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Immunosuppression

David Munn probably wouldn’t have thought that the work he did decades ago would have made such a big wave in the field of tumor immunotherapy. After all, before he discovered the function of IDO, his wish was to become a pediatrician.
Munn was born in Atlanta. After reading his undergraduate course, he chose to go to Georgia medical school to study doctor of medicine. Soon after he graduated, he found the focus of his career: cancer of children.
Pediatric cancer is almost untreatable in the 50s and 60s of last century, and children with these cancers are equivalent to having been sentenced to death. But with the advent of chemotherapeutic drugs and its growing use, about sixty or seventy percent of cancer children can be cured by the 80s Munn graduation.
This is indeed a remarkable progress, but behind the high cure rate is the heavy cost faced by children who are receiving chemotherapy. Many patients have obvious toxic reactions after chemotherapy, some side effects will occur after a long time of withdrawal, and there is evidence that chemotherapeutic drugs can affect the cognitive ability of children, thus causing a lot of inconvenience to their future studies and life.
If there are other options, chemotherapy may not be a good choice. Nevertheless, at that time, Munn, like most other doctors, did not have a very good solution.
Munn was working for the memorial Sloan Caitlin cancer center in New York for the first time when he was exposed to tumor immunity. But at that time, the understanding of tumor immunity was still very superficial, and even the treatment method used was tumor immunotherapy.
In the 80s of last century, the hospital where Munn was located had already started bone marrow transplantation for children. But the purpose of bone marrow transplantation is not to treat cancer, but to save patients who have been devastated by chemotherapeutic drugs, because chemotherapy drugs can not only kill cancer cells, but also destroy the patient’s immune system, which can cause fatal infection. So the purpose of bone marrow transplantation was simple at that time, in order to rebuild the patient’s immune system. From this point of view, bone marrow transplantation is not really immune therapy.

And in order to avoid the emergence of graft versus host response, T cells needed to be removed before bone marrow transplantation to ensure higher purity of stem cells. Because the prevailing way was so, Munn did not think there was any problem. And they found that if the number of T cells was reduced to 1/1000, it could eliminate immune rejection.
But when there are more and more data on bone marrow transplantation, researchers have found that the lighter immune rejection is not a bad thing for patients, because the graft can not only attack the normal cells of the host, but also kill the cancer cells. So many people at the time began to realize that the success of bone marrow transplantation for these patients was largely due to the presence of these immune responses.
This discovery has been in the mind of Munn, and he knows the findings are very important, but they can’t explain the detailed mechanism of the graft – versus – host response to kill cancer cells. After all, there are still a lot of gaps in the study of immunology at that time.
But there is a key factor that is obvious, that is, the existence of T cells. T cells are crucial to the formation of graft versus host responses, and the graft versus host response seems to be one of the most important reasons for these patients’ remission. In what way is T cells in the mystical way to mediate this reaction?
T cells really fascinate Munn at that time because he knows that T cells can control virus infection, and viruses usually have few genes, but the ten or two genes are enough to activate the human immune system, to induce the human immune system to identify and remove the virus infected cells. There are hundreds of mutations in cancer cells. Why is the immune system unable to attack tumors?
This is indeed a very interesting question, and the researchers in the field of tumor immunology also had the same thinking. In fact, a lot of researchers were conducting research on tumor immunotherapy, and Steve Rosenberg of NIH was one of them.

Rosenberg is a doctor with great scientific talent and clinical insight. The mainstream view that the immune system was unable to combat tumors was that the human immune system was not able to identify tumor cells, but Rosenberg found that many melanoma patients could respond to IL-2 (see: from Wei Zexi to Emily Whitehead, a huge breakthrough in tumor Immunocytic therapy) and even able to cure it. The more a part of the patient. This actually negates the previous view that the human body’s own immune system can indeed identify and kill tumor cells.
But the key question is, why does the body’s immune system ignore the presence of the tumor without the use of IL-2? Can a tumor inhibit the function of the immune system?
In fact, some studies have found that there is immune suppression in the human body. In fact, we can find a very good example to prove the existence of this mechanism, which is the development of the fetus in the womb, because the fetus is not physically attacked by the immune system during the development of the fetus.
Although the fetus in the womb is connected to the mother’s blood system, the T cells in the mother’s blood can flow through the placenta to the fetus. However, half of the fetuses are from the father. In this case, the genetic products of fathers from many sources should be identified as foreign materials.
But in fact, the immune system does not attack these so-called foreign objects. At the time, some scientists speculated that the possible reason was that the fetus did not have antigen presentation. But Munn’s accidental discovery in the experiment completely overturned this theory.

