REGULATION OF EAE WITH RECOMBINANT TCR LIGANDS

Summary

Principal Investigator: Arthur Vandenbark
Affiliation: Oregon Health and Science University
Country: USA
Abstract: The overall goal of this program is to test critically the general hypothesis that myelin antigen reactive T cells and the MS risk-associated HLA-DR2 allele contribute to the pathogenesis of multiple sclerosis (MS). To this end we developed a recombinant TCR ligand (RTL), a single chain two domain human HLA-DR2 class II molecule covalently linked to the immunodominant MOG-35-55 epitope that induced long-term tolerance and reversed established clinical signs of MOG-peptide-induced EAE in transgenic (Tg) DR2-expressing mice. The initial DR2/MOG-35-55 construct (VG312) that we produced had self-adherent surfaces and tended to form stable oligomers with an average composition of 14-subunits. The effect of oligomerization on the inhibitory function of the constructs is unknown, but potentially the oligomers might have a lower functional molarity and thus less inhibitory activity in vivo than the monomers. On the other hand, the oligomers might be able to cross-link the TCRs more efficiently than monomers, resulting in more or different signaling through the TCR that might affect inhibitory activity. We have now produced a DR2/MOG-35-55 monomer (VG342) by modifying amino acid residues in the self-contact surface that will allow a functional comparison with the 14-mer VG312 construct. Additionally, we have produced constructs that contain mouse (m)MOG versus human (h)MOG peptides with different affinities for TCRs from mice with EAE, and a new monomeric form (VG342-T) that lacks the thrombin (T) cleavage site that was engineered into the peptide-joining region of the original construct. Our goal in this application is to compare these five forms of the DR2/MOG-35-55 construct for therapeutic efficacy, induction of tolerance, and effects on mouse and human MOG-35-55 specific T cell lines, clones, and a hybridoma that we recently developed from the DR2 mice. Specifically, in this application we will address the specific hypothesis that the degree and mechanism of tolerance is governed or influenced by 1) differences in the affinity of the RTL for the TCR, 2) differences in functional avidity of RTL binding to the TCR, and 3) cleavage and release of free peptide from the RTL. Finally, we will evaluate the degree of bystander suppression induced by RTLs and follow the fate of RTL-treated T cells. These are the first studies ever to evaluate the effect on tolerance of monomeric versus oligomeric TCR blockage in vivo, and will provide the necessary foundation for clinical application of these recombinant TCR ligands (RTLs) in patients with MS.
Funding Period: 2005-04-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Treatment of passive experimental autoimmune encephalomyelitis in SJL mice with a recombinant TCR ligand induces IL-13 and prevents axonal injury
    Halina Offner
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Immunol 175:4103-11. 2005
  2. ncbi AlphaB-crystallin-reactive T cells from knockout mice are not encephalitogenic
    Chunhe Wang
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, 97239, and Department of Neurology, Oregon Health and Science University, USA
    J Neuroimmunol 176:51-62. 2006
  3. pmc Antigen-specific therapy promotes repair of myelin and axonal damage in established EAE
    Chunhe Wang
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon, USA
    J Neurochem 98:1817-27. 2006
  4. ncbi Monomeric DR2/MOG-35-55 recombinant TCR ligand treats relapses of experimental encephalomyelitis in DR2 transgenic mice
    Jason M Link
    Portland V A Medical Center, Neuroimmunology Research R and D 31, 3710 SW US Veterans Hospital Rd, Portland, OR 97239, USA
    Clin Immunol 123:95-104. 2007
  5. ncbi 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
    Sushmita Sinha
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA
    J Neurosci 27:12531-9. 2007
  6. pmc Recombinant T cell receptor ligands: immunomodulatory, neuroprotective and neuroregenerative effects suggest application as therapy for multiple sclerosis
    Halina Offner
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA
    Rev Neurosci 19:327-39. 2008
  7. pmc Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand
    Sushmita Sinha
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA
    J Neurosci 29:3816-23. 2009
  8. pmc Recombinant T cell receptor ligand treats experimental stroke
    Sandhya Subramanian
    Neuroimmunology Research, Portland VA Medical Center, Portland, OR 97239, USA
    Stroke 40:2539-45. 2009

Scientific Experts

  • H Offner
  • Chunhe Wang
  • Jason M Link
  • Sandhya Subramanian
  • Sushmita Sinha
  • Gregory G Burrows
  • Arthur A Vandenbark
  • Thomas M Proctor
  • Chris Roberts
  • Bing Zhang
  • Lisa Miller
  • Marjorie R Grafe
  • Patricia D Hurn
  • Yasuharu Kosaka
  • Jianya Huan
  • Rony Dahan
  • Marjorie Grafe
  • Laurie J Kaler

Detail Information

Publications8

  1. ncbi Treatment of passive experimental autoimmune encephalomyelitis in SJL mice with a recombinant TCR ligand induces IL-13 and prevents axonal injury
    Halina Offner
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Immunol 175:4103-11. 2005
    ....
  2. ncbi AlphaB-crystallin-reactive T cells from knockout mice are not encephalitogenic
    Chunhe Wang
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, 97239, and Department of Neurology, Oregon Health and Science University, USA
    J Neuroimmunol 176:51-62. 2006
    ..These results suggest that alphaB-specific T cells are immunocompetent but not encephalitogenic in 129SvEv mice, and that immune tolerance may not be the main factor that limits the encephalitogenic potential of alphaB...
  3. pmc Antigen-specific therapy promotes repair of myelin and axonal damage in established EAE
    Chunhe Wang
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon, USA
    J Neurochem 98:1817-27. 2006
    ..These findings indicate that RTL therapy targeting encephalitogenic T cells may promote CNS neuroregenerative processes...
  4. ncbi Monomeric DR2/MOG-35-55 recombinant TCR ligand treats relapses of experimental encephalomyelitis in DR2 transgenic mice
    Jason M Link
    Portland V A Medical Center, Neuroimmunology Research R and D 31, 3710 SW US Veterans Hospital Rd, Portland, OR 97239, USA
    Clin Immunol 123:95-104. 2007
    ....
  5. ncbi 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
    Sushmita Sinha
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA
    J Neurosci 27:12531-9. 2007
    ..These findings indicate that targeted immunotherapy of antigen-specific T-cells can result in a reversal of CNS lesion formation and lend strong support to the application of the RTL approach for therapy in MS...
  6. pmc Recombinant T cell receptor ligands: immunomodulatory, neuroprotective and neuroregenerative effects suggest application as therapy for multiple sclerosis
    Halina Offner
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA
    Rev Neurosci 19:327-39. 2008
    ..These properties of RTL suggest that this novel antigen-specific approach may hold unusual promise as a therapy for multiple sclerosis...
  7. pmc Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand
    Sushmita Sinha
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA
    J Neurosci 29:3816-23. 2009
    ..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...
  8. pmc Recombinant T cell receptor ligand treats experimental stroke
    Sandhya Subramanian
    Neuroimmunology Research, Portland VA Medical Center, Portland, OR 97239, USA
    Stroke 40:2539-45. 2009
    ..We tested the hypothesis that RTL would improve ischemic outcome in the brain without exacerbating defects in the peripheral immune system function...