NKTreg white blood cells migrate into liver, suppress immune responses: Research

After a transplant - and to assure that the new organ is not rejected - patients are put on life-long therapy to suppress their immune system (IS), which, nevertheless, needs to be left intact enough to be able to defend the body against all kinds of disease. A tricky balance as the many rejected organs attest. But a discovery by Maria Monteiro and Luis Graça, two Portuguese scientists, could change all this, at least for the liver. Their work, just out in the Journal of Immunology, describes how they found a new type of white blood cell - baptised NKTreg (reg from regulatory) - that, once activated, migrate into the liver and suppress any immune response in its vicinity. What is most remarkable is that the immune system elsewhere is left intact. And the implications do not end in better liver transplants as, once these cells create an "immune tolerant organ", we can graft any type of tissue or express any gene that the body might need into it, knowing that it would be safe from the IS. The potential of the discovery is such that a patent by Monteiro and Graça for the production and therapeutic use of NKTreg cells in humans has already been accepted.

Controlling an unwanted immune response, whether to stop organ rejection after a transplant or for the treatment of autoimmune diseases - in which an abnormal IS attacks the own body- can be tricky. At the moment there are two types of approaches: general immunosuppression or deletion of entire "arms" of the IS. Both methods require a difficult equilibrium between stopping the damaging immune response while allowing patients to remain immuno-competent, and both carry potentially serious side effects. Most recent therapies fall in the second approach and work by deleting a particular type of cell or protein (an "arm" of the IS) at the core of the immune response we want to stop. While these methods can be extraordinarily effective - thousand of patients had their lives changed by them - unfortunately, they do not seem to work for long, probably because the IS adapts and brings other cells and proteins to do the job of the lost "arm". While this is not a problem for pharmaceutical companies that can go on developing new and even more expensive drugs, to patients it means a life of constant uncertainty and many potential problems- will the next new drug be effective, will it stop working, will then be yet another drug ready, what about side effects?

The truth is that these kinds of approaches are a far cry from a 21st century medicine with emphasis in personalised and very specific therapies, and it is crucial that new and better treatments are found.

It is in this context that a family of white blood cells called regulatory T cells has been hailed as "next big thing" - shown to suppress immune responses and part of the body's mechanisms to stop undesired immune responses, these cells could be key to more specific treatments while are also less prone to be "overridden" by the body control mechanisms.  And in fact, human trials for their use in transplantation are already under way although much work needs to be done. But meanwhile another family of white blood cells - called NKT cells - has also came to the attention of scientists when shown to protect mice from several autoimmune diseases, including diabetes and autoimmune encephalomyelitis (EAE) - the animal equivalent of multiple sclerosis

To try to understand better the potential of NKT cells Marta Monteiro, Luis Graça and colleagues at the Instituto de Medicina Molecular, University of Lisbon and the Instituto Gulbenkian de Ciência in Oeiras, Portugal looked at mice protected from EAE using NKT cells (like shown by others). In these mice they analysed the lymph nodes that drain the brain - the logic being that since EAE affects the brain, protective cells should be found in the lymph nodes directly linked to it. To their surprise they discover a total new population of NKT cells that expressed Foxp3 - a marker for regulatory T cell, linked to these cells immunosuppressive capabilities. When these new NKT cells were studied in laboratory they revealed several other similarities - not only they share many other receptors of regulatory T cells but, like them, both Foxp3 and their suppressive abilities are triggered by a protein called TGFbeta - leading Monteiro and Graça  to name them NKTreg cells.

But how do these cells act when in the body? To answer this question, and after activating NKT cells to become NKTreg (so Foxp3 positive) and tag them with a fluorescent marker so they could be easily traced, Monteiro and Graça injected the (suppressive) cells back into mice. Remarkably these cells homed straight to the liver - in this they are very different from regulatory T cells that move into all lymphoid organs; spleen, lymph nodes, etc - suggesting that in normal conditions NKTreg cells could perform some immunosuppressive role in this organ.

The implications of this discovery are important and many. In liver transplants although success rate has increased substantially the odds that the organ will survive up to 15 years are still only around 58%,  with as many as 10-15% of patients experiencing organ rejection before the end of the first year. Not only that, but current immunosuppression therapies are costly and affect patients' life expectancy by putting them at higher risk of cancer and mortal infections. NKTreg cells - if proved to function in the same way in humans, and Monteiro has already shown that we at least have them - might be the answer to these problems.

As Luis Graça explains "the liver is already the transplanted organ with higher chances of success due to its unique characteristics, by using these new cells we might be able to achieve almost 100%  organ acceptance and this without touching the remaining IS, what is remarkable. Patients might be able to survive with only a minimum dose of other immunsuppressors".

But there are other major implications to be able to create a "bubble of tolerance" within the body. Many diseases caused by the absence of a molecule or metabolic tissue are being treated with therapies that insert replacements into the body. The problem is that the IS soon or later detects these new "parts" and attacks them.  The liver is already a place where the immune system seems to be less vigilant - probably so it is not over-activated all the time by the food and microbial molecules that come through the digestive system - add NKTreg cells to this organ and it can became the perfect place to hide anything from the IS.

And in fact,  at the moment, some diabetic patients - that lack insulin to metabolise sugars - already have insulin-producing grafts on their liver, while some gene therapies, for example for the production of clothing factors in haemophilia (a disease where patients can not coagulate their blood) are already being expressed in the organ. NKTreg, if they work in the same way in humans as in mice, can radically improve the chances of success of these and other therapies. The potential of being able to create a contained area of immunosuppression within the body without touching the remaining immune responses elsewhere in the body, is immense.  But first we need to see if and how NKTreg cells work in humans and that is what Monteiro and Graça plan to do next.

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