The Evolution of the Danger Theory
The Evolution of the Danger Theory
We can see this in several ways. First, by looking at current drugs. For example cyclosporin A (CsA) is an immunosuppressant that has kept many transplant patients alive. However, it has kept these people alive at great expense and at great risk of infection, and at the risk of preventing tolerance, because it blocks the wrong signals. I'm not the first person to say this. Sir Roy Caln was a liver transplanter in Cambridge, UK, back when CsA was first discovered. He showed, in a rat model of liver transplantation, that transplanted livers could induce tolerance even without immunosuppressants, and that this tolerance would allow a liver-transplanted rat to accept a skin graft from the liver donor. However, if Caln gave CsA at the same time as the liver transplant, he prevented the induction of tolerance. This was done in the mid 1970s and should have woken people up to the dangers of CsA. Alan Kirk later published a study describing kidney transplants in six monkeys that were given anti-CD40L to block signal 2. He gave the blocking antibodies for 5 months then stopped. None of the monkeys rejected, and by the time he published some of the monkeys had carried their grafts for 6 years and still had not rejected. This shows that the details matter. We should be mimicking the body's own ways of inducing tolerance, with signal 2 blockers that can be given for a short time, rather than signal 1 blockers that must be given for the life of the patient.
Second, we should look at limiting the damage done during transplant procedures. One day I was in Holland talking about danger, and Jan van Rood – who founded Eurotransplant – jumped up in the back having realized why completely unmatched living donor kidneys do better post-transplant than matched cadaver kidneys. When you use living donors for transplantation there are a number of benefits with regards to damage. First, you do not have to perfuse the kidney and therefore you do not get reperfusion injury. Second, you do not have the time for injury and damage to occur while it is being transported around the country between hospitals. In living donor transplant, the donor and recipient are normally in the same operating theater and the kidney is taken from the donor and transferred directly to the recipient. This results in far less damage, far fewer alarm signals and a much greater tolerizing capacity. So, creating minimal damage and blocking signal 2 would be the things to do to get better transplant results.
Third, we could try blocking the alarm signals. Walter Land, ex-head of experimental surgery at the Medical School, Munich, Germany, was one of the first surgeons to understand the danger model. In a way, he discovered it before I published it. He had run a clinical trial in kidney transplant patients to try to enhance immediate kidney function. Sometimes, for unknown reasons, a transplanted kidney never starts functioning. Land hypothesized that maybe reperfusion injury and the attendant oxygen radicals damaged the kidney so much that it could not function. Therefore, he decided to give a single shot of the oxygen free radical scavenger, superoxide dismutase (SOD) at the time of transplant. Forty-four patients got the SOD and 44 did not, but otherwise they were treated completely the same. It turned out that the SOD made a slight difference in immediate function but not a great one. They followed the patients anyway and, a few years later, Land was approached by his computer analyst who had found the amazing result that the 44 patients that got the shot had experienced almost no acute rejection episodes, compared to the patients that did not get the SOD. Land and his institute carried out more studies in rats looking at the effect of SOD and found that it was highly effective, and started telling the world that immunity was greatly influenced by tissue damage.
Unfortunately, because a single shot of SOD is an inexpensive treatment, the clinical trial that would be needed to take this treatment to the clinic would be so much more expensive than any potential profit, no pharmaceutical company is likely to pursue it. There are many such treatments discovered by researchers. These are the kinds of treatments for which the clinical trials ought to be funded by a public health system, such as the NHS in the UK, or indeed insurance companies in countries like the USA. It would ultimately save these groups tons of money in long-term follow-up of these patients, and save the patients a lot of pain; but it is unlikely to happen.
Because of the success with SOD, and with living kidney donors, I think that we should focus on minimizing damage and blocking signal 2. Blocking the alarm signals would be a difficult proposition, as there are too many of them. Anything that is normally found inside a cell, and not outside, can be an alarm signal and many have already been found, such as DNA, RNA, ATP, uric acid crystals, hyaluron break-down products, heat shock proteins, and (my favorite) mitochondria. Right now, I'm not sure what kinds of drugs we would try to use to block all these.
