all, since it might require several corrections to bring any benefit. However, I would say that there will be a measurable benefit even with small improvements. The 80% olds have so many deteriorations that even a slight improvement will boost the immune system several folds ...

Posted by: cuberat at October 8th, 2020 7:12 AM

@Barbara T.: For a 60 year old, a restored thymus would probably be pretty good and sufficient for a sizable boost to immune function, judging by what happens to 60-somethings treated with sex steroid ablation drugs for prostate cancer. Once you get up to 80, I think there is a strong argument for restoration of hematopoietic stem cell function and regeneration of damaged/fibrotic lymph nodes to be needed as well. It is an open question as to whether you'd also need exhausted, senescent, and otherwise bad immune cells removed, or whether their numbers will diminish naturally given a renewed supply of new immune cells.

Posted by: Reason at October 8th, 2020 8:18 AM

Hi there! Just a 2 cents.

I would wager that thymus rejuvenation would have a strong impact (or at min. sizeable/substantial one) that is tangible interms of health improvement. If you are already healthy (enough) then probably not much change (it will be better..but you won't necessarily 'notice it' since you werel already nearly full best health). For older people, it can bring health improvement since they can suffer frailty/immune fragility/sluggish immune system - getting flu, covid, viral disease and cancer.
But as others said, it depends on the rest, it'S not just thymus itself that will save you/your immune system; the thymus must produce t-cells, these are related to the immature immune cells from the bones (bone marrow); if you have osteoporosis (low BMD (bone mineral density)) in old age, you can suffer are immune problems because can'T make immune cells as much (bone marrow not at best; frail bones will mean immune problems at some point).
Strong bones/marrow filled = better chances of immuneity. There's also the lymp nodes that are part of the whole thing.

Currently, the strongest effect on the thymus is darkness (therapy)...instead of light therapy.
It was shown that darkness/light has dramatic effect on thymus. This can be due to heavy production of hormones during darkness (melatonin (pineal gland), serotonin, tryptophan,
5-HT, HGH...), these hormones have substantial effect on thymus/immune system; they help it.
And thymus is first receiver. Our circadian clock entrains and drives our sleep/awake cycle; by the appearance of light and disappearance of it; in darkness (like at night when sun/day light is gone). The biggest 'soft' threat is us spending our time in 'blue light therapy' (LED monitors), as we sit for hours on and end watching copmuter/tv...screensm even mobile phones...alll LED screens - which produce blue light spectrum; this damages the brain cells, eye cells, skin cells...same as UV radiation (in fact, blue light is close in spectrum 'wave length' to Ultra-violet light; so both cause oxidation of DNA; UVa is strongest, but blue light is too; it is used to kill bugs and bacterias; it can kill human cells too; since same thing/same make-up -> DNA). It is also used (like the CSI tv show like FBI detectives) by coroner/for autopsy and 'finding fingerprints' invisible at light, but visible 'under blue light' in darkness. Just putting your hand in blue light projected by a cinema projector - damages your skin (just like sun tanning/bed tanning by its UV rays (UVa mainly and UVb) radiation/exposure); it causes formation of Amadory/Skin Tanning/Browing of skin (melanin production to counter UV rays; but in so, it causes macromolecular damage in the ECM (extracellular matrix) and thus disorganizes the 'neatly woven' collagen scaffoles (wrinkles and crosslinks - Glucosepane/AGEs/ALEs and other oxidized residues (mostly lipofuscin..while in the eye it'S A2E drusen/a type of pigment produced as the phospholipid are peroxidized in the iris/retina (oxidative stress by light's UV or blue light radiation); which can cause later cataract/eye vision loss become blind)). Thus, you don't want to spend your whole time in total darkness (because you won't see the 'light of day'..nor the day of ...light). As in, you will 'stay in' and not go outside 'in day light' (like a vampire basically). For me, I did darkness therapies some times and they definitely affect me - I can tell the effect; Light is important too because your cells depend on UV/light exposure - just a little bit; to produce ATP; it's why excess darkness it bad in the long run; you Need light; but exces light = thymus involution acceleration. So...what to do (since acn't live without light..can't live without darkness); I guess the same thing; doing the 7 hours of darkness at night; but Lessening the daylight exposure - don'T spend 'frying/tanning' under the beach sun..bad. And, do darkness therapy - turn off LED lights/computer/block blue light...and 'live in darkness' like in the old days/cave age. No, this won'T save you or anything; it's just an observation/suggestion.

Just a 2 cents.

PS: After reading that senescent cells have an important/critical function - which is to prevent blood hemorhaging...and here we are with 'senolytics'...we will have to be careful...because Good THings..turn bad..when given at the Wrong time (i.e....when you are ill...something that was good (while you were healthy) is now toxic/poison - in your current compromised health state). This means thearpies in the future will have to ultra-strict because errors will happen and some people will die (of whatever 'secondary effect' - by human error). It's that fidgety/picky/finnicky in the body. What works 'some times'...other times, in diff. situation, in doesn't anymore. Very catch22/double-faced, it's why we will need to redouble caution (and it s*cks because that means FDA bodies will make More Clinical Trials - Longer...because 2ndary effects possible depending on healhtstate - the worse 2ndary 1, death).

Posted by: CANanonymity at October 8th, 2020 7:48 PM

PPS: The sun light/UVb/UVa are related to immunity becayse UV rays produce cholacalciferol (Vitamin D3) in the skin (not just skin pigment production or tanning/oxidation of skin fibroblast cells), this Vit. D3 is what drives the immune system (it's why sunlight exposure Boosts the immune system (and even Boosts mitos/produce ATP BY Light) - but so does darkness too). Some people spend their days tanning inthe sun...they don't have much imune problems....becayse Overproduction of Vitamin d3; Vit. D3 is related to all-cause mortality (low blood d3), and especially, immune failure; it atucally saved me because it restores correct HDL/LDL ratio/it ordesr the liver to refunction correctly. Thus, you don'T want 'never have light' because light boost immune system and also produces Vitamin C (the Other sun vitamin/ascorbate; mariners used to die of 'scorbu/rickets' and this vitamin was given as a remedy that cured their disease - an immune disease; thus Vit. C is Also a immune vitamin; its name -ascorbate/ascorbic acid is the name of the disease 'scorbu') which is crucial for skin function (Vit C is needed to correct crosslinking of collagen/for its formation and is allaround antioxidant - yet, it is 2-faced and produces oxidation Too - thus it is 'pro-oxidizer/pro 'healthy ager'...rather than a Pure antioxidant with no oxidation ever); but the radiation/oxidation caused by light rays - destroy the thymus/its DNA/causes severe oxidative stress there..in the long run. So, msut dose it - you want to preserve the thymus (an element of immune system) - yet, you need your 'Sunshine Vitamin D3/Vit.C in your skin' for Also immunity...again, catch22.

Posted by: CANanonymity at October 8th, 2020 7:58 PM

Thanks!|

Posted by: Barbara T. at October 9th, 2020 5:12 AM

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