Immunosuppression and induction of anergy by CTLA4Ig in vitro: effects on cellular and antibody responses of lymphocytes from rats with experimental autoimmune myasthenia gravis.
The pathogenic antibody response to acetylcholine receptor (AChR) in experimental autoimmune myasthenia gravis (EAMG) is T cell dependent. Therefore, it should be possible to design specific immunotherapeutic approaches to treat EAMG (and human MG) by interfering with AChR-specific helper T cells. Productive T cell activation by antigen requires at least two signals: one signal delivered through the T cell receptor by antigen and a second costimulatory signal delivered through the CD28 receptor via the B7 counterreceptor expressed on antigen-presenting cells. Here we show that interference with the B7 costimulatory signal, using a soluble CD28 analogue, CTLA4Ig, resulted in a profound decrease in IL2 production and significantly decreased lymphoproliferative responses and antibody responses by primed lymph node cells from rats with EAMG, when stimulated with AChR in vitro. Nonclonal AChR-specific T cell lines, when stimulated with AChR in the presence of CTLA4Ig, were also inhibited in their ability to proliferate and to produce the cytokines IL2 and IFN-gamma. They remained deficient in their ability to produce IL2 when restimulated with AChR plus fresh antigen-presenting cells and showed variable inhibition of proliferation. The induction of hyporesponsiveness was accompanied by the expression of functional IL2 receptors, as shown by vigorous proliferative responses to addition of exogenous IL2. These results indicate that specific antigen stimulation in the presence of CTLA4Ig can induce certain features typical of anergy. CTLA4Ig provides a promising approach for the immunomodulation of MG and other antibody-mediated autoimmune diseases.
McIntosh
K R
KR
Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287-7519, USA.
Linsley
P S
PS
Drachman
D B
DB
D000069594:Abatacept; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology* / Q000627:therapeutic use; D060908:CTLA-4 Antigen; D002460:Cell Line; D017635:Clonal Anergy / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects; D009157:Myasthenia Gravis / Q000276:immunology* / Q000628:therapy; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007376:Interleukin-2; D011950:Receptors, Cholinergic; D000069594:Abatacept; D007371:Interferon-gamma