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Cytokine Switch and Bystander Suppression of Autoimmune Responses to Multiple Antigens in Experimental Autoimmune Encephalomyelitis by a Single Recombinant T-Cell Receptor Ligand

Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2009; 29(12):3816-23. DOI: 10.1523/JNEUROSCI.5812-08.2009
Source: PubMed

ABSTRACT Recombinant T-cell receptor ligands (RTLs) can reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner, and are currently in clinical trials for treatment of subjects with multiple sclerosis (MS). Antigen specificity of RTL raises the question as to whether this treatment would be successful in MS patients where target antigens are unknown. Using spinal cord homogenate or combinations of two different peptides to induce disease, we found that treatment with single RTL could reverse EAE as long as targeted T-cells were present. Therapy with three different RTLs each caused a significant reduction in IL-17 and increases in IL-10 and IL-13 in peptide-activated splenocytes, reduced proliferation of both cognate and bystander specificities of lymph node cells, and reduced inflammatory lesions and secreted IL-17 and IL-2 from peptide-activated spinal cord cells. These results show that treatment with single RTLs can induce a cytokine switch in cognate T-cells that inhibits both the target and bystander T-cells, providing new evidence for the potential applicability of RTL therapy in MS.

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    • "Recombinant T cell receptor (TCR) ligands (RTL) containing the membrane distal α1+β1 domains of class II MHC molecules linked covalently to specific myelin peptides can induce T cell tolerance and reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) when administered i.v. or s.c. after onset of disease. RTLs containing the syngeneic MHC moiety in combination with the cognate encephalitogenic myelin peptide successfully treated monophasic EAE in Lewis rats (Burrows et al., 1998; Wang et al., 2003), chronic EAE in HLA-DR2 transgenic mice (Chou et al., 2004; Link et al., 2007; Vandenbark et al., 2003), relapsing EAE in SJL/J mice (Huan et al., 2004; Offner et al., 2005; Sinha et al., 2009b), and chronic EAE in C57BL/6 mice (Sinha et al., 2007). One such construct, RTL1000, containing the human MOG-35-55 peptide linked to the HLA-DR2 moiety, was recently tested successfully in a Phase 1 safety trial in Multiple Sclerosis (MS) subjects (Yadav et al., 2010). "
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    ABSTRACT: Recombinant T cell ligands (RTLs) ameliorate experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner. We evaluated effects of RTL401 (I-A(s) alpha1beta1+PLP-139-151) on splenocytes from SJL/J mice with EAE to study RTL-T cell tolerance-inducing mechanisms. RTLs bound to B, macrophages and DCs, through RTL-MHC-alpha1beta1 moiety. RTL binding reduced CD11b expression on splenic macrophages/DC, and RTL401-conditioned macrophages/DC, not B cells, inhibited T cell activation. Reduced ability of RTL- incubated splenocytes to transfer EAE was likely mediated through macrophages/DC, since B cells were unnecessary for RTL treatment of EAE. These results demonstrate a novel pathway of T cell regulation by RTL-bound APCs.
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    • "Crucial to this discussion, RTL551 can successfully treat EAE induced with either hMOG-35-55 peptide or mMOG-35-55 peptide (HO unpublished observation). Therapeutic activity directed against the hMOG-35-55 determinant as well as bystander T cells (Sinha et al., 2009) reactive against other rhMOG determinants could explain how RTL551 might regulate multiple T cell specificities that likely contribute to rhMOG-induced EAE. This potent regulatory effect on the T cell component of EAE could then prevent anti-MOG antibody enhancement of disease as discussed above without direct effects on antibody responses or MOG-reactive B cells. "
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