Applied BioLogics

Multiple Sclerosis
DOI: 10.1177/1352458506073176
Mult Scler 2006; 12; 677
Neil Scolding
Stem cell therapy in patients with multiple sclerosis
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Stem cell therapy in patients with multiple sclerosis
It is an unusual week that does not see some new
headline in the lay press concerning stem cells and
their exciting potential for curing this or that
disease. Predictably, conditions that are currently
considered incurable claim the most attention, and
amongst these multiple sclerosis (MS) is hardly the
least conspicuous. The challenging emergence of
any number of profiteering outfits dedicated to
pocketing enormous sums from the sale directly to
patients of so-called stem cell therapies has added
controversy to the already much excited lay media.
Claims and counterclaims rebound, leaving not
only patients and carers but also the clinical and
scientific community bemused if not a little weary.
Media headlines apart, there is of course nothing
unusual or inappropriate about clinical uncertainty
regarding the efficacy or promise of an emerging
therapy. But in relation to MS, the (not quite)
simultaneous appearance of two very different
species of stem cell therapy has complicated mat-
ters. Two significant position papers in this issue of
Multiple Sclerosis offer valuable insights into the
current status of one form of stem cell therapy

which might be termed immune reconstruction by
haematopoetic or bone marrow stem cell transplan-
tation.
The second type, tissue reconstruction by stem cell
transplantation, aiming to exploit the transdiffer-
entiation and reparative properties of stem cells
(including, to complicate matters further, bone
marrow-derived or mesenchymal stem cells), re-
mains as yet an experimental technique in relation
to MS, albeit on the verge of clinical study and

away from neurology
at a much more advanced
stage of clinical testing in cardiac disease [1].
A topic already more than sufficiently complex
for most of us has, however, received in the past
couple of years an added layer of intrigue. It is
increasingly apparent that the clear mechanistic
boundary, apparently logically assembled, between
tissue reconstructive stem cell therapy and immune
reconstructive (bone marrow) stem cell therapy is
not so much of a boundary after all. Increasingly it
is accepted that when stem cells contribute to repair
they utilize a variety of mechanisms. Direct trans-
differentiation to replace damaged specialized cells,
whilst it may occur, seems often not to be quanti-
tatively very significant, and may represent only a
very minor contribution to the repair process

which is both surprising and ironic, as it was the
pluripotent ability of stem cells that triggered such
an explosion of interest and excitement (and fund-
ing!) in their reparative potential, and more gen-
erally in regenerative medicine. In fact, a variety of
other mechanisms, including the encouragement
of angiogenesis, neuroprotection, growth factor
production, the recruitment and stimulation of
endogenous (tissue-based) progenitors, and modu-
lation of the local immune response may, in
different situations, diseases and tissues, play
much more important roles than mere transdiffer-
entiation [2,3]. And of course the last of these,
the significant ability of (perhaps particularly)
mesenchymal stem cells to modulate immune
responses [4], shows clearly that so-called tissue-
reconstructive and so-called immune-reconstruc-
tive stem cell therapies have too rapidly been
nosologically divided.
So, returning to clinical practice, what have we
learned about therapy from the two papers in this
issue? Harry Openshaw and colleagues [pp 824

