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Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis

Niannian Ji, Animesh Somanaboeina, Aakanksha Dixit, Kazuyuki Kawamura, Neil J. Hayward, Christopher Self, Gary L. Olson and Thomas G. Forsthuber
J Immunol October 11, 2013, 1300407; DOI: https://doi.org/10.4049/jimmunol.1300407
Niannian Ji
*Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249;
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Animesh Somanaboeina
*Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249;
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Aakanksha Dixit
*Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249;
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Kazuyuki Kawamura
*Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249;
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Neil J. Hayward
†Daiamed, Cambridge, MA 02141; and
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Christopher Self
‡Provid Pharmaceuticals, Monmouth Junction, NJ 08852
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Gary L. Olson
‡Provid Pharmaceuticals, Monmouth Junction, NJ 08852
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Thomas G. Forsthuber
*Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249;
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Abstract

The strong association of HLA-DR2b (DRB1*1501) with multiple sclerosis (MS) suggests this molecule as prime target for specific immunotherapy. Inhibition of HLA-DR2b–restricted myelin-specific T cells has the potential to selectively prevent CNS pathology mediated by these MHC molecules without undesired global immunosuppression. In this study, we report development of a highly selective small molecule inhibitor of peptide binding and presentation by HLA-DR2b. PV-267, the candidate molecule used in these studies, inhibited cytokine production and proliferation of myelin-specific HLA-DR2b–restricted T cells. PV-267 had no significant effect on T cell responses mediated by other MHC class II molecules, including HLA-DR1, -DR4, or -DR9. Importantly, PV-267 did not induce nonspecific immune activation of human PBMC. Lastly, PV-267 showed treatment efficacy both in preventing experimental autoimmune encephalomyelitis and in treating established disease. The results suggest that blocking the MS-associated HLA-DR2b allele with small molecule inhibitors may be a promising therapeutic strategy for the treatment of MS.

Footnotes

  • This work was supported by National Institutes of Health Grants NS048731 (to Provid) and G12MD007591 (to T.G.F.), National Multiple Sclerosis Society Grant RG3701 (to T.G.F.), and Fast Forward (to Provid and T.G.F.).

  • The online version of this article contains supplemental material.

  • Received February 11, 2013.
  • Accepted September 6, 2013.
  • Copyright © 2013 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis
Niannian Ji, Animesh Somanaboeina, Aakanksha Dixit, Kazuyuki Kawamura, Neil J. Hayward, Christopher Self, Gary L. Olson, Thomas G. Forsthuber
The Journal of Immunology October 11, 2013, 1300407; DOI: 10.4049/jimmunol.1300407

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Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis
Niannian Ji, Animesh Somanaboeina, Aakanksha Dixit, Kazuyuki Kawamura, Neil J. Hayward, Christopher Self, Gary L. Olson, Thomas G. Forsthuber
The Journal of Immunology October 11, 2013, 1300407; DOI: 10.4049/jimmunol.1300407
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