Author: Calkins, Evan ; Meza-Romero, Roberto ; Chaudhary, Priya ; Vandenbark, Arthur A ; Benedek, Gil ; Offner, Halina ; Kent, Gail ; Bourdette, Dennis

BACKGROUNDOne of the main challenges in treating multiple sclerosis (MS) is reversing the effects of accumulated damage in the central nervous system (CNS) of progressive MS subjects. While most of the available drugs for MS subjects are anti-inflammatory and thus are limited to relapsing-remitting MS subjects, it is not clear to what extent their effects are capable of inducing axonal repair and remyelination in subjects with chronic MS.METHODSA chronic model of experimental autoimmune encephalomyelitis (EAE) was used to evaluate the potency of partial MHC (pMHC) class II constructs in treating progressive EAE.RESULTSWe demonstrated an estrogen receptor alpha (ERα)-dependent increased dose requirement for effective treatment of female vs. male mice using pMHC. Such treatment using 100-μg doses of RTL342M or DRα1-mMOG-35-55 constructs significantly reversed clinical severity and showed a clear trend for inhibiting ongoing CNS damage, demyelination, and infiltration of inflammatory cells into the CNS in male mice. In contrast, WT female mice required larger 1-mg doses for effective treatment, although lower 100-μg doses were effective in ovariectomized or ERα-deficient mice with EAE.CONCLUSIONSThese findings will assist in the design of future clinical trials using pMHC for treatment of progressive MS.

25 Jan 2012·Investigative Opthalmology & Visual ScienceQ2 · MEDICINE

Neuroprotective Effects of Recombinant T-cell Receptor Ligand in Autoimmune Optic Neuritis in HLA-DR2 Mice

Q2 · MEDICINE

ArticleOA

Author: Brown, Lori ; Burrows, Gregory G. ; Andrew, Shayne ; Vandenbark, Arthur A. ; Adamus, Grazyna ; Meza-Romero, Roberto

PURPOSEOptic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve and leads to apoptotic retinal ganglion cell (RGC) death, which contributes to the persistence of visual loss. Currently, ON has no effective treatment. The goal was to determine the effectiveness of immunotherapy with recombinant T-cell receptor ligand (RTL) in preventing ON in humanized HLA-DR2 transgenic mice.METHODSExperimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein in humanized HLA-DR2 (DRβ1*1501) transgenic mice. Five consecutive doses of RTL342M were administrated at the onset of ON. The development of autoimmune ON was assessed by histopathology at different time points. The levels of myelin loss, axonal loss, and RGC damage were examined by immunofluorescence.RESULTSHLA-DR2 mice developed chronic ON 2 days before EAE characterized by progressive neurodegeneration in both organs. RTL342M significantly suppressed inflammation in the optic nerve and spinal cord and provided protection for at least 30 days. Examination of myelin loss showed a marked suppression of demyelination and an increase in myelin recovery in the optic nerve. Moreover, RTL342M treatment revealed a neuroprotective effect on optic nerve axons and RGCs in retinas at postimmunization (PI) day 62.CONCLUSIONSRTL342M suppressed clinical and histologic signs of EAE/ON by preventing the recruitment of inflammatory cells into the optic nerve and showed neuroprotective effects against ON. However, to achieve full therapeutic benefit, more doses may be needed. These findings suggest a possible clinical application of this novel class of T-cell-tolerizing drugs for patients with optic neuritis.

01 Apr 2007·Clinical ImmunologyQ3 · MEDICINE

Monomeric DR2/MOG-35–55 recombinant TCR ligand treats relapses of experimental encephalomyelitis in DR2 transgenic mice

Q3 · MEDICINE

Article

Author: Gregory G. Burrows ; Halina Offner ; Cathleen M. Rich ; Jason M. Link ; Arthur A. Vandenbark ; Maya Korat

Treatment of human autoimmune diseases such as multiple sclerosis (MS) will likely require agents that can prevent or reverse the inflammatory process that results in clinical relapses and disease progression. We evaluated the ability of a newly designed monomeric recombinant TCR ligand (RTL342M) containing HLA-DR2 peptide-binding domains covalently linked to MOG-35-55 peptide to prevent and treat both the initial episode and subsequent relapses of experimental autoimmune encephalomyelitis (EAE) in HLA-DR2 transgenic mice. Single doses of RTL342M given either i.v. or s.c. to HLA-DR2 mice produced a rapid (within 24 h) and dose-dependent reversal of clinical signs of paralytic EAE, and even a single dose < or = 2 microg could produce a significant treatment effect. Multiple daily doses were even more effective than the same total amount of RTL given as a single dose. By establishing the minimal effective dose, we determined that RTLs may be 50 times more potent than molar equivalent doses of myelin peptide alone. RTL342M given prior to induction of EAE prevented disease in most mice, and the remainder could be successfully retreated with RTL. Most important for clinical application, RTL342M was highly effective for treating EAE relapses when given periodically prior to the relapse or even after relapses had occurred. These data demonstrate the rapid and potent clinical effects of RTL342M at disease onset and during relapses in EAE and establish important principles governing the application of this novel approach as a possible therapy for patients with MS.

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Indication	Highest Phase	Country/Location	Organization	Date
Optic Neuritis	Discovery	US	Oregon Health & Science University	-

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