Slowing down the aging of our immune system

As we age the thymus, the central organ in our immune system, shrinks and is replaced by fat cells. By identifying the source of those cells, Dr Krisztian Kvell at the University of Pecs in Hungary hopes to slow down this process and prolong human health span.

The human immune system changes dramatically with age. There is a marked decline in the production of naive T lymphocytes in the thymus leading to a reduced diversity and altered repertoire of antigen specificities recognised by the immune system among naïve T cells.

Therefore, with age there is a progressive decline in the capacity of the immune system to react with foreign antigens associated with an increased reactivity with auto-antigens.

Senior lecturer in Immunology and Biotechnology, Dr Krisztian Kvell, is part of a research team based at the University of Pecs in Hungary, working on finding a practical solution to this biological problem with the help of national and international grants.

So how did the scheme get under way? “The project started when my supervisor, Dr Judit E. Pongracz, had a Wellcome grant between 2006 and 2009. She received this to study signalling pathways and signal transduction associated with the family of the Wnt molecules in the context of thymic development. “During these studies I was working as a post-doc during the period of the grant and we found some very interesting molecular traits of gene expression changes involved in thymic immune senescence.”

Dr Kvell in Dr Pongracz’s team studied how the thymus goes through the process of adipose involution during the course of a lifetime. Adipose tissue has been known to replace the thymic epithelial network during ageing, but little was known about the underlying molecular mechanisms.

Dr Kvell explains: “The thymus is a central immune organ that goes through significant morphological change during senescence. That is to say, it undergoes adipose involution, so it shrinks and becomes replaced by adipose tissue composed of fat cells and we have found molecular mechanisms that could be responsible for this event. When we were comparing the thymic epithelium in young and aged mice, we found signal transduction and gene expressional changes that were completely novel and related to adipose involution. The novelty of our research - and we are quite pioneering in this – was identifying the source of fat cells that replace the functional thymus.”

“There were two conventional hypotheses on what could be the source of these fat cells that replace the functional thymus during its senescence: one raised that these originate from invading mesenchymal cells, coming from elsewhere in the body, while the other suggested that resident mesenchymal cells could transform into adipose cells. We have performed experiments using cell lines and primary cells and outlined a third scenario to which thymic epithelial cells differentiate indirectly (via an intermediary mesenchymal step) into adipose cells, that constitutes thymic fat tissue, the end product of thymic senescence.

“This is a novel mechanism and it is perhaps shocking for the scientific community to see epithelial cells turning into fat cells, but I am working hard to convince other researchers. Our experimental data have been validated on several levels and on several occasions as proved by the list of our publications in internationally acknowledged high impact scientific journals.”

So what, one may wonder, is the actual route of this senescence process? “Every organ or tissue has its own pace of senescence and for the thymus starts rather early which actually means that in humans the process begins at a young adult age at maybe 20 years and by 50 years adipose involution is already finished in the thymus”

Dr Kvell goes on to point out two practical drawbacks to this process. “One is that elderly people are more prone to get viral infections. The other is that they are also more likely to develop certain auto-immune diseases because of impaired thymic functionality. It appears that we have identified the molecular mechanism of senescence related adipose involution and this marks molecular targets for intervention. At cellular level we are now actually capable of postponing or slowing down this event.”

While much contemporary medical research may be aimed at prolonging the human lifespan, there is also an element of qualitative research aimed at improving the conditions of our physiology within our ‘allotted’ lifespan. Dr Kvell is keen to stress that his work fits this latter category.

“Our final goal would be to slow down the process of immune-senescence in humans and actually our goal is not to further prolong human lifespan, but rather to increase, let’s say ‘health-span’ within lifespan. This means to live equally long like today, but also maintain immune fitness for longer periods. This has huge economic significance with the potential to ease financial burden on the healthcare systems of Western societies.

“We have been working on the original project, from which this grew, since 2006 and currently I have a grant that is a three-year Hungarian post-doctoral research grant. Dr Pongrácz also has additional grants –e.g. “Science Please” Research Team on Innovation grant No: SROP-4.2.2/08/1/2008-0011- providing further support to our studies. No wonder that the research work is ahead of its schedule and we are currently planning future experiments.”

Although at present much of the research is being carried out at cellular level, nevertheless, Dr Kvell is aiming to advance the work in the form of establishing transgenic or genetically modified mice. “So far most of our data have been confirmed at cellular level, but now we are eager to move on and prove that this mechanism is also applicable in mouse models. We are planning to create transgenic mice for the molecules that are involved in this senescence process (namely Wnt4 and LAP2alpha), so we would like to try actually both directions - to both increase and decrease the rate of thymic involution process. This is quite costly so currently we are in the process of seeking funds in the form of applying for EU FP7 and NIH funds.”

The next few years are likely to prove crucial to the development of the research, as Dr Kvell explains. “I would think that in a few years’ time we shall be able to see our hypothesis being confirmed in experimental animals – in transgenic mice. Then the next big step is the gearing up towards potential human applications.”

Even then there are the inevitable medical ethical issues to be faced: In an increasingly limited cash pool, who is to decide who should benefit and who should not for instance? “As always in human applications it is quite difficult to decide who should benefit from the treatments and who should not if there are limited resources available.”

So how, I wondered does Dr Kvell spend his time these days? “Much of our job is spent conducting research on computer or applying for research grants and then we also have the research students working with us who need a lot of attention. But of course we always have time for our major and most appreciated task: lab-work.

I personally employ a broad spectrum of methods on a daily basis including working with cell lines and primary cells, mouse models and we utilise various types of viral vectors used for the genetic modification of cell lines, primary cells and mouse models. This is also the basis of our next step: making transgenic animals.”

“Immunology was my first speciality and biotechnology is closely related, although it is a more novel field of science and now I have more of a leaning towards this.” The next stage in what is inevitably going to be a lengthy, drawn-out process is the creation of the transgenic mice. Once again a grant has come to the aid of the researchers. “We do have parallel research grants running and we are just on the verge of starting a transgenic animal facility of our own.”

“In this facility we will be capable of creating our own transgenic animals. It is also going to be a Specific Pathogen Free (SPF) facility, meaning that these animals would be kept in very special, clean – though not sterile – conditions, which is a must in immunology for performing credible experiments.”

“We have now an EU grant which allows us to build this SPF transgenic animal facility and then to purchase all the instruments required to establish the mentioned transgenic animals”

Click here to contact Krisztian Kvell.

Published: Monday, 17th October 2011