Surgery to transplant a donor liver, small bowel, kidney, heart, lung or other organ is heroic, intense and intricate. However, many of the surgical problems have been solved over the last several decades. Now, the main challenge to long-term success in organ transplantation is how to prevent the patient’s immune system from rejecting the new organ.
Although recipients of transplanted organs often live normal, productive lives, they typically need lifelong immunosuppressive medications to avoid transplant rejection. These medications result in heightened susceptibility to infection. At that point, transplantation becomes a medical problem, and the immune system is key.
According to Dr. Gay Crooks, co-director of the UCLA Broad Stem Cell Research Center and a professor of pathology and laboratory medicine, pediatrics and orthopaedic surgery, all solid organ transplantations have immune rejections of the patient to the organ as their major problem. This creates a need for essentially lifelong immune suppressive drugs that have real side effects.
Transplantation may cause an increased risk of:
In response to this problem, researchers in many fields at UCLA are working on solutions to provide better outcomes for patients who receive donor organs at UCLA’s transplant center.
By testing 38 cytokines, researchers can see if there are pro-inflammatory factors that predict organ rejection, factors that suppress inflammation, or a mixture of both. They can also produce an immunity profile for organ rejection in each patient.
If there is one focus in many of the transplantation studies underway at UCLA, it is the thymus. The thymus is the gland that sits in front of the heart, in the middle of the lung’s lobes. It educates the adaptive immune system, coaching immune T (“T”hymus) cells to become “warriors” that recognize and kill abnormal cells or invading microbes.
In recent years, it has become clear that a second class of T cells is also created in the thymus that turns off an immune response when needed. Dr. Crooks calls them “peacemakers.” Peacemakers are further trained in the body’s periphery — perhaps the gut, perhaps the lymph nodes — to modulate and downplay an immune reaction. After all, if there were only warriors, we wouldn’t survive for very long due to rampant autoimmunity.
In organ transplantation, doctors tend to suppress the warriors. However, researchers are now trying to train the system better, either at the thymus level or in the periphery, to engage the peacemakers. This is the opposite of cancer immunotherapy, which is designed to disrupt the peacemakers and arm the warriors.
One strategy to reduce organ rejection emerges from the field of bone marrow transplantation. Bone marrow is where immune system cells are first made, and bone marrow transplantation essentially replaces a sick patient’s own immune system.
This procedure is also called “hematopoietic” stem cell transplantation. It refers to the blood-forming stem cells that make all forms of blood cells, including those that make up the immune system.
Following a stem cell transplant, there is a struggle between the new immune cells that come from the donor and the cells that remain in the patient. However, the thymus educates the donor blood stem cells to become more tolerant of existing immune and tissue cells. This can see patients off all immune suppressive drugs in as little as three months because they now have a new immune system but that immune system thinks it is home.
Several centers in the U.S. are experimenting with giving patients both a new organ and a stem cell transplant from the donor. UCLA is looking at that possibility, but its researchers want to take a bigger step forward. Dr. Crooks says her work is to look at transplanting a donor’s thymus — a piece of it — along with the organ.
Before that thymus is transplanted, UCLA researchers plan on rejuvenating it. The thymus starts to deteriorate very early in life and so does the output of tolerant T cells. Immunity falls off as you age meaning fewer warriors, which in turn is not good to fight cancer. This also leads to less effective immunizations, and fewer peacemakers, which can explain a number of conditions like chronic inflammation and autoimmune diseases.
Dr. Crooks and other UCLA researchers are identifying the molecular signals that drive the thymus early in life to create its huge repertoire of immune cells. A multi-specialized group of investigators is involved in this thymic work, including:
The future of organ transplantation therapy is in creating new organs that perfectly match the patient’s immune system. But that involves a very big hurdle — developing the know-how needed to coax stem cells to morph into organs.
Teams of UCLA researchers working on every organ that might be transplanted are studying the very basis of that organ generation, asking questions things:
After methods for regeneration are developed, researchers believe they will be able to further alter the stem cell so that the organ it creates will not be rejected when transplanted into a patient.
Gene editing is the ability of researchers to remove, add or replace genes as desired. UCLA researchers are investigating a procedure that selectively edits human leukocyte antigen, HLA— the “fingerprint-like” proteins on the surface of cells that are different for every individual — in order to eliminate immune rejection.
In this scenario, some or all of the HLA proteins are deleted in the stem cell and a set of HLA genes that matches the patient’s HLA profile can be added. According to Dr. Crooks, the organ that develops would be close enough to the patient’s immune profile that an immune reaction would not occur.
What would then be possible are “off-the-shelf” organs that could be matched to the transplant populations. The future, Dr. Crooks says, is healthy new organs as needed with no rejection issues.