At 21, multiple sclerosis (MS) had Jennifer Molson “wheelchair bound.” But since her stem cell transplant, she has worked, driven, danced at her own wedding.
The story had a room of 1,000 professional stem cell scientists sniffling at the International Society for Stem Cell Research (ISSCR) meeting—said sniffling reaching a crescendo when the quiet, pretty Molson concluded: “I’m living proof stem cells can save lives.”
Diagnosed with Relapsing Remitting MS, Molson had failed many standard treatments when she tried a hematopoietic stem cell transplant (HSCT, or bone marrow transplant (BMT)) in 2002, as part of a clinical trial.
That trial, first reported on in 2013 by three Canadian centers, has seen dramatic results: none of the trial’s 14 immuno-monitoring sub-study patients saw remissions in the first two years. The transplants halted all new focal inflammatory MS disease, verified by both medical examinations and brain MRI’s. A paper on a larger cohort of 24 patients is being compiled.
There have been 500 MS HSCTs worldwide. MS is an inflammatory autoimmune disease in which the immune system is thought to attack its own nervous system via the myelin protecting nerve fibers.
Results globally have been mixed. Indeed, Molson’s doctors, Ottowa Hospital’s Harold Atkins and Mark Freedman, wrote in a 2012 review that “although a few patients have had dramatic improvements after HSCT, most reports of improvement are modest.”
Not so in this study. One reason, Atkins conjectured in a recent email to Bioscience Technology: a more intense regimen than usual was used to wipe out the immune system of Molson and the other Canadian patients.
The trend was toward more “non-myeloablative” approaches. But while gentler, these may not ablate enough immune cells trained on attacking “self-antigen.” Self-antigen are proteins on cells marking them as “self.”
“I suspect, but it is hard to prove, that the high-dose chemotherapy we use dampens the ability of the immune system to react,” said Atkins, an Ottowa Hospital Blood and Marrow Transplant Program transplantation expert, in his email. “This reduces the robust immune response to antigens in these autoimmune patients to a more `normal’ reactivity.”
He continued: “There does appear to be a dose-response effect. Low-intensity regimens used for transplant, or slightly lower regimens that do not need transplant, have a higher rate of reappearance of the autoimmune disease. Our program has focused on using high-dose regimens that are myeloablative [i.e., that near-completely wipe out bone marrow cells]. The myeloablation is of course an off-target effect. We use the dose intensity to eliminate the pre-existing autoreactive immune system.”
The Canadians also took care to replace the “old” immune systems with T-cell-eradicated grafts that were as purely ”stem-cell” as possible. This way, theoretically, fewer of the old “bad boy” self-reactive T cells remain, giving the stem cells a chance to create new immune systems.
Clues About Culprits
Intense examination of the new immune systems of 14 patients has given the Canadians new clues about cause. While the teams did find some self-reactive cells in their successfully transplanted patients, they also found their blood contained a pro-inflammatory subset of CD4 T cells, called TH17 CD4 T cells, that was less competent than normal; less able to rouse aggressive attacks.
In the same successful patients’ blood, there was also an increase in regulatory, anti-inflammatory CD4 T cells.
In 2005, a group from the National Institute of Neurological Disorders and Stroke similarly found—for the first time—that more than the sledgehammering of old cells is at play when stem cell transplants succeed. That group found, said the Canadians in their 2013 paper, that “a lack of re-emergence of pro-inflammatory CNS-reactive T cells in the reconstituting immune repertoire" could be the basis for a “robust and sustained therapeutic effect.”
But this wasn’t easy to track, as many teams were trying more non-myeloablative treatments. These are less dangerous, but they leave more old T cells behind, “making it difficult to distinguish between newly developed autoreactive T cells and those that may have persisted in the host of autologous graft,” the Canadians wrote. “As part of the Canadian MS BMT Study, we had a unique opportunity to test this hypothesis, given the use of a high intensity immunoablative cheomotherapy regimen, as well as T-cell-depleted, autologous stem cell grafts, designed to most effectively eliminate residual T cells.”
They concluded: “Our study provides a unique window into mechanisms that may underlie development of new inflammatory disease activity in patients with MS. Although additional mechanisms may apply, we demonstrate that the diminished capacity of peripheral T cells to mount IL-17 responses…is associated with the dramatic and sustained abrogation of disease activity following high-intensity immunoablation and autologous HSCT in MS. Although this highly aggressive treatment paradigm does not provide direct insights into mechanisms underlying disease activity in the broad MS population, our findings suggest that Th17 and Th1/Th17 CD4 T cells, as well as Tc17 CD8 T cells… may represent the peripheral effector T-cell subsets most relevant to the initiation of new relapsing disease activity in this cohort of patients with aggressive MS.”
A Role for the Environment?
And since the transplants were autologous (from the patients’ own bodies), the Canadians’ success indicates MS may not start in the stem cell, and may have environmental roots.
Harvard University’s Laurence Turka led a 2014 study finding patients do best with more diversity, post-transplant, in their T cell repertoire. “I don’t think any autoimmune disease starts in the hematopoietic stem cells,” he told Bioscience Technology. “It is probably much more complicated…. HSCT has a very profound effect on the T cell repertoire, eliminating a lot of T cell receptor antigen specificities, not just MS-related ones. New antigen specificities, which are presumably not auto-reactive, take their place.”
Concluded Atkins to Bioscience Technology: “It is well known that immunogenetic predisposition is not the entire story. For most monozygotic (identical) twins only have about a 30 percent concordance rate, where both would be afflicted by an autoimmune disease. This highlights the importance of the interplay between genetics and environment. While the environmental triggers of autoimmunity are not well described, they are distributed in time and space. They aren’t around all the time. If they were around all the time, one would expect that identical twins would have a much higher concordance rate. Twins are usually raised together and are in the same environment for 18-20 years of their lives and are both exposed to the same challenges.”
Follow Cynthia Fox on twitter at @cynthfox.