Allotransplantation, the procedure to transfer an organ or tissue from one individual to another of the same species, can be very hard. Ho was a housewife. Her husband, Xu, suffered from uraemia and had to be dialyzed three times a week. The only way to free him from this tiring routine was a kidney transplant. However, his elder sister, who was the only match in the family, refused to help after long hesitation. There was little hope that he would last long enough to wait for another match owing to the long waiting list. Ho wished to donate her kidney to help save her husband but her effort was in vain. She felt helpless when Xu died an agonizing death in 2018.
Matched or Not: <The Real Challenge
It is a painful experience when your doctor tells you that you can’t save your loved one’s life, not because of constraints of money or time, or operative techniques, but a lack of matched organs. Nowadays, millions of patients are awaiting a life-saving transplant. According to the Global Observatory on Donation and Transplantation (GODT), only about 160,000 organ transplants are performed worldwide each year, less than 10% of the global demand.
Why do so many patients need matched organs in order to have transplant surgery? The real challenge is the allograft rejection reaction. When it occurs, your body will treat the donated organ as an invader and attempt to fight against it, which leads to failure of transplantation.
Why does an Allograft RejectionOccur?
Imagine that your body is an international airport, and that your immune system a large number of security inspectors, who check every single cell that enters your body after an organ transplant. Each cell has to show valid identification to pass through. If it fails to do so, your immune system will sound the alarm and expel it immediately. The validity of the identification is determined by the Major Histocompatibility Complex (MHC), a group of genes clustered on the surface of a cell. In humans, they are called Human Leukocyte Antigens (HLA). MHC genes hold the key to the allograft rejection reaction, for they play a crucial role in helping the immune system distinguish between "self" and "non-self".
MHC genes are highly polymorphic. As mentioned by the Immuno Polymorphism Database (IPD), 40,437 HLA alleles have been discovered as of October 2024. A mismatch between the donor and recipient MHC genes will cause an acute allograft rejection after transplant surgery, so it is important to find a perfectly matched donor organ. Unfortunately, the polymorphism of MHC genes makes things extremely difficult. It is often too late for a recipient to receive a call saying that an MHC-matched organ has been found.As a result, 25-80% of the precious donor organs have not been used.
What is the Donor MHC-specific Thymus Vaccination Strategy?
Faced with the challenge of the allograft rejection reaction, we have been striving to find a solution. We here present the Donor MHC-specific Thymus Vaccination (DMTV) strategy, which may unlock the future of organ transplantation.
Our DMTV strategy is based on an entirely new concept that an allograft rejection can be avoided by enabling the immune system, especially T cells, to recognize the MHC genes of a donor’s organ as valid identification before transplantation. In other words, we can create an environment that allows cells harboring different types of MHC genes to coexist in an immune competent individual. To achieve this, we perform ectopic expression allogeneic MHC genes (MHCallo), or the donor MHC genes, in the recipient’s thymus through adeno-associated virus (AAV) infection. In the process, T cells interact with the MHC genes from both the donor and recipient. Those T cells with low affinity to both genes undergo natural apoptosis, which means they die. Those with overly high affinity to both genes are also eliminated to prevent them from attacking the body’s own healthy tissue. Those remaining after the process are called mature T cells. They will be tolerant to both the donor and recipient MHC genes, that is to say they view the donor MHC genes as “self”. The key components in this process are the expression vectors of the donor MHC genes, i.e. the AAV vectors, which we refer to as the “thymus vaccine”. With the DMTV strategy, doctors can perform transplant surgery with a low or no possibility of an allograft rejection. There is no need for a permanent regimen of immunosuppressant drugs.
Our Vision for the Future of the DMTV Strategy
It still takes time to make a thymus vaccine for a specific human patient. For effectiveness and safety, the concept of thymus vaccines needs to be evaluated in non-human primate animals before it can be further applied in human recipients. For the sake of efficiency, we propose that it will be practical to produce thymus vaccines for all HLA variants in advance and reserve them for future use. When a donor organ becomes available, the doctor can inject the target recipient with a thymus vaccine that suits him or her so that the transplant surgery can be performed smoothly without worrying about the problem of MHC mismatches. Thus, the waiting time can be greatly reduced and there will be a substantial decrease in the nonuse rate for all organs.
We hope that in the near future our specially designed thymus vaccines will bring benefit to recipients who have already undergone organ transplantation, making their immune systems compatible with the donor organs. Fewer or no immunosuppressant drugs will, therefore, be required, which lowers the risks of unwanted infections or malignant tumours and eventually improves the recipients’ quality of life. We honestly expect that more patients with end-stage organ failure will be saved with the promotion and application of our DMTV strategy in the clinical scenarios, and that there will never be a repeat of the tragedy like Xu’s.