Prevention and reversal of experimental autoimmune myasthenia gravis by a monoclonal antibody against acetylcholine receptor-specific T cells.
We have recently described an algorithm to design, among others, peptides with complementarity contour to autoimmune epitopes. Immunization with one such peptide resulted in a monoclonal antibody (mAb), termed CTCR8, that specifically recognized Vbeta15 containing TCR on acetylcholine receptor (AChR) alpha-chain residue 100-116-specific T cells. CTCR8 was found to label the cell surface of AChR100-116-specific T cell lines and clones, immunoprecipitate the TCR from such cells, and block their proliferative responses to AChRalpha100-116. In the present report, we have found that there is a marked reduction in IFN-gamma and no effect on IL-10 production in a CTCR8-treated AChRalpha100-116-specific T cell line. Interestingly, when AChR100-116-primed, primary T cells were stimulated with peptide and treated with CTCR8, there was once again inhibition of IFN-gamma but also marked stimulation of IL-10 production. The change in the Th1/Th2 cytokine profile was paralleled by a reduction in AChR-specific IgG2a and IgM with no effect on IgG1. Remarkably, the most profoundly inhibited Ab population was that which causes experimental autoimmune myasthenia gravis (EAMG) by reaction with the main immunogenic region (alpha61-76) of the AChR. Based on these results, CTCR8 was tested for prophylactic and therapeutic effects in EAMG. EAMG induced by immunization with purified native Torpedo AChR was both inhibited and reversed by CTCR8. These findings suggest a means to produce therapeutic mAb for the treatment of autoimmune diseases.
Xu
L
L
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama, 35294-0005, USA.
Villain
M
M
Galin
F S
FS
Araga
S
S
Blalock
J E
JE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D002455:Cell Division; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D011950:Receptors, Cholinergic; D007371:Interferon-gamma