TY - JOUR
T1 - Specific immunotherapeutic strategy for myasthenia gravis
T2 - targeted antigen-presenting cells
AU - Reim, Johannes
AU - McIntosh, Kevin
AU - Martin, Stephen
AU - Daniel B., Drachman
N1 - Funding Information:
We are gratefult o Dr. D.M. Segal for helpful advice, to D. Maurath-Lucaasn d R.N. Adams for expert technicaal ssistancea,n dto C.F. Salemif or preparation of the manuscriptS. upportedin part by grants from the NationalI nstituteos f Health (1RO1 NS23719)t, he Muscular DystrophyA ssociation,t he Arthur Clarke Foundationt,h e MyastheniaG ravis Foundationa nd the Dana Foundation.
PY - 1992/11
Y1 - 1992/11
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
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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 - Advances in Neuroimmunology
JF - Advances in Neuroimmunology
SN - 0165-5728
IS - 1
ER -