HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by El-Amine, M. Articles by Scott, D. W. Search for Related Content PubMed PubMed Citation Articles by El-Amine, M. Articles by Scott, D. W. Pubmed/NCBI databases Substance via MeSH

Mechanisms of Tolerance Induction by a Gene-Transferred Peptide-IgG Fusion Protein Expressed in B Lineage Cells^{1 ,2}

^* Department of Immunology, American Red Cross, J. Holland Laboratory, Rockville, MD 20855; and Department of Immunology, George Washington University Medical Center, Washington DC 20037

A gene therapy model has been designed to induce tolerance to multiple epitopes expressed in-frame on a soluble IgG fusion protein scaffold. Tolerance to the repressor cI sequence p1-102 or its immunodominant epitopes (p12-26, p73-88) can be elicited when bone marrow (BM) or LPS blasts are transduced and injected into naive or even primed recipients. To explore the mechanism of tolerance, class II^-/- (knockout, KO) BM cells were transduced with p1-102-IgG and transferred to irradiated recipients. These cells failed to induce tolerance to challenge with p1-102 epitopes, whereas transduced +/+ BM cells did. This supports the importance of class II MHC on the tolerogenic APC rather than secretion and representation in tolerogenesis. When BM cells from µMT KO mice were transfected with p12-26-IgG and injected into irradiated mice, these transduced BM cells also failed to induce tolerance to an immunodominant epitope. These results suggest the direct involvement of B cells in tolerance to p1-102 epitopes. IL-10 KO BM cells infected with a p12-26-IgG construct were still tolerogenic. Importantly, anti-CTLA-4 injections reversed tolerance in primed, but not in naive, recipients of transduced LPS blasts. These data emphasize the importance of MHC class II presentation, B cell involvement, and CTLA-4 engagement in induction and/or maintenance of tolerance.

This article has been cited by other articles:

				A. S. De Groot, L. Moise, J. A. McMurry, E. Wambre, L. Van Overtvelt, P. Moingeon, D. W. Scott, and W. Martin Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes" Blood, October 15, 2008; 112(8): 3303 - 3311. [Abstract] [Full Text] [PDF]

				Y. Su, G. Carey, M. Maric, and D. W. Scott B Cells Induce Tolerance by Presenting Endogenous Peptide-IgG on MHC Class II Molecules via an IFN-{gamma}-Inducible Lysosomal Thiol Reductase-Dependent Pathway J. Immunol., July 15, 2008; 181(2): 1153 - 1160. [Abstract] [Full Text] [PDF]

				P. B. Silver, R. K. Agarwal, S.-B. Su, I. Suffia, R. S. Grajewski, D. Luger, C.-C. Chan, R. M. Mahdi, J. M. Nickerson, and R. R. Caspi Hydrodynamic Vaccination with DNA Encoding an Immunologically Privileged Retinal Antigen Protects from Autoimmunity through Induction of Regulatory T Cells J. Immunol., October 15, 2007; 179(8): 5146 - 5158. [Abstract] [Full Text] [PDF]

				M. Werner-Klein, C. Dresch, P. Marconi, and T. Brocker Transcriptional Targeting of B Cells for Induction of Peripheral CD8 T Cell Tolerance J. Immunol., June 15, 2007; 178(12): 7738 - 7746. [Abstract] [Full Text] [PDF]

				M. T. Litzinger, Y. Su, T. C. Lei, N. Soukhareva, and D. W. Scott Mechanisms of Gene Therapy for Tolerance: B7 Signaling Is Required for Peptide-IgG Gene-Transferred Tolerance Induction J. Immunol., July 15, 2005; 175(2): 780 - 787. [Abstract] [Full Text] [PDF]

				T. C. Lei and D. W. Scott Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins Blood, June 15, 2005; 105(12): 4865 - 4870. [Abstract] [Full Text] [PDF]

				C. M. Snyder, K. Aviszus, R. A. Heiser, D. R. Tonkin, A. M. Guth, and L. J. Wysocki Activation and Tolerance in CD4+ T Cells Reactive to an Immunoglobulin Variable Region J. Exp. Med., November 8, 2004; (2004) jem.20031234. [Abstract] [Full Text] [PDF]

				E. Dobrzynski, F. Mingozzi, Y.-L. Liu, E. Bendo, O. Cao, L. Wang, and R. W. Herzog Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer Blood, August 15, 2004; 104(4): 969 - 977. [Abstract] [Full Text] [PDF]

				V C Kyttaris, Y-T Juang, and G C Tsokos Gene therapy in systemic lupus erythematosus Lupus, May 1, 2004; 13(5): 353 - 358. [Abstract] [PDF]

				M. El-Amine, J. A. Hinshaw, and D. W. Scott In vivo induction of tolerance by an Ig peptide is not affected by the deletion of FcR or a mutated IgG Fc fragment Int. Immunol., July 1, 2002; 14(7): 761 - 766. [Abstract] [Full Text] [PDF]

				M. E. F. Melo, J. Qian, M. El-Amine, R. K. Agarwal, N. Soukhareva, Y. Kang, and D. W. Scott Gene Transfer of Ig-Fusion Proteins Into B Cells Prevents and Treats Autoimmune Diseases J. Immunol., May 1, 2002; 168(9): 4788 - 4795. [Abstract] [Full Text] [PDF]