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. pmc HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis
    Roberto Meza-Romero
    Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239
    J Immunol 192:4164-73. 2014
  2. pmc Characterization of human platelet binding of recombinant T cell receptor ligand
    Asako Itakura
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, USA
    J Neuroinflammation 7:75. 2010
  3. pmc CCR6: a biomarker for Alzheimer's-like disease in a triple transgenic mouse model
    Sandhya Subramanian
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Alzheimers Dis 22:619-29. 2010
  4. pmc A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance
    Arthur A Vandenbark
    Research Service, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Autoimmun 40:96-110. 2013
  5. pmc Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects
    Gil Benedek
    Department of Veterans Affairs Medical Center, Neuroimmunology Research, Portland, OR 97239, USA
    Eur J Immunol 43:1309-21. 2013
  6. pmc Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis
    Gregory G Burrows
    Department of Neurology, Oregon Health and Science University, Portland, 97239, USA
    Metab Brain Dis 27:143-9. 2012
  7. pmc 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
    Sushmita Sinha
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon, United States of America
    PLoS ONE 6:e21868. 2011
  8. pmc Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice
    Suzan Dziennis
    Department of Anesthesiology and Peri Operative Medicine, Oregon Health and Science University, Portland, USA
    Metab Brain Dis 26:123-33. 2011
  9. pmc TCR-like antibodies distinguish conformational and functional differences in two- versus four-domain auto reactive MHC class II-peptide complexes
    Rony Dahan
    Faculty of Biology, Technion Israel Institute of Technology, Haifa, Israel
    Eur J Immunol 41:1465-79. 2011
  10. pmc Neuroprotective effects of recombinant T-cell receptor ligand in autoimmune optic neuritis in HLA-DR2 mice
    Grazyna Adamus
    Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
    Invest Ophthalmol Vis Sci 53:406-12. 2012

Scientific Experts

  • H Offner
  • Chunhe Wang
  • GREGORY GEORGE BURROWS
  • GRAZYNE ADAMUS
  • Jason M Link
  • Arthur A Vandenbark
  • Sushmita Sinha
  • Sandhya Subramanian
  • Roberto Meza-Romero
  • Rony Dahan
  • Gil Benedek
  • Yoram Reiter
  • Shayne Andrew
  • Jianya Huan
  • Jeffery L Mooney
  • Richard Bucala
  • Yuan K Chou
  • Suzan Dziennis
  • Patricia Ayala
  • Patricia D Hurn
  • Asako Itakura
  • Lisa Miller
  • Marjorie Grafe
  • Thomas M Proctor
  • Nerri Duvshani
  • Xiaolin Yu
  • Dennis Bourdette
  • Abigail C Buenafe
  • Lin Leng
  • Moran Tabul
  • Lisa M Miller
  • Sarah Mader
  • Adolph J Ferro
  • Kozaburo Akiyoshi
  • Paco S Herson
  • Xuefang Ren
  • Christopher Linington
  • Joseph E Aslan
  • Owen J T McCarty
  • Claude C A Bernard
  • Joseph F Quinn
  • Ishan A Patel
  • Thomas Proctor
  • Teri L Wadsworth
  • Owen Jt McCarty
  • Ashley Emerson-Webber
  • Tara C White-Adams
  • Christopher J Harris
  • Maren Lindner
  • Chris Roberts
  • Bing Zhang
  • Marjorie R Grafe
  • Yasuharu Kosaka
  • Laurie J Kaler

Detail Information

Publications22

  1. pmc HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis
    Roberto Meza-Romero
    Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239
    J Immunol 192:4164-73. 2014
    ....
  2. pmc Characterization of human platelet binding of recombinant T cell receptor ligand
    Asako Itakura
    Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, USA
    J Neuroinflammation 7:75. 2010
    ..The mechanisms by which RTLs impede local recruitment and retention of inflammatory cells in the CNS, however, are not completely understood...
  3. pmc CCR6: a biomarker for Alzheimer's-like disease in a triple transgenic mouse model
    Sandhya Subramanian
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Alzheimers Dis 22:619-29. 2010
    ....
  4. pmc A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance
    Arthur A Vandenbark
    Research Service, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Autoimmun 40:96-110. 2013
    ..These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases...
  5. pmc Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects
    Gil Benedek
    Department of Veterans Affairs Medical Center, Neuroimmunology Research, Portland, OR 97239, USA
    Eur J Immunol 43:1309-21. 2013
    ..Thus, binding of partial MHC complexes to CD74 blocks both the accessibility and availability of CD74 for MIF binding and downstream inflammatory activity...
  6. pmc Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis
    Gregory G Burrows
    Department of Neurology, Oregon Health and Science University, Portland, 97239, USA
    Metab Brain Dis 27:143-9. 2012
    ....
  7. pmc 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
    Sushmita Sinha
    Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon, United States of America
    PLoS ONE 6:e21868. 2011
    ..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...
  8. pmc Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice
    Suzan Dziennis
    Department of Anesthesiology and Peri Operative Medicine, Oregon Health and Science University, Portland, USA
    Metab Brain Dis 26:123-33. 2011
    ..These data demonstrate effective treatment of experimental stroke with RTL551 within a therapeutically relevant 4 h time window through immune regulation of myelin-reactive inflammatory T-cells...
  9. pmc TCR-like antibodies distinguish conformational and functional differences in two- versus four-domain auto reactive MHC class II-peptide complexes
    Rony Dahan
    Faculty of Biology, Technion Israel Institute of Technology, Haifa, Israel
    Eur J Immunol 41:1465-79. 2011
    ..These results demonstrate for the first time distinct conformational determinants characteristic of activating versus tolerogenic MHC-peptide complexes involved in human autoimmunity...
  10. pmc Neuroprotective effects of recombinant T-cell receptor ligand in autoimmune optic neuritis in HLA-DR2 mice
    Grazyna Adamus
    Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
    Invest Ophthalmol Vis Sci 53:406-12. 2012
    ..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...
  11. pmc RTL therapy for multiple sclerosis: a Phase I clinical study
    Halina Offner
    Neuroimmunology Research, Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd, Portland, OR 97239, United States
    J Neuroimmunol 231:7-14. 2011
    ..RTL1000 represents a novel approach for the treatment of MS that promises potent immunoregulation and CNS repair without global immunosuppression...
  12. pmc 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
    Sushmita Sinha
    Neuroimmunology Research R and D 31, Portland VA Medical Center, Portland, OR 97239, USA
    J Neuroimmunol 225:52-61. 2010
    ..These results demonstrate a novel pathway of T cell regulation by RTL-bound APCs...
  13. pmc Recombinant TCR ligand reverses clinical signs and CNS damage of EAE induced by recombinant human MOG
    Sushmita Sinha
    Neuroimmunology Research, Portland VA Medical Center, 3710 SW U S Veterans Hospital Rd, Portland, OR 97239, USA
    J Neuroimmune Pharmacol 5:231-9. 2010
    ..The results of our study lend support for the use of RTL therapy for treatment of MS subjects whose disease includes inflammatory T cells as well as those with an additional antibody component...
  14. 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...
  15. 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...
  16. 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
    ....
  17. 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...
  18. 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...
  19. 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...
  20. 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...
  21. 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
    ....