Struggle for Tolerance in a Hostile World
Dr. Mohamed Sayegh Search for Immunologic Tolerance to Avoid Transplant Rejection
Some while ago, a friend of Dr. Mohamed Sayegh, “a nephrologist, a colleague and a friend of the family,” passed away after the complications of a kidney graft he had received from his wife many years ago. It seems that rejection, acute or chronic, is the final fate of any transplant, and the recipient should expect it sooner or later.
Dr. Sayegh is “interested in understanding the mechanism of transplant rejection and how to fool the immune system to accept the transplant, a term called immunologic tolerance.” His team has even used transgenic animals to study the mechanism of rejection and tolerance. Dr. Sayegh is mostly focused on promoting research at the regional level nowadays.
Donating one of your kidneys does not shorten your life expectancy, but it may add up to 20 happy years to the lifespan of those with kidney failure. It is the most promising, and most of the time the only, therapeutic measure for a so-called end-stage renal patient with irremediably dysfunctional kidneys.
The American surgeon Joseph Murray (1919-2012) performed the first successful kidney transplant in 1954, which brought him the 1990 Nobel Prize in Physiology or Medicine. In that revolutionary transplant surgery, the recipient received a kidney from his twin brother, which gave him another eight long years to live.
This so-called isograft is a type of transplant in which the donor and the recipient are not the same but are genetically identical. Isograft is technically a kind of allograft, or a graft from another person, but is immunologically similar to autograft, or a graft from the same person, in that it does not trigger an immune response.
However, not everyone has a twin willing to donate a kidney to his/her sibling, let alone for other organs that have no extra copy that could be spared. Limiting the kidney grafts supply to a diminished source of genetically identical twins would not answer the huge demand for organ or tissue transplants.
Today, about 100,000 kidney transplant surgeries are performed worldwide every year, up to 60% of all transplant surgeries followed by liver, heart, and lung, respectively. Though the kidney transplant is the most common transplant surgery, it has the longest waiting list, too, with more than 5 people for each available kidney.
The main hurdle that should be passed somehow is a problem called histocompatibility, or tissue compatibility, having similar genetics for cell surface protein. Immune cells check these proteins to discern if the cells carrying them on their surfaces belong to their own body or an invading foreign organism. In the latter case, the graft would be rejected by the recipient’s immune system.
The rejected graft would be destroyed and lose its function. Routine clinical procedures include testing a potential recipient’s compatibility to an available organ and using immunosuppressant drugs.
Let us have a look at the immunology of transplants. The alloresponse -- in which the prefix “allo-” from Greek means other and different -- is the immune system response to different cells and tissues belonging to other individuals. For such a response, the immune system must first recognize the foreign or allogenic molecules by a mechanism called allorecognition, short for alloantigen recognition. An organism defends itself against any potential invader through this phenomenon that has been observed in all vertebrates and other multicellular animals. The recognition is done using molecules called antigens on the surface of the non-self cells.
There is much polymorphism in these surface proteins called the major histocompatibility complex (MHC) molecules. If the molecules are genetically dissimilar, they are immunologically incompatible and will be recognized by the recipient’s immune system. As the term histocompatibility implies, MHCs were first discovered in the process of tissue transplantation between individuals with incompatible genetics: The donor cells had MHCs on their surfaces that were incompatible with host cells.
In humans, T-cells or T lymphocytes, a kind of white blood cells, are in charge of distinguishing between self and non-self cells antigen. Allopeptides bound to MHC molecules are displayed on the surface of antigen-presenting cells (APCs) to be recognized by T-cells. In transplantation, T-cells recognize the foreign antigens of the donor’s cells and react accordingly. This is where the graft rejection process begins. Even a minor incompatibility may provoke a strong reaction from host T-cells.
Recognition by T-cells takes place directly or indirectly, depending on the allograft characteristics. In the direct pathway, recipient T-cells recognize the allogeneic MHC molecules expressed by APCs of the donor as foreign. These cells that display non-self allogenic antigens -- MHC-peptide complex -- on their surface, exit the grafted organ soon after transplant and reach the host T-cells through the lymphatic system and teach them directly about their potential targets.
However, the recognition may occur indirectly when recipient T-cells recognize a self MHC molecule bound to a peptide with different amino acids. The alloantigens from graft are internalized, after engulfing surface proteins of donor cells by the recipient APCs, and then presenting them in the form of peptides on their MHC molecules. These “wrong” peptides, or allopeptides, will be presented on the recipient APCs, not the donor APCs, as is the case in the direct allorecognition.
Both direct and indirect allorecognition may be involved at the same time in allograft rejection. Direct allorecognition often leads to acute rejection of allografts soon after transplantation, while indirect allorecognition often contributes to chronic rejection in the long-term through damaging the graft with progressive loss of function that leads to graft loss finally.
The indirect pathway of allorecognition leading to chronic allograft rejection is the subject Dr. Sayegh and his colleagues have researched thoroughly in the past decades. They have devised, among others, a clinically useful novel assay that shows the occurrence risk of indirect allorecognition and chronic rejection in humans and then developed specific therapeutic strategies to prevent or interrupt this process.
For transplantation to be successful, the human leukocyte antigen (HLA) of the donor and the recipient must be the same, which is seldom the case. Even a minor HLA mismatch, which is actually unavoidable, leads to allorecognition and increases the risk of graft rejection. “We examined the response to incompatible HLA peptides as a predictor of chronic rejection,” Dr. Sayegh says.
Immunology is a hostile world; a cell eats cell world, to use Thomas Hobbes analogy. It takes a savior and brilliant approach to bring tolerance to such a milieu. Dr. Sayegh believes that the most critical question in the field is “the mechanism of immunologic tolerance and how to fool the immune system to accept a foreign organ without rejection and immunosuppression.” This would revolutionize tissue and organ transplantation. “This is still elusive,” he says.