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Biotech / Medical : STEM -- StemCells, Inc. -- Ignore unavailable to you. Want to Upgrade?

To: WWS who wrote (196)	1/25/1999 9:01:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 805

>> Richard, I must admit to not knowing as much as I should about the status of immune response systems within the CNS.<< That makes two of us, so let's keep talking until an expert drops in. I'm used to seeing surprises when testing is extended to humans or to a larger sample of humans in expanded trials. Thus the basic skepticism. I come from a camp that says that anti-viral immune responses in the brain can do more damage than an unchecked virus, from old Michael Oldstone-like observations. That's a pretty old camp. Also, I come from a stance that certain diseases such as MS involve an inflammatory component that does not involve exogenous insult. I'm just throwing out "show me" questions. If the answers are firmly in-hand, then we can turn to other questions..... the competitive benefit relative to projects such as those at GLFD/AMGN and VRTX, for example. This is neuro stuff. I'm just skimming, out of my league, asking questions. If someone can provide simple answers that will make me a devout believer, then I'll get rich at the expense of being a public idiot. Tisk, tisk. If this is all open-and-shut given (1) the preclinical and clinical data that is already in-hand, and (2) the methods that exist for isolation and expansion of the donor cells, then a simple "letter to the shareholders" from CTII should boost the market cap to about $1 billion, overnight. Could you please have them draft that document and send it to me for editing, one day before release? One trading day, that is. So.... yeah, there's lots of data out there that indicates that primary immune responses are difficult to initiate in the brain. I'm extremely interested in this concept, and would love to see CTII carry it forward with success. Just saying that, from my perspective, there are lots of outstanding questions. For example, is there a "stroma-like" microenvironment that is optimal for success? Have there been other cell types in the fetal transplants, apart from the stem cells, that have "enabled" the stem cells? BTW..... some would say that the success of embryonic neural transplants as a treatment for patients with Parkinson's disease has been limited. For women who believe that men think with their balls....... Nat Biotechnol 1996 Dec;14(13):1692-5 Testis-derived Sertoli cells survive and provide localized immunoprotection for xenografts in rat brain. Sanberg PR, Borlongan CV, Saporta S, Cameron DF Department of Surgery, University of South Florida College of Medicine, Tampa 33612, USA. psanberg@com1.med.usf.edu Transplantation of neural tissue into the mammalian central nervous system has become an alternative treatment for neurodegenerative disorders such as Parkinson's disease. Logistical and ethical problems in the clinical use of human fetal neural grafts as a source of dopamine for Parkinson's disease patients has hastened a search for successful ways to use animal dopaminergic cells for human transplantation. The present study demonstrates that transplanted testis-derived Sertoli cells into adult rat brains survive. Furthermore, when cotransplanted with bovine adrenal chromaffin cells (xenograft), Sertoli cells produce localized immunoprotection, suppress microglial response and allow the bovine cells to survive in the rat brain without continuous systemic immunosuppressive drugs. These novel features support Sertoli cells as a viable graft source for facilitating the use of xenotransplantation for Parkinson's disease and suggest their use as facilitators, (i.e., localized immunosuppression) for cell transplantation in general.

To: WWS who wrote (196)	1/25/1999 11:02:00 PM
From: scaram(o)uche	Respond to of 805

sounds very positive..... Neuroscience 1997 Mar;77(2):599-609 Addition of allogeneic spleen cells causes rejection of intrastriatal embryonic mesencephalic allografts in the rat. Duan WM, Brundin P, Widner H Wallenberg Neuroscience Center, Department of Physiology and Neuroscience, Lund University, Sweden. To address the importance of antigen-presenting cells for the survival of intracerebral neural allografts, allogeneic spleen cells were added to the graft tissue before transplantation. Dissociated embryonic, dopamine-rich mesencephalic and adult spleen tissues were prepared from either inbred Lewis or Sprague-Dawley rats. A mixture of neural and spleen cells was sterotaxically transplanted into the right striatum of adult Sprague-Dawley rats. Controls were neural allografts without addition of allogeneic spleen cells and syngeneic neural grafts with or without the addition of syngeneic spleen cells. Six weeks after transplantation, brain sections were processed immunocytochemically for tyrosine hydroxylase, specific for grafted dopamine neurons, and a bank of markers for various components in the immune and inflammatory responses. The neural allografts which were mixed with allogeneic spleen cells were rejected. In these rats, there were high levels of expression of major histocompatibility complex class I and II antigens, intense cellular infiltration including macrophages and activated microglial cells, and a presence of cluster of differentiation 4- and 8-immunoreactive cells in the graft sites. Moreover, there were increased levels of intercellular adhesion molecule-1, tumour necrosis factor-alpha and interleukin-6 in and around the grafts which were undergoing rejection. In contrast, syngeneic neural grafts survived well regardless of whether they were mixed with syngeneic spleen cells or not, and control neural allografts also exhibited unimpaired survival. No significant difference was observed in the number of grafted dopamine neurons among these three latter groups. The levels of expression of the different markers for inflammation and rejection were generally lower in these grafts than in implants of combined allogeneic neural and spleen cells. In summary, intrastriatal neural allografts, which normally survive well in our animal model, were rejected if allogeneic spleen cells from the same donor were added to the graft tissue. The added spleen cells caused strong host immune and inflammatory responses. The study gave support to the notion that immunological privilege of the brain does not provide absolute protection to immunogenetically histoincompatible neural grafts. Acta Neuropathol (Berl) 1998 Jan;95(1):85-97 Time-dependent expression of donor- and host-specific major histocompatibility complex class I and II antigens in allogeneic dopamine-rich macro- and micrografts: comparison of two different grafting protocols. Brandis A, Kuder H, Knappe U, Jodicke A, Schonmayr R, Samii M, Walter GF, Nikkhah G Institute of Neuropathology, Hanover Medical School, Germany. Neural transplantation, as a therapeutic approach to Parkinson's disease, still requires allogeneic graft material and raises questions of immunosuppression and graft rejection. The present study investigated the time course of major histocompatibility complex (MHC) expression and astrocytic response in allogeneic dopaminergic grafts, comparing two different grafting protocols. Adult 6-hydroxydopamine-lesioned Lewis 1.W rats received intrastriatal cell suspension grafts from the ventral mesencephalon of DA rat fetuses, either as single 1-microliter macrograft via metal cannula or as four micrografts of 250 nl/deposit via a glass capillary. No immunosuppression was administered. Immunohistochemistry was performed at 1, 3, 6, and 12 weeks after grafting, using antibodies against donor- and host-specific MHC class I and II antigen, glial fibrillary acidic protein (GFAP) and tyrosine hydroxylase (TH). Most animals showed good allograft survival up to 12 weeks after transplantation with no signs of rejection. Reinnervation of the lesioned striatum by TH-positive neurites was observed from 3-6 weeks on. Expression of donor-specific MHC class I was comparably low in both allogeneic grafting groups, while host MHC class I and II reaction as well as astrocytic response tended to be higher in the macrografted animals. Donor MHC class II was not observed at any time point. It is concluded that intraparenchymal allografts of fetal mesencephalic cell suspensions can survive well in the rat Parkinson model without immunosuppression for at least 12 weeks, and that the expression of moderate amounts of donor-specific MHC class I antigen does not suffice to initiate a rejection process. In addition, the microtransplantation approach may reduce the level of trauma and subsequent MHC and GFAP expression and may, thereby, minimize the risk of graft rejection.