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Additional Evidence for Lymph Node Degeneration to be an Important Obstacle for Attempts at Thymus Rejuvenation

The thymus atrophies with age, and since its primary function is to support the maturation of T cells, this means that the supply of new T cells, fresh and ready for action, also declines with age. This contributes greatly to immunosenescence, the progressive age-related failure of the immune system to respond to pathogens and destroy damaged or malfunctioning cells. Numerous research groups are attempting to restore the thymus to youthful size and activity, and thus also restore the supply of T cells, and reverse loss of immune function. A wide variety of approaches are under development, from gene therapies and small molecules aimed at the controlling proteins of thymic activity to tissue engineering and cell therapies.

Thymic rejuvenation is only one aspect of comprehensive restoration of youthful immune function. The hematopoietic stem cell population in bone marrow that generates immune cells becomes damaged and declines in function with age. These calls must be replaced in a manner that is far safer, more reliable, and cost-effective than current hematopoietic stem cell transplants. The accumulated debris of years of malfunctioning, damaged, and senescent immune cells must be safely destroyed. Further, of late the compelling argument has been made that lymph nodes become so dysfunctional with age that they will block the benefits of raised numbers of effective immune cells. Lymph nodes play a vital role in the immune response, acting as a sort of coordination point for immune cells to talk to one another. Thus regeneration of lymph nodes appears to be on the agenda as well.

Each of those tasks is big enough to build a company around, but all need to be accomplished at the end of the day. The way in which these compound development projects typically work is that every company involved works on achieving success in one line of work, even though the scope of benefits is reduced by the absence of the other programs. That success can then be used to generate interest and funding enough to start tackling those other programs. Sometimes this takes an industry and many companies collaborating, sometimes a single company can work its way through over the years. The way forward is at least fairly clear.

The open access paper here is effectively a call to arms on the lymph node dysfunction issue, the formally published results from scientific work publicized last year. The researchers use one of the weaker approaches to thymic rejuvenation in order to demonstrate that raised amounts of new T cells emerging from the thymus fail to help the immune response to infection when lymph nodes are dysfunctional in older animals. In this respect, the proposition is that there are three limiting factors here, that arise at differing times and to differing degrees across the course of aging, rather than only two: (a) hematopoietic stem cell output of immune cells, (b) thymic activity to allow those immune cells to mature, and (c) the integrity of lymph nodes to allow immune cells to coordinate and act.

One of the more interesting aspects of lymph node aging is that it involves significant amounts of fibrosis, the replacement of correct tissue structure with scar-like structures. In recent years fibrosis has been strongly connected with cellular senescence and the detrimental effects these cells have on regeneration and the extracellular matrix in their surroundings. Removal of senescence cells is a going concern, shown to improve many measures of function in older animals. So when approaching the lymph node challenge the first thing to try is probably the established senolytics, drugs that can selectively destroy a fraction of senescent cells. I believe that no-one in the senescence community has yet earnestly looked into what happens in the lymph nodes of animals treated with senolytics, but that will change soon enough.

Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates

The thymus undergoes age-related involution, that includes progressive loss of thymic epithelial and hematopoietic lineage cellularity, an increase in adiposity, and reduced T-cell output. In the periphery, fewer naïve T cells are available, and the old T-cell compartment is less able to respond to infections and cancer. This is believed to contribute to increased vulnerability of older adults to emerging and reemerging infections. More recent evidence suggests that secondary lymphoid organ (SLO) organization and structure also undergo changes with increased age, and the impact of these changes upon naïve T-cell survival and function is beginning to be understood.

A "holy grail" of T-cell aging research is to achieve functional rejuvenation of T-cell function. Early experiments with surgical castration have shown that transient thymic rejuvenation is possible, as measured by increased thymic volume and cellularity. Similar results have since been obtained using pharmacological sex steroid blockade as well as injection of growth factors. While some of these studies have shown some improvement in peripheral immune function in treated mice, the ultimate tests of functional immunity in the face of microbial challenge were not performed. Therefore, the question remains how well thymic rejuvenation improves the peripheral T-cell pool with aging, and whether it confers improved protection against infection.

To address this question, we examined the effects of (a) keratinocyte growth factor (KGF) administration in mice and nonhuman primates, or (b) sex steroid ablation (SSA) in mice using an antagonist of the luteinizing hormone-releasing hormone receptor, degarelix (Firmagon). Despite robust thymic rejuvenation in response to both interventions, we found no evidence of improved peripheral T-cell maintenance. KGF-treated old mice were not more effective at mounting CD8 T-cell responses to, or clearance of, Listeria monocytogenes. Similarly, degarelix did not improve CD8 T-cell responses to, or survival of old mice following challenge with, West Nile virus (WNV).

While rejuvenated thymi produced substantial numbers of recent thymic emigrants (RTE), these RTE did not significantly contribute to T-cell populations in the SLO of old mice compared to adults. We further found that old lymph nodes exhibited considerable fibrosis and degeneration of structure. These data indicate that restoration of thymic function by itself may not be sufficient to improve the immune response in elderly and suggest that interventions to simultaneously alleviate defects in aging SLO may need to be considered when designing strategies to improve immune response in older organisms.

Comments

Another potential avenue for fibrotic tissue is telomerase therapy as demonstrated by Blasco et al. it can reverse fibrosis in model animals. It is absolutely worth exploring the utility of that approach to see if it can address fibrotic tissue in the lymph nodes.

Posted by: Steve Hill at November 21st, 2018 8:32 AM

It is not entirely clear from reading this paper whether or not restoration of the size of the thymus results in a restoration of the structure. Seeing some histological evidence of restoration would have been nice; especially if it showed a reversal of adiposity. That said, there does appear to be an increase in the total number of thymocytes and the total number of double positive thymocytes. The latter purported as being a measure of thymic generative activity. They point out that there is an age-related increase in fibrosis and disorganization in the structure of lymph nodes. It may be the case that this change in lymph node structure is the primary reason for recent thymic emigrants (RTEs) not showing an increased presence in lymph nodes. However, there is a possibility that there are also some T cell intrinsic mechanisms at play. Perhaps a way to better assess the function of the RTEs derived from the old animals treated by sex steroid ablation would be to isolate them and then by way of adoptive cell transfer assess their ability to home to secondary lymph nodes in younger mice (e.g., the adult mice aged 2-4 months). This could also be done the other way around (adult RTEs into aged mice). One could get a better sense of the RTE intrinsic and extrinsic mechanisms at play.

Posted by: aaron at November 25th, 2018 11:09 PM

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