How Has the Danger Theory Revealed the Directions That Need to Be Taken for Future Drugs & Transplantation Protocols?
We can see this in several ways. First, by looking at current drugs. For example cyclosporin A (CsA) is an immunosuppressant that has kept many transplant patients alive. However, it has kept these people alive at great expense and at great risk of infection, and at the risk of preventing tolerance, because it blocks the wrong signals. I'm not the first person to say this. Sir Roy Caln was a liver transplanter in Cambridge, UK, back when CsA was first discovered. He showed, in a rat model of liver transplantation, that transplanted livers could induce tolerance even without immunosuppressants, and that this tolerance would allow a liver-transplanted rat to accept a skin graft from the liver donor. However, if Caln gave CsA at the same time as the liver transplant, he prevented the induction of tolerance. This was done in the mid 1970s and should have woken people up to the dangers of CsA. Alan Kirk later published a study describing kidney transplants in six monkeys that were given anti-CD40L to block signal 2. He gave the blocking antibodies for 5 months then stopped. None of the monkeys rejected, and by the time he published some of the monkeys had carried their grafts for 6 years and still had not rejected. This shows that the details matter. We should be mimicking the body's own ways of inducing tolerance, with signal 2 blockers that can be given for a short time, rather than signal 1 blockers that must be given for the life of the patient.
Second, we should look at limiting the damage done during transplant procedures. One day I was in Holland talking about danger, and Jan van Rood – who founded Eurotransplant – jumped up in the back having realized why completely unmatched living donor kidneys do better post-transplant than matched cadaver kidneys. When you use living donors for transplantation there are a number of benefits with regards to damage. First, you do not have to perfuse the kidney and therefore you do not get reperfusion injury. Second, you do not have the time for injury and damage to occur while it is being transported around the country between hospitals. In living donor transplant, the donor and recipient are normally in the same operating theater and the kidney is taken from the donor and transferred directly to the recipient. This results in far less damage, far fewer alarm signals and a much greater tolerizing capacity. So, creating minimal damage and blocking signal 2 would be the things to do to get better transplant results.
Third, we could try blocking the alarm signals. Walter Land, ex-head of experimental surgery at the Medical School, Munich, Germany, was one of the first surgeons to understand the danger model. In a way, he discovered it before I published it. He had run a clinical trial in kidney transplant patients to try to enhance immediate kidney function. Sometimes, for unknown reasons, a transplanted kidney never starts functioning. Land hypothesized that maybe reperfusion injury and the attendant oxygen radicals damaged the kidney so much that it could not function. Therefore, he decided to give a single shot of the oxygen free radical scavenger, superoxide dismutase (SOD) at the time of transplant. Forty-four patients got the SOD and 44 did not, but otherwise they were treated completely the same. It turned out that the SOD made a slight difference in immediate function but not a great one. They followed the patients anyway and, a few years later, Land was approached by his computer analyst who had found the amazing result that the 44 patients that got the shot had experienced almost no acute rejection episodes, compared to the patients that did not get the SOD. Land and his institute carried out more studies in rats looking at the effect of SOD and found that it was highly effective, and started telling the world that immunity was greatly influenced by tissue damage.
Unfortunately, because a single shot of SOD is an inexpensive treatment, the clinical trial that would be needed to take this treatment to the clinic would be so much more expensive than any potential profit, no pharmaceutical company is likely to pursue it. There are many such treatments discovered by researchers. These are the kinds of treatments for which the clinical trials ought to be funded by a public health system, such as the NHS in the UK, or indeed insurance companies in countries like the USA. It would ultimately save these groups tons of money in long-term follow-up of these patients, and save the patients a lot of pain; but it is unlikely to happen.
Because of the success with SOD, and with living kidney donors, I think that we should focus on minimizing damage and blocking signal 2. Blocking the alarm signals would be a difficult proposition, as there are too many of them. Anything that is normally found inside a cell, and not outside, can be an alarm signal and many have already been found, such as DNA, RNA, ATP, uric acid crystals, hyaluron break-down products, heat shock proteins, and (my favorite) mitochondria. Right now, I'm not sure what kinds of drugs we would try to use to block all these.
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