Robert Lechler of King’s College London: ‘In recent years we have acquired enormous insights into how to turn the immune system on and off’

For transplant patients, the body’s own defences can be fatal. Breakthrough research offers new hope

Source Robert Lechler on Financial Times

“Although I was well aware of the time ticking away throughout the procedure — everyone was — I could only continue to work carefully and systematically and, at all costs, efficiently,” surgeon Joseph Murray recalled of the operation that made him famous.

“There was a collective hush in the operating room as we gently removed the clamps from the vessels newly attached to the donor kidney. As blood flow was restored, [the] new kidney began to become engorged and turn pink . . . There were grins all around.

” No wonder: the procedure that Murray described in his 2001 autobiography was the first successful human organ transplant. Carried out in Boston, US, in 1954, it saved the life of 23-year-old Richard Herrick and ushered in one of the great success stories of 20th-century medicine.

Organ transplantation would go on to save thousands of lives, and transform hundreds of thousands of others; Murray won a Nobel Prize for his pioneering work.

Herrick and Murray benefited from an exceptional circumstance: the fact that Herrick had an identical twin who was willing to donate his kidney.

Transplants between individuals other than identical twins are more problematic, because the genetic differences trigger a vehement immune response. The transplanted organ is identified as a large mass of foreign tissue, and is rejected.

Overcoming this challenge was the focus of the transplant pioneers for many years — including Murray, many of whose subsequent non-twin patients died.

An early breakthrough, prescribed from the early 1960s, was a drug called azathioprine, which inhibited white blood cells — the vehicle for the body’s immune response — from multiplying. Used along with large doses of steroids, it had significant side effects but greatly boosted a patient’s chance of still being alive one year after a transplant — though only to about 50 per cent.

Another advance came in the 1970s, when the Swiss pharmaceutical company Sandoz discovered cyclosporin, a more potent immunosuppressant. It was introduced into the clinic about a decade later and led to a marked improvement in early survival, with fewer side effects.

Today, thanks to it and other immunosuppressants, more than 90 per cent of transplanted kidneys survive beyond 12 months, and their recipients enjoy a return to a normal quality of life. The same goes for other organs too, and transplantation has become the treatment of choice for end-stage failure of many organ systems, including kidney, liver, heart and lung.

While this is an impressive achievement, transplantation has three limitations. First, the immunosuppressive drugs have side effects; as a consequence of their potency, patients have an increased incidence of infections and of cancer.

Second, although early success rates have seen a dramatic improvement, there is a steady attrition rate after the first year of survival, so that the average half-life of a kidney transplant from a deceased donor is approximately 12 years — in other words, 50 per cent of patients will have a transplant that lasts at least that long, but 50 per cent won’t. Patients whose kidney transplant has failed have to return to dialysis and await a second or even a third transplant.

And there we run into the third limitation: namely, that there aren’t enough organs to meet demand. Public campaigns to drive donation, such as the move towards presumed consent, go some way to address this. But given the need for organs to be taken from donors whose hearts are still beating (though whose brains have died), supply will always fall short.

It is these three problems that have spurred my own team, and laboratories around the world, to pursue research into transplantation tolerance. The aim is to make the transplant recipient’s immune system selectively blind to the new organ, while leaving it intact to defend the patient against infections and cancer.

This may sound fanciful, but in recent years we have acquired enormous insights into how to turn the immune system on and off. These have had a substantial impact in several areas of medicine, notably oncology. Some cancers that were untreatable a few years ago can now be treated; what used to be considered death sentences can now be thought of as long-term conditions.

An extraordinary facet of the immune system is its ability to discriminate between our own proteins and the proteins made by bacteria, viruses and fungi — between ‘self’ and ‘not-self’

There is a symmetry between cancer immunotherapy and immune manipulation in transplantation. With cancer, the goal is to persuade the immune system to attack something that it is inclined to ignore; with transplants, the goal is to persuade the recipient’s immune system to ignore something that it is inclined to attack.

Patients with autoimmune diseases present the same challenge: here too the immune system mounts a response that needs to be silenced.

This highlights an extraordinary facet of the immune system, namely its ability to discriminate between our own proteins and the proteins made by bacteria, viruses and fungi — between “self” and “not-self”, in other words.

There is nothing categorically different between our own proteins and those made by pathogens; in both cases they are simply strings of amino acids. The fact that the immune system manages most of the time to discriminate between the two is essential to our survival.

One key mechanism for avoiding autoimmunity is a small population of white blood cells called “regulatory T-cells”. Their critical role has been demonstrated by genetically engineering mice that lack them; these mice develop multiple autoimmune pathologies.

More recently, a small number of human families have been identified in whom a gene that is vital for the formation of these cells is mutated, and whose members likewise suffer from autoimmune syndromes.

It appears that regulatory T-cells work in several ways to suppress immune responses, including by reducing the potency of the specialised cells that present foreign proteins to the immune system and so prime it to destroy anything carrying those proteins.

