Research: Trial of Myelin reactive MHC constructs

R
Yadav V et al. Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple
Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation
Study. Autoimmune Dis. 2012;2012:954739. Epub 2012 Apr 5.
Background.
Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain
protein construct containing the outer two domains of HLA-DR2 linked to
myelin-oligodendrocyte-glycoprotein- (MOG-) 35-55 peptide. Analogues of
RTL1000 induce T-cell tolerance, reverse clinical and histological
disease, and promote repair in experimental autoimmune encephalomyelitis
(EAE) in DR2 transgenic, C57BL/6, and SJL/J mice. 
Objective.
Determining the maximum tolerated dose, safety, and tolerability of
RTL1000 in multiple sclerosis
(MS) subjects. 
Methods. This was a multicenter, Phase I dose-escalation
study in HLA-DR2(+) MS subjects. Consecutive cohorts received RTL1000
doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within
each cohort randomly received a single intravenous infusion of RTL1000
or placebo at a 4 : 2 ratio. Safety monitoring included clinical,
laboratory, and brain magnetic resonance imaging (MRI) evaluations. 
Results. Thirty-four subjects completed the protocol. All subjects
tolerated the 2-60 mg doses of RTL1000. Doses ≥100 mg caused hypotension
and diarrhea in 3 of 4 subjects, leading to discontinuation of further
enrollment. 
Conclusions. The maximum tolerated dose of RTL1000 in MS
subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a
novel approach for MS treatment that may induce immunoregulation
without immunosuppression and promote neural repair.
           A peptide (yellow thing) in HLA-DR2
For T cells to be activated they must see the antigenic peptide (a fragment of a protein, such as a myelin protein) in the context of major histocompatibility complex in addition to co-stimulatory signals provided by molecules such as CD80 and CD86. However it the T cell does not get the costimulatory signals it either triggers the T cell to be silenced  by a process called anergy, of the cells are stimulated to commit suicide. It only does this and would not be expect to have any side-effects, unlike current immunosuppressive drugs that removes alot of the immune repertoire and can lead to increased susceptibility to infection.  It is clear from genetic studies that HLA-DR2 is a variant of the major histocompatibility complex  that is a predisposing susceptibility factor for MS. This molecule is common in Northern Europeans and accounts for a reason why MS is more common in Northern Europeans. 
This HLA-DR2 molecule has been linked to a myelin peptide  (a small stretch of amino acids) with the idea that this drug called RTL1000 will inhibit myelin-reactive T cells. They have shown that this works in mice and can inhibit MS-like disease from developing. However, I believe the efficacy claims are wildly exaggerated. In my opinion there is absolutely no reason why this molecule would promote repair and remyelination directly. However because it inhibited the damaging immune response it may of allowed the natural repair processses to do some repair, but this is very differnt from the the drug actually causing repair as implied.
This new drug has passed through its first test in humans, the next one will be do this in MSers. Whilst this paper is perhaps and advertisement for investors, it has to be said the authors have declared conflicts of interest,as long as your arm, because the are recieving stuff for doing the study. However this all transparent and above-board. If MS is not autoimmune then the approach will fail

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