Tag Archives: thymus

Discarded Thymus glands offer new hope for people with autoimmune disease

The thymus is one of those under appreciated organs you just don’t hear much about. Sitting in your chest, just in front of your heart, the thymus is at its largest and most active during infancy and childhood. By adulthood, the thymus has shrunk to practically nothing, being mostly replaced by fat. It plays an important role in the health of your immune system, and is the location where certain immune cells, called T-cells, go to mature and develop properly.

The thymus is like a schoolhouse for T-cells where they learn important lessons, like “recognize these sets of proteins as part of our own body and don’t attack them, but attack anything you don’t recognize because it must be a foreign intruder”. It allows the immune system to develop what is known as Central Tolerance. Without central tolerance, we develop auto-immune disease, which is essentially your immune system fighting a civil war against other parts of your own body. Diseases like Lupus, Type 1 diabetes, Myasthenia gravis, and many others are autoimmune diseases with the immune system actively damaging some parts of the body. In Type 1 diabetes, for instance, the immune system targets your pancreatic islet cells for destruction, resulting in loss of your bodies ability to make insulin.

 

The thymus is an organ where T-cells mature, and may be a source of regulatory T-cells that have the potential to treat autoimmune disease.

The thymus is an organ where T-cells mature, and may be a source of regulatory T-cells that have the potential to treat autoimmune disease.

 

It is also known that there are many varieties of T-cells, each with unique and important roles to play in immune function. One type of T-cell is known as the Regulatory T-cell or Treg. Tregs are special because they help to keep the other cells of the immune system from getting too wild and out of control (a recipe for autoimmune disease). They can go into an inflammatory situation where lots of immune cells are activated and ready to rumble, and tell those cells, “alright, everyone just calm down”, thereby suppressing the immune response. Some studies have show that Tregs can be infused into patients with autoimmune disease to help control their symptoms. They might even be a valuable way to suppress the immune system in people with an organ transplant, like a kidney or heart. Tregs are a way to use one part of the immune system to control other parts of the immune system – like fighting fire with fire – in the case of autoimmune disease.

These treatments, while promising, are still not fully evaluated and are not standard of care as of yet. One reason that not much research has been done using Tregs as a therapy is that they are hard to come by. They can be collected from the blood of donors, then grown in the lab to try to get enough cells for treatment, but the process is inefficient and doesn’t result in a large number of Treg cells.

This month in the American Journal of Transplantation, a team of Canadian researcher showed that discarded human thymuses are an excellent source of Tregs that can be harvested and used to treat a variety of immune mediated disease. So why would there ever be a discarded thymus? It turns out that when an infant is undergoing heart surgery, as might be done to correct a cardiac birth defect, the thymus is huge and in the surgeons’ way, and must be removed to gain access to the heart. This is true in infants where the thymus is very large compared to the heart, but not a problem in adults where the thymus has already atrophied to a tiny insignificant size.

Tregs can be identified and isolated based on unique protein markers on their cell surfaces such as CD25+,CD4+, and FOXP3. Other immune cells show different sets of markers making it possible to identify the different cell types, and select only the ones needed. The researchers found that they could identify and isolate many more Tregs from one discarded infant thymus, than could be generated from the blood of an adult donor. In fact, they could show that there are more Tregs in an infant thymus than are present in the entire circulation of an adult. They also found that the Tregs from discarded infant thymus function better compared to those recovered from the process of blood donation. It is thought that this might be due to the immaturity of Tregs coming from thymus versus blood, since those in the blood have been around longer and show other markers of cellular aging, such as shorter telomere length.

Perhaps if more Tregs become available from thymus harvesting, more clinical studies studies will be conducted that may hopefully find effective ways to treat autoimmune diseases that today are very difficult to control and create much suffering in the lives of so many people.

 

Reference Article:
1. Am J Transplant. 2016 Jan;16(1):58-71. doi: 10.1111/ajt.13456. Epub 2015 Sep 28.  Discarded Human Thymus Is a Novel Source of Stable and Long-Lived Therapeutic Regulatory T Cells.
Dijke IE1,2, Hoeppli RE3, Ellis T1,2, Pearcey J1,2, Huang Q3, McMurchy AN3, Boer K4, Peeters AM4, Aubert G5, Larsen I1,2, Ross DB2,6, Rebeyka I2,6, Campbell A3, Baan CC4, Levings MK3, West LJ1,2,6.

Whole organ ‘grown’ in animals for the first time

A whole functional organ has been successfully grown in animals for the first time; a group of Scottish researchers created a group of cells which, when transplanted into a mouse, developed into a fully functional thymus – a critical part of the immune system. The findings could lead to a revolution in organ transplant.

The thymus is a vital part of the immune system, generating T-Cells.

The thymus is a specialized organ of the immune system. Within the thymus, T-cells mature. T cells are critical to the adaptive immune system, where they adapt specifically to foreign invaders. Each T cell attacks a specific foreign substance which it identifies with its receptor. Scientists at the Medical Research Council centre for regenerative medicine at the University of Edinburgh have successfully created a thymus, inside a mouse, starting from just cells collected from an embryo.

