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Good comparison of the 3 recent studies of tissue transplant survival. Both good news and bad news. Two studies found evidence that after many years, some of the transplanted cells showed signs of Parkinson's pathology. However as Dr. Ole Isacson, one of the authors points out, ""But the bottom line is still that 99% of the cells in all 3 papers appeared to be unaffected, which is pretty remarkable."These studies may have implications for future treatments using cell transplantation, such as stem cells. "Possible Evidence of Host-to-Graft Spread in Parkinson's Disease Cell Transplants" by Susan Jeffreyfrom Medscape http://www.medscape.com/viewarticle/572858?src=mpnews&spon=26&uac=29890SX --> April 11, 2008 — Results of 2 new reports looking at long-term survival of fetal mesencephalic dopaminergic neurons in postmortem Parkinson's disease (PD) patients who underwent transplant up to 16 years earlier have shown that, although these cell transplants appear to have survived and did provide some symptomatic relief, some appear to have developed alpha-synuclein–positive Lewy bodies in the grafted neurons. However, a third report, looking at 5 patients up to 14 years after transplant, has shown no such pathology. The divergent findings have sparked some debate among the groups on what may explain these differences and whether the changes seen by the first 2 groups essentially represent "host-vs-graft" progression of Parkinson's disease in the transplanted cells, as those groups speculate it does. All 3 brief reports were published online April 6 in Nature Medicine. Ongoing process? To try to mitigate the loss of striatal dopamine, some patients with Parkinson's disease have received fetal ventral mesencephalic transplants, researchers, led by Jeffrey H. Kordower, PhD, from Rush University Medical Center, in Chicago, Illinois, write in 1 of the 3 Brief Communications articles. "Double-blind, sham-controlled studies did not establish clinical benefit, although significant improvement was observed in subpopulations of patients upon post hoc analysis," they write. One of the central questions with this approach was whether transplanted cells might fall victim to progressive disease in PD, the exact process of which is still largely unknown. Grafts examined in postmortem studies of patients who died about 18 months after implantation showed robust survival, Dr. Kordower and colleagues write, but PD pathology progresses over decades, raising the question of whether these cases just did not survive long enough to show disease pathology in grafted neurons. In their current report, Dr. Kordower and colleagues discuss postmortem analysis of 1 patient who received grafted nigral neurons 14 years earlier. They found that the grafted neurons had Lewy-body–like inclusions that stained positively for alpha-synuclein and ubiquitin and showed reduced immunostaining for dopamine transporter. "These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra," they write. "These findings give us a bit of pause for the value of cell-replacement strategy for Parkinson's disease," Dr. Kordower said in a statement from Rush. "While it is not clear to us whether the same fate would befall stem-cell grafts, the next generation of cell-replacement procedures, this study does suggest that grafted cells can be affected by the disease process." In a second Brief Communication in the same issue, first and corresponding authors Jia-Yi Li, PhD, and Patrik Brundin, MD, PhD, from the Wallenberg Neuroscience Center, in Lund, Sweden, and colleagues report on postmortem analysis of tissue from 2 PD patients who received transplanted fetal mesencephalic dopaminergic neurons 11 and 16 years earlier. Despite long-term survival of the grafted cells in both patients, they found histopathological changes characteristic of PD, including the presence of alpha-synuclein–positive Lewy bodies in grafted neurons in both patients. "Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells," they write. "However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief." No Signs of Neurodegeneration However, a third report looking at long-term postmortem analysis in 5 patients 9 to 14 years after transplantation of fetal midbrain cell suspensions comes to a different conclusion. Researchers, with first and corresponding authors Ivar Mendez, MD, PhD, from Dalhousie University and Queen Elizabeth II Health Sciences Center, in Halifax, Nova Scotia, and Ole Isacson, MD, from Harvard University, in Boston, Massachusetts, report that grafted dopamine and serotonin neurons survived without signs of neurodegeneration in these patients for up to 14 years, despite ongoing degeneration of midbrain dopamine neurons and other dopamine structures in the host parkinsonian brain. The lack of degeneration in the grafts, they write, does not imply that the disease does not eventually affect these dopamine neurons but rather "proves that under the appropriate conditions of integration and reduced inflammatory response obtained by our methods, grafted neurons can avoid significant degeneration long term. "These results have major implications for the etiopathogenesis of Parkinson's disease, as the host brain does not necessarily create conditions that cause Parkinson's disease–related neurodegeneration in the transplanted neurons," they conclude. "Moreover, these findings encourage the future use of fetal- and stem-cell–derived dopamine neurons for people with Parkinson's disease." Asked about these divergent findings, Dr. Isacson told Medscape Neurology & Neurosurgery that he feels any conclusions about an ongoing disease process made in the other 2 papers