scorpion wrote:Which seem to have had positive results...
Both Nash et al. and we seem to agree that HSCT might be an effective therapy for multiple sclerosis (MS) patients in the so-called inflammatory stage of the disease. These patients appear to benefit from the intense immunosuppression and the reprogramming of their immune system (Muraro et al., 2003; Martin, 2007). The benefit for these patients has been clinically shown and is documented in MRI studies. Thus the most promising MS population for a therapy study with HSCT might be patients in early disease stages with an aggressive disease course who do not respond to the approved or applied immunomodulatory or immunosuppressive treatments. Such studies are conducted in the United States (HALT MS) as stated in the comment by Nash et al. The glass may be half full for these patients.
On the other hand the glass appears to be half empty for patients with long-standing, progressive MS and a high EDSS score. The patients included in our study belong to this group. Presumably, in this so-called neurodegenerative phase of disease, attempts to affect the peripheral immune system do not hinder or prevent clinical progression nor do they reverse existing clinical deficits. This has been shown in the transplanted patients examined in our manuscript (Metz et al., 2007), but also for other therapies such as Campath-1, an antibody causing the depletion of T cells (Coles et al., 1999). The continuing cerebral atrophy in MRI studies described after HSCT (Inglese et al., 2004) may have its correlate in the ongoing axonal damage and demyelination after HSCT seen in our study or could have been due to the drugs used for immunoablation as part of the HSCT procedure (Chen et al., 2006).
Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis
The present study analyses autopsy material from five multiple sclerosis patients who received autologous stem cell transplantation. A total of 53 white matter lesions were investigated using routine and immunohistochemical stainings to characterize the demyelinating activity, inflammatory infiltrates, acutely damaged axons and macrophages/microglial cells. We found evidence for ongoing active demyelination in all of the five patients. The inflammatory infiltrate within the lesions showed only very few T cells and CD8+ cytotoxic T cells dominated the T cell population. B cells and plasma cells were completely absent from the lesions. High numbers of acutely damaged axons were found in active lesion areas. Tissue injury was associated with activated macrophages/microglial cells. The present results indicate that ongoing demyelination and axonal degeneration exist despite pronounced immunosuppression. Our data parallel results from some of the clinical phase I/II studies showing continued clinical disease progression in multiple sclerosis patients with high expanded disability system scores despite autologous stem cell transplantation.
The authors measured brain atrophy in nine patients undergoing immunoablation and autologous hematopoietic stem cell transplantation for multiple sclerosis. From baseline to 1 month after treatment, atrophy was 10 times faster than before treatment. A patient with non-CNS lymphoma showed comparable acute brain atrophy after analogous therapy. These observations suggest that brain atrophy after immunoablation may not be due entirely to the resolution of edema but may be related to chemotoxicity.
Whether CD8þ T cells survived the severe immunosuppression, or alternatively infiltrated the CNS after transplantation remains unanswered.
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