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Autologous hematopoietic stem cell transplantation: the glass seems to be half full for aggressive, early forms of MS and half empty for advanced MS

Imke Metz, Claudia F. Lucchinetti, Harry Openshaw, Antonio Garcia-Merino, Hans Lassmann, Marc S. Freedman, Biagio Azzarelli, Oldrich J. Kolar, Harold L. Atkins, Wolfgang Brück
DOI: http://dx.doi.org/10.1093/brain/awm181 e90 First published online: 3 October 2007

Sir, We would like to respond to the above submitted correspondence by Nash et al. on our article ‘Autologous stem cell transplantation fails to stop demyelination and neurodegeneration’.

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).

An important objection by Nash et al. is the lowest number of acutely damaged axons in the patient with the longest survival time. The demyelination in the investigated patients is found at the plaque edge of chronic active lesions. The macrophages/microglial cells contain LFB- and MBP-positive degradation products, a feature that has been described by Prineas et al. (2001) as the pathology of lesions in secondary progressive MS. In this disease stage, a classification into the different immunopathological subtypes of MS according to Lucchinetti et al. (2000) is no longer possible. The microglial activation is a known feature of long-standing MS lesions. We can certainly not rule out that the cause of death of the patients and the preceding events played a role in the activation of microglia. We are aware of the fact that our study is limited by the low number of patients, the short survival time and the impossibility of comparing the histology from one patient pre- and post-therapy. The best possible procedure for us was thus the comparison with the published literature data from MS autopsies of most likely untreated patients.

These open questions urge the collection and examination of this rare autopsy material, which we would be glad to do. Another promising approach to elucidate the neuropathological changes in vivo could be the MRI evaluation of axonal damage with markers such as N-acetyl aspartate (NAA) by spectroscopy. Unfortunately, no specific MRI marker for investigating ongoing demyelination exists.

In conclusion, while we are aware of the limitations of our study and thank Nash et al. for their constructive and helpful comments, we believe that the detailed immunopathological description of these five cases after HSCT can provide important information about the timing and effect of aggressive therapies such as HSCT or others (e.g. antibodies) in progressive MS.