are "quite speculative." "I believe the most direct explanation is that they had some low-grade chronic inflammation around their transplants that we did not see. There is some evidence in their paper to suggest that, and we know that low-grade inflammation may be 1 of the factors that could make cells a little more likely to degenerate," Dr. Isacson said. "But the bottom line is still that 99% of the cells in all 3 papers appeared to be unaffected, which is pretty remarkable." He pointed out that their own work involved the transplantation of cell suspensions, while in the paper by Kordower and colleagues sections of tissue were transplanted. "They have perhaps something that they have induced by the transplantation surgery that then makes some of their neurons after 14 years perhaps undergo some structural change," he speculated. In an interview with Medscape Neurology & Neurosurgery, Dr. Kordower acknowledged this difference in methods but said he did not feel that would completely explain the difference they saw, since the patients included in the paper by Li and colleagues were done using methods identical to that of Dr. Isacson's group. It is also possible that, given 1 of the patients in the report by Dr. Isacson and colleagues had a relatively small number of implanted cells, these changes could have been present but in too small a graft for them to be visualized, Dr. Kordower added. "I think what may account for the differences is that it just doesn't happen every time," Dr. Kordower said, referring to the possible ongoing PD process. "This is one of the problems with doing case studies. It doesn't tell you what does happen. It tells you what can happen." At the end of the day, though, even if the disease process does continue and ultimately affect some of the implanted cells, there were still "many, many" cells in all 3 reports that were completely healthy and functioning in the long term, Dr. Kordower said; the affected cells they saw were still the "vast minority." "It doesn't really speak to whether cell-replacement therapy is or is not viable because of these changes," he added. If there is disease progression to new cells, though, this represents "a huge advance in trying to understand what causes the degenerative process, and it's quite a distinctive one. There are lots of ways to cause inflammation in brains . . . but you don’t get Lewy bodies," he pointed out. "There's something very specific about the pathological process of Parkinson's disease that causes a Lewy body, and this is being seen in these 13-year-old cells, and that's amazing." "A Positive, Not a Cautionary, Story" Curt R. Freed, MD, from the University of Colorado Health Sciences Center, in Denver, did some of the early work in this field, along with colleague Robert Breeze, MD, and has perhaps the largest series, with a total of 61 patients who have been treated since 1988. In this series, Dr. Freed said they have seen no protein deposits in dopamine neurons from postmortem cases up to 14 years after transplant. "While I think these articles are worth noting, the European authors had no reason to say that the transplants had developed Parkinson's from the patient's brain," Dr. Freed told Medscape Neurology & Neurosurgery in an email comment. "There was no evidence of 'host-vs-graft' reaction. That is language from the immunologic literature on transplants. Since the mechanism by which Parkinson's develops is unknown in most patients, and because the precipitation of alpha-synuclein and ubiquitin protein is not unique to Parkinson's, there is no indication that the cells have developed a Parkinson condition," Dr. Freed noted, adding he intends to write a letter to the editor of Nature Medicine pointing this out. Why the other groups saw some degeneration in their grafts may reflect differences in transplant methods, he said, echoing Dr. Isacson's point. "Every group does transplants differently, and some groups have changed their methods after every few patients transplanted," he noted, particularly so with patients in the paper by Li et al. But Dr. Freed added, "Let's look on the positive side." All 3 Nature Medicine papers, as well as their own experience in Colorado, have shown that fetal dopamine cell transplants can survive without the need for immunosuppression and function indefinitely, he concludes. "This is a positive, not a cautionary, story." New Cell Types on the Horizon In a paper also released this week, published online April 7, 2008 in the Proceedings of the National Academy of Sciences, Dr. Isacson's group, with first author Marius Wernig, PhD, from the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, report results on a possible new source of dopaminergic cells to address PD that may potentially provide an alternative to the controversial use of fetal tissue. They have "reprogrammed" fibroblasts genetically, turning them into functioning stem cells that can give rise to multiple types of nervous system cells. They were then able to demonstrate, in a rat model of PD, that these cells integrated into the brain, showed electrophysiological activity, and improved symptoms in the rats. "We've succeeded now both with mouse and human cells to get almost the authentic cell type that we transplant like fetal cells, so we hope to use that as a future cell source," Dr. Isacson said. In the study by Kordower et al, the authors report competing financial interests, available in the paper. Funding sources for each of the studies is outlined in the respective papers. Nat Med. Published online April 6, 2008. Abstract Abstract Abstract Proc Natl Acad Sci. Published online April 7, 2008. 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