One of the greatest challenges in medicine is the need for replacement organs. Every 10 minutes another person’s name is added to the national organ transplantation waiting list, the length of which now exceeds 100,000. Eighteen of these people die each day. Those who are fortunate enough to receive an organ often have to take immunosuppressive drugs for the rest of their lives, thus making them more vulnerable to other infections, and even then their new organs may gradually be rejected by their immune system.
One potential way to overcome this problem is through the creation of a chimeric immune system by mixing the immune (hematopoetic) stem cells of the recipient with that of the donor. As explained in last week’s issue of Science Translational Medicine:
According to Greek mythology, the Chimera was a fire-breathing creature made of parts from different animals: the body of a lioness, a snake’s head at the end of the tail, and the head of the goat. Sightings of this fearsome beast portended any of a number of terrible disasters. In the context of organ transplantation, a ”chimera” can indicate both desirable and disastrous outcomes. For example, hematopoietic chimerism, in which the immune cells in the graft recipient come from both the host and the donor, may promote graft tolerance, but may also cause graft-versus-host host disease (GVHD), in which the donor immune cells attack the healthy tissue of the host.
The underlying problem behind rejection and GVHD – both of which shrink the potential donor pool – is matching. Now, a novel procedure has come one step closer to overcoming the matching problem and achieving transplantation tolerance. In an exciting, albeit small, study the University of Louisville team transplanted mismatched, unrelated donor kidneys into eight patients along with a mix of donor hematopoetic stem cells and a special population of tolerance-inducing facilitator cells (FCs). These FCs have been shown in animal models to improve engraftment (acceptance of the graft) and avoid GVHD. The results and potential meaning are well-summarized by Science Translational Medicine:
Five of eight kidney transplant recipients exhibited durable chimerism and were weaned off immunosuppressive therapies by 1 year after transplantation, with no signs of GVHD or engraftment syndrome. If confirmed in larger patient cohorts, this approach to transplantation could free some patients from the difficulties associated with lifelong immunosuppression and add transplantation as a viable option for patients for whom no matched donors exist.
An editorial written in STM about the study lauds that this procedure “may potentially have an enormous, paradigm-shifting impact on solid-organ transplantation” and that “few transplant developments in the past half-century have been more enticing than these that put transplantation tolerance within our grasp.” This editor followed up with the primary investigator of the study, Dr. Suzanne Ildstad from Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, to ask about the future of the procedure as well as other applications that are being explored:
Shiv Gaglani, Medgadget: Your paper refers to applications “not only in sold organ and cell transplant recipients but also for…hemoglobinopathies, inherited metabolic disorders, and autoimmune diseases.” What other applications are currently being explored using this novel chimeric approach?
Dr. Suzanne Ildstad: We are currently working on applying this procedure to sickle cell disease, thalassemia, metachromatic leukodystrophy, and in the near future, Type 1 diabetes.
Medgadget: When is the earliest we could see this technique in the clinic?
Ildstad: Currently all of the above are in clinical trials with the exception of Type 1 diabetes.
Medgadget: Given that the chimeric approach enabled your transplant patients to be weaned off of immunosuppresive drugs, do you have any data on whether these patients are less susceptible to traditional problems of immunosuppression (e.g. viral, fungal, bacterial infection)?
Ildstad: It will take more subjects and long-term follow up. As we describe in the paper, so far all complications have occurred while the subjects were still on double drug [immunosuppression with tacromilus and mycophenolate mofetil] treatment.
Paper in Science Translational Medicine: Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoetic Stem Cell Transplantation
Editorial in STM: The Quest for Transplantation Tolerance: Have We Finally Sipped from the Cup?
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