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RTL551 Treatment of EAE Reduces CD226 and T-bet+ CD4 T Cells in Periphery and Prevents Infiltration of T-bet+ IL-17, IFN-γ Producing T Cells into CNS

By Sushmita Sinha, Lisa M. Miller, Sandhya Subramanian, Gregory G. Burrows, Arthur A. Vandenbark and Halina Offner

Abstract

Recombinant T cell receptor ligands (RTLs) that target encephalitogenic T-cells can reverse clinical and histological signs of EAE, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTL therapy on expression of pathogenic and effector T-cell maturation markers, CD226, T-bet and CD44, by CD4+ Th1 cells early after treatment of MOG-35-55 peptide-induced EAE in C57BL/6 mice. We showed that 1–5 daily injections of RTL551 (two-domain I-Ab covalently linked to MOG-35-55 peptide), but not the control RTL550 (“empty” two-domain I-Ab without a bound peptide) or Vehicle, reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced the frequency of CD226 and T-bet expressing CD4+ T-cells in blood and inhibited expansion of CD44 expressing CD4+ T-cells in blood and spleen. Concomitantly, RTL551 selectively reduced CNS inflammatory lesions, absolute numbers of CNS infiltrating T-bet expressing CD4+ T-cells and IL-17 and IFN-γ secretion by CNS derived MOG-35-55 reactive cells cultured ex vivo. These novel results demonstrate that a major effect of RTL therapy is to attenuate Th1 specific changes in CD4+ T-cells during EAE and prevent expansion of effector T-cells that mediate clinical signs and CNS inflammation in EAE

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3130056
Provided by: PubMed Central

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Citations

  1. (2001). A crucial role for CD44 in inflammation.
  2. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment.
  3. (2007). A promising therapeutic approach for multiple sclerosis: recombinant T-cell receptor ligands modulate experimental autoimmune encephalomyelitis by reducing interleukin-17 production and inhibiting migration of encephalitogenic cells into the CNS.
  4. (2010). Binding of recombinant T cell receptor ligands (RTL) to antigen presenting cells prevents upregulation of CD11b and inhibits T cell activation and transfer of experimental autoimmune encephalomyelitis.
  5. (2003). CD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation.
  6. (2009). CD226 Gly307Ser association with multiple autoimmune diseases.
  7. (2005). CD226 is specifically expressed on the surface of Th1 cells and regulates their expansion and effector functions.
  8. (2009). Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand.
  9. (1999). Design, engineering and production of functional single-chain T cell receptor ligands.
  10. (1996). DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes.
  11. (1995). Early activation signal transduction pathways of Th1 and Th2 cell clones stimulated with anti-CD3. Roles of protein tyrosine kinases in the signal for IL-2 and IL-4 production.
  12. (1995). Experimental autoimmune encephalomyelitis in rodents as a model for human demyelinating disease.
  13. (2000). Failure to suppress the expansion of the activated CD4 T cell population in interferon gamma-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis.
  14. (2001). Impairment in the expression and activity of Fyn during differentiation of naive CD4+ T cells into the Th2 subset.
  15. (2010). In vivo imaging of partially reversible th17 cell-induced neuronal dysfunction in the course of encephalomyelitis.
  16. (2004). Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis.
  17. (1996). Male SJL mice do not relapse after induction
  18. (2004). Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch.
  19. (1999). Physical and functional association of LFA-1 with DNAM-1 adhesion molecule.
  20. (2006). pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity.
  21. (2006). Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells.
  22. (2008). Recombinant T cell receptor ligands: immunomodulatory, neuroprotective and neuroregenerative effects suggest application as therapy for multiple sclerosis.
  23. (2003). Recombinant TCR ligand induces early TCR signaling and a unique pattern of downstream activation.
  24. (2003). Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice.
  25. (2010). Recombinant TCR Ligand Reverses Clinical Signs and CNS Damage of EAE Induced by Recombinant Human MOG.
  26. (2001). Rudimentary TCR signaling triggers default IL-10 secretion by human Th1 cells.
  27. (2004). Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.
  28. (2009). T-bet is essential for encephalitogenicity of both Th1 and Th17 cells.
  29. (2006). T-bet is essential for the progression of experimental autoimmune encephalomyelitis.
  30. (2007). T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity.
  31. (2005). Treatment of passive experimental autoimmune encephalomyelitis in SJL mice with a recombinant TCR ligand induces IL-13 and prevents axonal injury.
  32. (1993). Where, when, and how to detect biased expression of disease-relevant V beta genes in rats with experimental autoimmune encephalomyelitis.