Miraculous metabolism

When Munn was in Sloan, he and his supervisor, Nai-Kong Cheung, had been trying to cultivate two kinds of immune cells, T cells and macrophages. The purpose of this work is actually simple, in order to observe whether macrophages that can phagocytic tumor cells can activate T cells. The process is also exactly what we now know about antigen presentation. Macrophages present the broken protein fragments to kill T cells after phagocytosis of the tumor cells.
At that time, people did not know much about the function of these types of immune cells. It was not known that macrophages were not typical antigen presenting cells, and it was more appropriate to use dendritic cells to carry out the experiment. So now it seems reasonable to fail in the experiment.
People who are not familiar with basic scientific research are always curious about where the pleasure of scientific research comes from. Perhaps Munn’s research can answer this question very well. Although the experiment failed to achieve the intended purpose, they had some unexpected findings. When they put macrophages together with T cells, they found that T cells could not be activated, but were inhibited by function.
I feel that anyone who has enthusiasm for scientific research will not be able to sleep in the face of such a result. So how can the function of T cells be suppressed?
A postdoctoral fellow in Munn laboratory found that macrophages had high metabolic activity. This is not actually a new discovery, but do they suspect that it is because macrophages are consuming too much nutrients, causing a nutritional deficiency in T cells, which can cause their function to be inhibited?
To test the conjecture, the tireless blogger decided to stay up at night and add the nutrients needed for the two cell cultures every hour. By daybreak, he found that the function of T cells was not inhibited under adequate nutrition.

It seems that the riddle will soon be unraveled. The most crucial factor they face now is what kind of nutrients limit the function of T cells. In fact, this method is not very difficult. Use 100% spent medium to cultivate T cells, and then add nutrients one by one.
They list a very long list of nutrients, but after trying all kinds of nutrients, they have no results. Folic acid? Iron? Glutamic acid? None of them。 Until they added a drop of tryptophan to the medium, miracles happen. They completely reverse the inhibition of T cells.
Munn’s team was excited. They found that macrophages could consume tryptophan through IDO (indolamine 2, 3- two oxidase). But nobody knows about the specific functions of IDO. No one has studied the function of IDO before.
But it was obvious that people knew more about tryptophan’s function at that time. Tryptophan pathway has been a hot topic in the pharmaceutical industry because tryptophan can transform serotonin into human body. Many drugs that affect serotonin, such as Prozac, have brought huge profits to pharmaceutical companies. So chemists have synthesized a lot of tryptophan derivatives.
Munn tested some of the IDO inhibitory activities of some tryptophan analogues, and he successfully discovered a small molecule that could inhibit IDO function. Next, it is time to test the activity of the IDO inhibitor (in vivo), but what kind of mouse model can make it convenient for them to study the function of IDO?
In the course of the discussion, one of the Munn teams said that IDO could be obtained from the placenta, and the placenta is a good example of acquired peripheral tolerance. Why not do it based on the fetus / placenta? This is really a good proposal.
So Munn decided to use antibodies to mark the location of IDO in placenta, which may also provide more information for IDO function analysis. Subsequently, they found that IDO could be expressed in syncytial trophoblastic cells (syncytiotrophoblast).

In the next experiment, Munn chose the transplanted mouse model, which was transplanted into the fetal mouse (pup). The logic of the experiment is easy to understand, because a mouse’s sudden appearance in the fetus can theoretically cause an immune system to cause an abortion, but if IDO can inhibit the T cells of the mother’s mother and then inhibit the function of the immune system, the fetus can be retained. If IDO inhibitor is used to inhibit its function, it may lead to immune reaction leading to miscarriage. The results of the experiment are also consistent with expectations. They also published the experimental data on Science (DOI: 10.1126 / science. 281. 5380.1191).
Although the article was published in 1998, it was only a few years later that people realized the importance of IDO in tumor immunity. So what has happened to IDO in recent years?
Want to know what to do, and listen down.

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