A half-century quest for a holy grail of organ transplantation seemed on the verge of ending in March 2012 when a group of researchers announced some kidney transplant patients had been drug-free for more than a year.
This January, they did it again.
This announcement had the only other group to pull off that particular feat—researchers at Massachusetts General Hospital (MGH)—speculating the day of drug-free organ transplantation may be at hand.
“The six-decade long quest for tolerance for kidney transplant patients may finally be nearing its end,” wrote James Markmann and Tatsuo Kawai of MGH in Science Translational Medicine.
In 2009, Northwestern Memorial Hospital—led by the University of Louisville's Suzanne Ildstad and Northwestern University's Joseph Leventhal—began transplanting into patients hematopoietic (blood) stem cells and kidneys from donors who were not immunological matches.
To the researchers' delight, new immune systems blossomed in most patients. And those patients experiencing full and durable “macrochimerism”—or long-term residence of large numbers of the donor stem cells in the new immune systems—did the seemingly impossible. When immunosuppressive drugs were removed, their bodies accepted their new kidneys without the common deadly complication of graft v. host disease (GVHD) for a year—and counting.
“If [results] are sustained and expanded in number,” wrote Markmann and Kawai, “they may potentially have an enormous, paradigm-shifting impact on solid-organ transplantation.”
Indeed, this January, the Ildstad group published an update finding exactly that: results were sustained in almost double the number of patients—so far.
“Complete immunosuppression withdrawal at one year after transplantation was successful in all patients with durable chimerism,” the group reported. “There has been no graft v. host disease.”
Researchers have pursued this particular holy grail since 1953, when University of Birmingham biologist Peter Medawar conducted immunology’s most famous experiment. He created a chimera, or immunologically composite creature. He did this by injecting blood cells from one mouse into a newborn one. Because the newborn's immune system was immature and just beginning to distinguish self from non-self, it accepted that foreign cell—and later, a skin graft from the same donor.
The medical profession has been transplanting organs into patients since the 1950's using a sledgehammer to force an artificial kind of immune tolerance. Patients take heavy doses of immunosuppressives, as many as 25 a day, to keep their immune systems drugged and unable to rouse and reject new organs. But those drugs also render transplant patients twice as likely to get cancer as the general population and leave them vulnerable to disorders from diabetes to heart disease. Years later, the organs are often eventually rejected.
Since Medawar, immunologists fantasized about a gentler approach: training patients’ immune systems to become chimeras; to accept all cells and organs from specified donors. But outside of patients and donors who were exact immunological matches, it didn’t work. Adult human immune systems seemed untrainable.
But in 2008, MGH reported in The New England Journal of Medicine (NEJM) that it had pulled it off. Four of five patients who were not exact immunological matches with their donors accepted kidneys from those donors, sans drugs, for years post-transplant. This was accomplished by partially leveling the immune systems of the patients with a careful, targeted, “non-myeloablative” shot of chemo and radiation, and then administering blood stem cells along with kidneys from the same donors.
Blood stem cells, immature if highly responsive cells that form in the bone marrow throughout life and become all the mature functional cells of the blood and immune system, provided the key. The donors’ blood stem cells—along with the patients’ remaining blood stem cells—formed new immune systems in the vacuums caused by the chemo and radiation. These unprecedented immune systems now recognized as “self” all cells of both the patients and their mismatched donors. This occurred because stem cells are in a comparatively immature, comparatively undifferentiated state not unlike that of Medawar's newborn mouse: trainable.
Still, the MGH group experienced some deadly GVHD, which can lead to rejection. The approach was not perfect.
But last year, Ildstad's group added a twist. They used a tougher preconditioning regimen, wiping out more of patients' native cells than MGH. And they added what they called “facilitating cells” to their stem cell/kidney transplants. The result: they achieved drug-free tolerance between mismatched donors and recipients sans GVHD.
They did this in the face of something extraordinary. Unlike the MGH group, whose patients experienced “mixed” chimerism that was often transient—new immune systems that retained relatively few donor cells—the Ildstad group achieved an enduring full chimerism. That is, a very large number of cells in their patients’ immune systems were made of donor cells—for a very long time. Yet zero GVHD was experienced.
This advance was "striking,” Markmann and Kawai noted.
Last month, in Clinical and Translational Research, the Ildstad group suggested their results were holding up so well, the field may want to adopt a new test for determining when to wean patients off drugs. The field is debating it. Meanwhile, many offer caveats. Larger studies with control groups are needed. The Ildstad group’s “facilitating cells” may elicit regulatory cells that orchestrate all the striking tolerance. But they are proprietary, an “x” factor, right now. More needs to be understood.
Immunologist Megan Sykes, a key architect of the MGH approach now heading labs at Columbia University, called the Ildstad results "remarkable." But she also remains "very excited" about MGH's approach (to be updated soon in the NEJM).
The “toxicity” of the Ildstad regimen, associated with some prolonged neutropenia and thrombocytopenia and "numerous infectious complications…is considerable," Sykes says. “I would agree that durable T cell chimerism is a marker for tolerance in that regimen, but not necessarily in others (like the MGH regimen).” Moreover, Sykes is not sure Ildstad is correct when analyzing assay results as evidence patients exhibit donor-specific hyporesponsiveness—that is, that patients’ new immune systems avoid targeting donor cells only. “She shows assays that I would interpret as global hyporesponsiveness [rather than] donor-specific,” Sykes says.
Furthermore, MGH's mixed chimerism allows key orchestrating patient cells to remain in the patient’s body. Those key orchestrating cells are native “antigen-presenting cells,” like dendritic cells, that can ensure tolerance throughout a patient's life. Without those native orchestrating cells—and the Ildstad patients presumably lack them since full donor chimerism is the Ildstad trademark—Sykes wonders if tolerance is in danger of fading.
As noted, Ildstad's “facilitating cells” may restore a form of the latter cells to the equation. But again: they are a mystery. There will be “cautious enthusiasm” for the Ildstad approach until more is known, says Thomas Spitzer, MGH Bone Marrow Transplant Program chief.
In the meantime, mysteries aside, it is unavoidable that both approaches are producing a growing number of historic transplant patients. “It is gratifying to see how healthy they are off the drugs,” says Ildstad.
Markmann and Kawai conclude: “Although only a taste of things to come, few transplant developments in the past half-century have been more enticing than these that put transplantation tolerance within our grasp.”
1. Leventhal, J. et al, “Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation,” Science Translational Medicine, Vol 4, Iss 124, March 7, 2012: 169-176.
2. Leventhal, J. et al, “Tolerance Induction in HLA Disparate Living Donor Kidney Transplantation by Donor Stem Cell Infusion: Durable Chimerism Predicts Outcome,” Clinical and Translational Research, Vol 95, Iss 1, January 15, 2013: 169-176.
3. Markmann, J. et al, “The Quest for Transplantation Tolerance: Have We Finally Sipped From the Cup?” Science Translational Medicine, Vol 4, Iss 124, March 7, 2012: 124fs5.
4. Leventhal, J. et al, “Evolving Approaches of Hematopoietic Stem Cell Based Therapies to Induce Tolerance to Organ Transplants: The Long Road to Tolerance,” Clinical Pharmacology and Therapeutics, Vol 93, Iss 1, January 2013: 36-45.
5. Waldmann, H. et al, “Community Corner: A step closer to effective transplant tolerance?” Nature Medicine, Vol 18 Iss 5, May 2012 : 664-665.