autologous blood and marrow transplantation - Blog Science ...

Fassas et al. 453
INTRODUCTION
Multiple sclerosis is a severely disabling, incurable disease caused by a T
cell-mediated destruction of myelin in the central nervous system. Affected areas
are characterized by disruption of the blood-brain barrier (BBB) and infiltration
with lymphocytes and macrophages. This leads to myelin breakdown and focal
neurologic dysfunction. The disease runs a relapsing-remitting course initially, but
after 10 years becomes chronic progressive (pMS) in 50% of the cases. Disability
accumulates more rapidly at this stage of secondary progression and, 5 years later,
more than half of the patients are unable to walk unaided. 1
In 15% of the cases, MS
is progressive from onset, with or without relapses (progressive-relapsing or
primary pMS, respectively). So-called malignant forms with very short survival
exist, too (1-3%). Life expectancy is reduced by -10 years, compared with an agematched
healthy population. 1
Treatment involves immunosuppressive or
immunomodulating agents, which appear to be active in the relapsing-remitting
form, whereas in the progressive forms all proposed treatments have very little,
only transient, or no effect. 2
The rationale for using SCT in autoimmune diseases (AD) including MS is
based on experimental data and also on clinical observations in patients with AD
and concomitant malignancies treated with SCT. 34
In experimental allergic
encephalomyelitis, an animal model of induced MS, prevention or regression of
disease can be achieved by allogeneic, syngeneic, or autologous SCT. 5-8
In the
clinical setting, cures of AD have been seen after alloSCT 4
and also prolonged
remissions have been noted after autoSCT. 4,9
Relapse rates in experimental SCT
depend on residual autoreactive clones surviving high-dose therapy or on high
lymphocyte content of reinfused grafts (autoSCT). 8
In clinical SCT, while relapses
occur after alio- or autoSCT, they are more frequent after autoSCT. 4
' 10
It is
postulated that alloSCT can cure AD through immune ablation, replacement of the
aberrant immune system, and also a graft-vs.-autoimmunity effect. 5
In autoSCT,
however, total immune ablation is an impossible goal, but the patient may benefit
from the profound immunosuppression of the conditioning regimen. One could
also envisage a sort of reeducation of the immune system through induction of
suppressor mechanisms or recapitulation of lymphocyte ontogeny. 11-13
Although more reasonable, an allogeneic transplant may be too toxic for the
treatment of AD. We have, therefore, used autoSCT to treat 24 patients with pMS
in two consecutive pilot phase I/II trials, in which we studied the medical and
neurologic toxicity of the protocol and also its efficacy in terms-ef improvement or
stabilization of the disease. In both trials, the same protocol was used with the
exception that CD34 selection was employed only in the second trial. Early results
of trial 1 have already been published (14). In this chapter, we provide an update
and also present the results of the second trial.