825] summarize the discussions relating to MS
held during a conference (Cellular Therapy for
Treatment of Autoimmune Diseases) held in Octo-
ber last year in California. On pages 814
823,
Riccardo Saccardi (a co-author also of the above
‘Meetings’ paper) and colleagues, on behalf of the
European Blood and Marrow Transplantation
Group (EBMT), provide an update on the mixed
group of 178 patients on their registry who have
received treatment with autologous haematopoietic
stem cells and 14 who had bone marrow transplan-
tation, all following immune-ablating induction
therapy (of slightly varying protocols).
One striking aspect of the European data is the
severity of disability of patients treated
a median
Expanded Disability Status Scale (EDSS) score of 6.5.
Given the increasing appreciation of the role of
neurodegeneration in the progression of disability
in MS, the suggestion that immune and inflamma-
tory mechanisms are far less important in this
process than in relapsing MS, and the proposition
that neuroprotection may therefore be a more
appropriate treatment strategy for progression
than immune-based therapies, this might be con-
sidered surprising. In fact, benefit from haemato-
poetic stem cell transplantation is reported in these
patients. EDSS at follow-up (median 41.7 months)
had decreased or remained stable in 63% of cases.
Does this suggest we would be wrong to jettison
immune approaches to treating patients with estab-
lished progression in MS? The results certainly
EDITORIAL Multiple Sclerosis 2006; 12: 677
678
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differ from data from alternative forms of immune
therapy
for example, Campath-1H therapy where
very intense lymphocyte depletion has little effect
on progressive disability if given after progression
has clearly commenced [5]. In the EBMT study,
neurological follow-up was only available on 142 of
the 178 patients, which might potentially skew the
results, and no data are offered as to whether recent
relapse (or steroid use) precluded entry, the authors
commendably acknowledging quite openly the
‘lacking of information on the presence of relapses
before and after therapy’. As given, the ASTIMS
inclusion criteria include reference to decline in
EDSS over the past year without appearing to
stipulate an absence of recent relapse activity to
account for this decline. Could stabilization or
spontaneous improvement following relapse there-
fore contribute to the overall EDSS results? Inter-
pretation is perhaps also complicated by the fact
that 124 patients had also received (as part of their
MS therapy, not just their conditioning) various
immune suppressant or immune-modulating thera-
pies, including azathioprine, interferons or cyclo-
phosphamide.
Notwithstanding these points, which as the
authors point out, may help justify further study,
we should recall that histopathologically even
primary progressive MS exhibits significant inflam-
mation. While this may be quantitatively less than
that seen in relapsing
remitting disease, a role for
the immune system
and antibodies in particular

continues to be supported [6]. A second, unre-
lated aspect of increasing disability is that relapse
activity makes a minor but nonetheless significant
contribution to residual and accumulating func-
tional deficits in progressive MS [7]. Therefore, as
the results reported here imply, we should indeed
perhaps pause before neglecting inflammation and
entirely abandoning anti-inflammatory treatments
in our rush to embrace neurodegeneration as the
sole cause of disability progression. None of which
is to overlook what seems a far more unambiguous
result, the very dramatic reduction in relapse rate in
the results emerging both in Europe and from the
Americas.
Toxicity remains a serious consideration. Early,
‘non-neurological’ toxicity was reported in 56% of
evaluable patients (a level expected of autologous
HSCT in any setting) and neurological toxicity in
17% of patients. Later toxicity (after two months)
was seen in 6% of patients, mostly infective (such as
Herpes zoster infection) or immunological (such as
new autoimmune thyroid disease: both intriguingly
similar to that seen after Campath-1H treatment).
Nine patients died for reasons considered related to
transplant procedure, though a further five patients
died from progression of their MS and were not
considered to be transplant-related deaths. None of
the former deaths occurred since 2001; the authors
indicating that avoiding high-intensity regimens
and better patient selection substantially reduce
this risk. One death is reported among eleven
patients treated in the Canadian trial. So, do we
yet know the place of autologous haematopoetic
stem cell transplantation in the treatment of severe
and aggressive MS? The answer must remain ‘not
yet’, despite the valuable new information in these
useful papers. As Riccardo Saccardi says, there
‘needs to be ...prospective, randomized controlled
trials’. Given the rapid emergence of other new
therapies, particularly monoclonal antibodies such
as Campath-1H, natalizumab and others, it may
well be that such trials need to be controlled by
comparison with one or other of these newer and
apparently more potent agents.
References
1. Rosenzweig A. Cardiac cell therapy
mixed results from
mixed cells. N Engl J Med 2006; 355: 1274
77.
2. Martino G, Pluchino S. The therapeutic potential of
neural stem cells. Nat Rev Neurosci 2006; 7: 395
406.
3. Rice CM, Scolding NJ. Adult stem cells
reprogram-
ming neurological repair? Lancet 2004; 364: 193
99.
4. Zappia E, Casazza S, Pedemonte E, Benvenuto F,
Bonanni I, Gerdoni E et al. Mesenchymal stem cells
ameliorate experimental autoimmune encephalomyelitis
inducing T-cell anergy. Blood 2005; 106: 1755
61.
5. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J
et al. The window of therapeutic opportunity in multiple
sclerosis: evidence from monoclonal antibody therapy. J
Neurol 2006; 253:98
108.
6. Pender MP. The pathogenesis of primary progressive
multiple sclerosis: antibody-mediated attack and no re-
pair? J Clin Neurosci 2004; 11: 689
92.
7. Lublin FD, Baier M, Cutter G. Effect of relapses on
development of residual deficit in multiple sclerosis.
Neurology 2003; 61: 1528
32.
Neil Scolding
University of Bristol Institute of Clinical Neurosciences,
Department of Neurology, Frenchay Hospital, Bristol
BS16 1LE, UK
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