Specific immunotherapeutic strategy for myasthenia gravis: targeted antigen-presenting cells

Johannes Reim, Kevin McIntosh, Stephen Martin, Daniel B Drachman

Research output: Contribution to journalArticle

Abstract

The pathogenesis of myasthenia gravis (MG) involves a T cell-dependent antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Inactivation of AChR-specific T cells should interrupt the immune response, resulting in therapeutic benefit. Since each individual's repertoire of T cells responds to a heterogeneous and unique spectrum of AChR epitopes presented in association with self-major histocompatibility complex (MHC) class II, an individualized approach is required to target all relevant AChR-specific T cells. The individual's own antigen-presenting cells (APC) can be used for this purpose, since they process and present the antigen appropriately, and express the correct MHC class II. A novel method of binding AChR to surface immunoglobulin with a heterobifunctional antibody conjugate allows us to use all B cells as APC. Conjugate-plus-AChR-treated B cells (AChR-APC) effectively targeted AChR-specific T cells, stimulating vigorous proliferative responses in a rat cell culture system. If APCs are 'fixed' with cross-linking reagents, they induce long-lasting or permanent 'anergy' of the specific T cells. We prepared AChR-APC, allowed them to process AChR in vitro, and fixed them with paraformaldehyde. Pre-culture of these fixed AChR-APC with AChR-specific T cells induced anergy: when restimulated with fresh AChR-APC, the T cells exhibited markedly reduced proliferative responses and IL-2 production, compared with responses of T cells pre-cultured with control fixed B cells. Implications for the design of antigen-specific therapeutic strategies for MG and other immune disorders will be discussed.

Original languageEnglish (US)
Pages (from-to)61-70
Number of pages10
JournalJournal of Neuroimmunology
Volume41
Issue number1
DOIs
StatePublished - 1992

Fingerprint

Myasthenia Gravis
Cholinergic Receptors
Antigen-Presenting Cells
T-Lymphocytes
B-Lymphocytes
Major Histocompatibility Complex
Cross-Linking Reagents
Antigens
B-Cell Antigen Receptors
Antibodies
Immune System Diseases
Autoimmunity
Interleukin-2
Epitopes
Cell Culture Techniques

Keywords

  • Acetylcholine receptor
  • Antibody conjugate
  • Autoimmune disease
  • B cell
  • T cell

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Clinical Neurology
  • Neurology

Cite this

Specific immunotherapeutic strategy for myasthenia gravis : targeted antigen-presenting cells. / Reim, Johannes; McIntosh, Kevin; Martin, Stephen; Drachman, Daniel B.

In: Journal of Neuroimmunology, Vol. 41, No. 1, 1992, p. 61-70.

Research output: Contribution to journalArticle

Reim, Johannes ; McIntosh, Kevin ; Martin, Stephen ; Drachman, Daniel B. / Specific immunotherapeutic strategy for myasthenia gravis : targeted antigen-presenting cells. In: Journal of Neuroimmunology. 1992 ; Vol. 41, No. 1. pp. 61-70.
@article{14a7a258332941259031445255b26969,
title = "Specific immunotherapeutic strategy for myasthenia gravis: targeted antigen-presenting cells",
abstract = "The pathogenesis of myasthenia gravis (MG) involves a T cell-dependent antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Inactivation of AChR-specific T cells should interrupt the immune response, resulting in therapeutic benefit. Since each individual's repertoire of T cells responds to a heterogeneous and unique spectrum of AChR epitopes presented in association with self-major histocompatibility complex (MHC) class II, an individualized approach is required to target all relevant AChR-specific T cells. The individual's own antigen-presenting cells (APC) can be used for this purpose, since they process and present the antigen appropriately, and express the correct MHC class II. A novel method of binding AChR to surface immunoglobulin with a heterobifunctional antibody conjugate allows us to use all B cells as APC. Conjugate-plus-AChR-treated B cells (AChR-APC) effectively targeted AChR-specific T cells, stimulating vigorous proliferative responses in a rat cell culture system. If APCs are 'fixed' with cross-linking reagents, they induce long-lasting or permanent 'anergy' of the specific T cells. We prepared AChR-APC, allowed them to process AChR in vitro, and fixed them with paraformaldehyde. Pre-culture of these fixed AChR-APC with AChR-specific T cells induced anergy: when restimulated with fresh AChR-APC, the T cells exhibited markedly reduced proliferative responses and IL-2 production, compared with responses of T cells pre-cultured with control fixed B cells. Implications for the design of antigen-specific therapeutic strategies for MG and other immune disorders will be discussed.",
keywords = "Acetylcholine receptor, Antibody conjugate, Autoimmune disease, B cell, T cell",
author = "Johannes Reim and Kevin McIntosh and Stephen Martin and Drachman, {Daniel B}",
year = "1992",
doi = "10.1016/0165-5728(92)90196-R",
language = "English (US)",
volume = "41",
pages = "61--70",
journal = "Journal of Neuroimmunology",
issn = "0165-5728",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Specific immunotherapeutic strategy for myasthenia gravis

