The major goal of this study was to evaluate the efficacy and mechanism of a rTCR
ligand (RTL) construct (I-A(s)/proteolipid
protein (
PLP)-139-151 peptide = RTL401) for treatment of SJL/J mice developing passive
experimental autoimmune encephalomyelitis (EAE) that did not involve coimmunization with the highly inflammatory CFA. Our results demonstrated clearly that RTL401 was highly effective in treating passive EAE, with kinetics of recovery from disease very similar to treatment of actively induced EAE. The potent RTL401 treatment effect was reflected by a partial reduction of infiltrating mononuclear cells into CNS, minimal inflammatory lesions in spinal cord, and preservation of axons injured in vehicle-treated mice during the progression of EAE. Interestingly, in the absence of CFA, RTL401 treatment strongly enhanced production of the Th2
cytokine,
IL-13, in spleen, blood, and spinal cord tissue, with variable effects on other Th1 and Th2
cytokines, and no significant effect on the Th3
cytokine,
TGF-beta1, or on FoxP3 that is expressed by regulatory T cells. Moreover, pretreatment of PLP-139-151-specific T cells with RTL401 in vitro induced high levels of secreted
IL-13, with lesser induction of other pro- and anti-inflammatory
cytokines. Given the importance of
IL-13 for protection against EAE, these data strongly implicate
IL-13 as a dominant regulatory
cytokine induced by RTL
therapy. Pronounced
IL-13 levels coupled with marked reduction in
IL-6 levels secreted by PLP-specific T cells from blood
after treatment of mice with RTL401 indicate that
IL-13 and
IL-6 may be useful markers for following effects of RTL
therapy in future clinical trials in
multiple sclerosis.