The cells were “reprogrammed” and mixed with other support-role cells, in a similar experiment to the lab-grown human brains which reached the maturity of a 9 week old foetus. The resulting thymus was structurally and functionally similar to a real one, prompting Prof Clare Blackburn, part of the research team, to say results are “tremendously exciting”.

“This was a complete surprise to us, that we were really being able to generate a fully functional and fully organised organ starting with reprogrammed cells in really a very straightforward way. This is a very exciting advance and it’s also very tantalising in terms of the wider field of regenerative medicine.”

For patients in need of a bone marrow transplant or in babies born without a thymus, the technique is extremely promising. Ways of helping elders or people with a less functional thymus also show promise. However, even if it works in mice, the risk of actually trying the technique in humans is huge. However, researchers are now testing pancreatic cells encapsulated in a device, which is then implanted in the patient. Another challenge is that the current technique uses embryo cells – so developing thymus would not be a tissue match for the patient. Also, scientists have to be sure the cells won’t start growing uncontrollably, in a cancerous way.

T-Cells are crucial for the immune system.

Prof Robin Lovell-Badge, from the National Institute for Medical Research, said:

“This appears to be an excellent study. This is an important achievement both for demonstrating how to make an organ, albeit a relatively simple one, and because of the critical role of the thymus in developing a proper functioning immune system. However… the methods are unlikely to be easy to translate to human patients.”

Dr Paolo de Coppi, who pioneers regenerative therapies at Great Ormond Street Hospital was also very excited, and more confident in the possibility of using the technique in humans:

“Research such as this demonstrates that organ engineering could, in the future, be a substitute for transplantation.Engineering of relatively simple organs has already been adopted for a small number of patients and it is possible that within the next five years more complex organs will be engineered for patients using specialised cells derived from stem cells in a similar way as outlined in this paper. It remains to be seen whether, in the long term, cells generated using direct reprogramming will be able to maintain their specialised form and avoid problems such as tumour formation.”

Journal Reference: Nicholas Bredenkamp,Svetlana Ulyanchenko,Kathy Emma O’Neill,Nancy Ruth Manley, Harsh Jayesh Vaidya& Catherine Clare Blackburn. An organized and functional thymus generated from ​FOXN1-reprogrammed fibroblasts. Nature Cell Biology (2014) doi:10.1038/ncb3023

The normal mouse thymus (left) contains only a small fraction of B-cells (red). If the gene FOXN4 is activated, a fish-like thymus with many B-cells develops. Image: Max Planck

Resetting the immune system back 500 million years

Researchers at the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE)  re-activated the expression of an ancient gene in mice. To their surprise, the gene in question which is dormant in all mammalian species caused the mice to develop  fish-like thymus. The thymus is an organ of paramount importance to the adaptive immune system, but in this particular instance, the thymus produced not only T cells, but also served as a maturation site for B cells – a property normally seen only in the thymus of fish. So, what we’re seeing is a resetting of the immune system to a state similar to what it was like 500 million years ago, when the very first vertebrates began to emerge. By closely following how these gene works, the scientists hope to build a model that will explain how the thymus evolved during the past hundreds of millions of years.

An ancient immune system, today

T-cells are a type of white blood cell that circulate around our bodies, scanning for cellular abnormalities and infections, and are essential to human immunity. These are matured by the epithelial cells in the thymus, but genetically-wise it’s the FOX1 gene that triggers their development. FOX1’s evolutionary ancestor is FOX4, an ancient gene that lies dormant in most vertebrates except jawed fish, such as cat sharks and zebra fish.

The team led by Thomas Boehm, director at the MPI-IE and head of the department for developmental immunology, activated FOX4 in mice. When both FOX1 and FOX4 are simultaneously activated, the researchers found the mouse thymus exhibited properties similar to those found in a fish. Coupled with previous findings, the results suggest that that thymus as we know it today in most vertebrates evolved from and was prompted by the FOX4 gene.  Through  an evolutionary gene duplication FOX1 was born. Initially  both genes must have been active, until finally only FOXN1 was active in the thymus.

The normal mouse thymus (left) contains only a small fraction of B-cells (red). If the gene FOXN4 is activated, a fish-like thymus with many B-cells develops. Image: Max Planck

The normal mouse thymus (left) contains only a small fraction of B-cells (red). If the gene FOXN4 is activated, a fish-like thymus with many B-cells develops. Image: Max Planck

A surprising find was that not only T-cells developed in the thymus of the mice, but also B-cells. Mature B-cells are responsible for antibody production. In mammals, they normally do not mature in the thymus, but in other organs, such as the bone marrow.

Boehm says that it’s not yet clear whether the B-cell development is based on the migration of dedicated B-cell precursors to the thymus, or to maturation from a shared T/B progenitor in the thymus itself.  Nevertheless, it’s remarkable how the researchers have uncovered a particular evolutionary innovation that occurred in an extinct species. Retracting evolutionary steps in our collective ancestral background might provide insights we dare not dream of.