These observations led us to pose a simple question: might it be possible to isolate this population of regulatory cells and program them to inhibit immunity against the foreign proteins of a transplanted organ? This worked in mice: regulatory cells that were purified and cultured ex vivo (outside the animal) prevented rejection of heart transplants from a different mouse strain.

To move closer to clinical application, we then used a “humanised mouse model”, in which a mouse that had been genetically engineered to lack any immune system of its own was replenished with a human immune system. This allowed us to determine whether infused human regulatory cells would be able to prevent rejection of human skin grafted on to the mouse. Again, this proved successful.

We hope to make the transplant recipient’s immune system selectively blind to the new organ, while leaving it intact to defend the patient against infections and cancer

Armed with these results, we obtained approval from the UK’s Medicines and Healthcare products Regulatory Agency to conduct Phase 1, safety, trials of regulatory cell therapy in transplant recipients.

This was just one stage in what has been a long journey. My team and at least one other first discovered regulatory T-cells in humans in 2001. Completing the experimental work in mice, studying the human regulatory T-cells and developing techniques to purify them and make them multiply outside the body took over 15 years.

We have just completed trials in kidney and liver transplant recipients. The treatment appears to have been safe — there were no serious adverse reactions — and there were hints that it improved on existing treatments in the kidney patients. None of the 12 treated patients experienced a rejection episode, while 15 per cent of the control group that did not receive regulatory cells had at least one rejection episode.

This paves the way for more in-depth trials, perhaps within the next two years, for which we plan to use regulatory T-cells that have been genetically modified to target their attention on the transplant; they should then set the rest of the immune system to ignore the transplant, while leaving it able to destroy all other types of invader. (In the phase 1 trials, regulatory T-cells were isolated and made to multiply ex vivo before being reintroduced into patients but were not reprogrammed.)

To test the treatment’s efficacy, we will slowly wean patients off their immunosuppressants, while carefully monitoring the replacement organ’s function, together with other biomarkers.

We are not alone in being optimistic about the potential of our approach: Syncona, a venture fund, has invested £34m in a spin-out company to carry out the trials and refine our techniques.

Exciting as these findings are, other lines of research may hold still greater promise. In particular, there has been real progress in the field of regenerative medicine, which aims to manipulate and enhance the body’s capacity to repair itself.

A key breakthrough came in the late 1990s, when researchers isolated human stem cells from embryos.

The distinctive property of stem cells is that they can develop into a range of bodily cells according to the biochemical signals that they are given, and potentially could be a limitless source of transplantable tissue.

However, the use of embryo-derived cells is encumbered by ethical issues — it is illegal in some jurisdictions — and, inevitably, such tissues would be mismatched with the recipient. The problem of organ supply might be solved, but not that of provoking an immune response.

More recently, attention has turned to so-called induced pluripotent stem cells (iPS cells). These are normal human cells that are reprogrammed to a stem-cell state and can then be differentiated into whatever cell type is desired.

This opens the possibility of generating iPS cells from the patient in need of a transplant: the new kidney, liver or other organ tissue that could be derived from those cells would be genetically identical to the patient’s existing tissue, so there would be no immune response.

So far researchers have generated simple tissues including cartilage and rudimentary organoids such as mini-kidneys. Time will tell whether complex organs, such as a fully formed kidney or heart, can be generated for transplantation.

Yet for all the potential of stem cells, the most exciting approach in regenerative medicine at present takes a different tack. The aim is to emulate the self-healing abilities of zebrafish and salamanders, which can regenerate their own tissues in a way that mammalian species cannot. If up to 20 per cent of the ventricular tissue in a zebrafish’s heart is excised, the damage will be repaired within two months; any such injury to a mammalian heart, however, inevitably leads to scarring, with no regeneration of heart muscle.

Mauro Giacca is an Italian cardiologist and regenerative medicine expert who has recently moved from Trieste to King’s College London; he and his colleagues have been working with mice and pigs, deliberately inducing a heart attack by blocking coronary arteries. This leads to tissue death — infarction — in the affected area, an injury that would normally develop into a scar. By manipulating patterns of gene expression in the tissue surrounding the infarct, Giacca and his colleagues have induced heart-muscle regeneration.

In time, it may be possible to translate this approach to humans and to other organs, although there are safety hurdles to be overcome. Once the damage has been repaired, for instance, a way must be found to stop the heart-muscle cells from multiplying; otherwise the affected area may become overdeveloped and disrupt the heart’s rhythm.

This field of medicine holds enormous promise for the future. We have come a long way from the days when an identical twin was a patient’s only hope of survival. As progress is made in promoting immune tolerance, and in persuading tissues to repair themselves, people who once had to endure chronic debilitating diseases may instead enjoy a new lease of life.

Robert Lechler is vice-principal (health) at King’s College London and president of the Academy of Medical Sciences

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