T2 - targeted antigen-presenting cells

AU - Reim, Johannes

AU - McIntosh, Kevin

AU - Martin, Stephen

AU - Drachman, Daniel B

PY - 1992

Y1 - 1992

N2 - The pathogenesis of myasthenia gravis (MG) involves a T cell-dependent antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Inactivation of AChR-specific T cells should interrupt the immune response, resulting in therapeutic benefit. Since each individual's repertoire of T cells responds to a heterogeneous and unique spectrum of AChR epitopes presented in association with self-major histocompatibility complex (MHC) class II, an individualized approach is required to target all relevant AChR-specific T cells. The individual's own antigen-presenting cells (APC) can be used for this purpose, since they process and present the antigen appropriately, and express the correct MHC class II. A novel method of binding AChR to surface immunoglobulin with a heterobifunctional antibody conjugate allows us to use all B cells as APC. Conjugate-plus-AChR-treated B cells (AChR-APC) effectively targeted AChR-specific T cells, stimulating vigorous proliferative responses in a rat cell culture system. If APCs are 'fixed' with cross-linking reagents, they induce long-lasting or permanent 'anergy' of the specific T cells. We prepared AChR-APC, allowed them to process AChR in vitro, and fixed them with paraformaldehyde. Pre-culture of these fixed AChR-APC with AChR-specific T cells induced anergy: when restimulated with fresh AChR-APC, the T cells exhibited markedly reduced proliferative responses and IL-2 production, compared with responses of T cells pre-cultured with control fixed B cells. Implications for the design of antigen-specific therapeutic strategies for MG and other immune disorders will be discussed.

AB - The pathogenesis of myasthenia gravis (MG) involves a T cell-dependent antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Inactivation of AChR-specific T cells should interrupt the immune response, resulting in therapeutic benefit. Since each individual's repertoire of T cells responds to a heterogeneous and unique spectrum of AChR epitopes presented in association with self-major histocompatibility complex (MHC) class II, an individualized approach is required to target all relevant AChR-specific T cells. The individual's own antigen-presenting cells (APC) can be used for this purpose, since they process and present the antigen appropriately, and express the correct MHC class II. A novel method of binding AChR to surface immunoglobulin with a heterobifunctional antibody conjugate allows us to use all B cells as APC. Conjugate-plus-AChR-treated B cells (AChR-APC) effectively targeted AChR-specific T cells, stimulating vigorous proliferative responses in a rat cell culture system. If APCs are 'fixed' with cross-linking reagents, they induce long-lasting or permanent 'anergy' of the specific T cells. We prepared AChR-APC, allowed them to process AChR in vitro, and fixed them with paraformaldehyde. Pre-culture of these fixed AChR-APC with AChR-specific T cells induced anergy: when restimulated with fresh AChR-APC, the T cells exhibited markedly reduced proliferative responses and IL-2 production, compared with responses of T cells pre-cultured with control fixed B cells. Implications for the design of antigen-specific therapeutic strategies for MG and other immune disorders will be discussed.

KW - Acetylcholine receptor

KW - Antibody conjugate

KW - Autoimmune disease

KW - B cell

KW - T cell

UR - http://www.scopus.com/inward/record.url?scp=0026439164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026439164&partnerID=8YFLogxK

U2 - 10.1016/0165-5728(92)90196-R

DO - 10.1016/0165-5728(92)90196-R

M3 - Article

C2 - 1460093

AN - SCOPUS:0026439164

VL - 41

SP - 61

EP - 70

JO - Journal of Neuroimmunology

JF - Journal of Neuroimmunology

SN - 0165-5728

IS - 1

ER -