From: Jeff Davis (jrd1415@yahoo.com)
Date: Wed Jun 12 2002 - 15:00:36 MDT
Tom Cowper and interested extropes,
Here's something to add to the MS data bank. I just
found it today, hot off the presses.
http://www.eurekalert.org/pub_releases/2002-06/joci-bc1053102.php
Beyond copolymer 1
Copolymer 1, also called glatiramer acetate, is an
unusual therapeutic compound, a heterogeneous mix of
polypeptides containing the four amino acids Y, E, A,
and K in definite ratios but with no uniform sequence.
Although its mode of action remains controversial,
this preparation clearly helps retard the progression
of human multiple sclerosis (MS) and of the related
autoimmune condition, studied in mice, experimental
autoimmune encephalomyelitis (EAE). Copolymer 1 is
presented on class II MHC molecules, including the
HLA-DR2 type that is associated with increased risk of
MS. This MHC molecule binds a defined auto-epitope
from myelin basic protein (MBP) and presents it to CD4
T cells, initiating an immune response against myelin
in the CNS. Fridkis-Hareli et al. reexamined the
structure of the DR2 peptide-binding groove and
concluded that the selection of amino acids used in
Copolymer 1 was far from optimal if the goal was to
compete against presentation of MBP peptides. Here
they show that YFAK and FAK copolymers, among others,
bind DR2 with higher affinity than does YEAK
(copolymer 1), allowing them to compete successfully
against an endogenous autoantigenic peptide. These
formulations were more effective than Copolymer 1 at
suppressing the activation of T cells bearing
DR2-restricted, MS patient?derived T cell receptors.
Crucially, the novel copolymers were also dramatically
more effective at suppressing EAE. Thus, mice injected
with either a defined antigenic peptide or whole
spinal cord homogenate normally initiate inflammatory
and cytolytic responses in the CNS. While Copolymer 1
reduced the incidence of this disease and delayed its
onset in most cases, several of the novel copolymers
prevented it entirely. Given the precedent of
Copolymer 1?s safety and efficacy in people with MS,
the use of other copolymers, perhaps optimized to
target an individual?s MHC haplotype, seems an
attractive scenario for MS and perhaps other
autoimmune diseases.
Best, Jeff Davis
"Everything's hard till you know how to do it."
Ray Charles
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