Altered peptide ligands of a myasthenogenic epitope as modulators of specific T-cell responses.
Myasthenia gravis (MG) is a T-cell regulated autoimmune disease. A peptide representing a sequence of the human acetylcholine receptor alpha-subunit (p195-212) was previously shown to stimulate proliferative responses of peripheral blood lymphocytes from MG patients and to be an immunodominant and myasthenogenic T-cell epitope in SJL mice. The authors generated a panel of analogues of p195-212 that contain single amino acid substitutions. Three of the analogues (203PHE, 204GLY and 207ALA) triggered low to no proliferative responses of a p195-212-specific T-cell line designated TCSJL195-212. Two of these analogues were able to stimulate the line to produce interleukin-2 (IL-2) and IL-4 (203PHE and 204GLY), whereas one analogue, 207ALA, did not stimulate the line to produce these cytokines. Binding assays revealed that the binding affinity of an altered peptide for a given major histocompatibility complex (MHC) molecule is not sufficient to determine whether it will be stimulatory or inhibitory to a native peptide-specific T-cell line. Two of the analogues, 204GLY and 207ALA, inhibited proliferative responses of cells of the TCSJL195-212 line when co-cultured with p195-212 and syngeneic antigen presenting cells (APC). The two inhibitory analogues were also able to inhibit proliferative responses of the TCSJL195-212 line when APC were pre-pulsed with p195-212, indicating that MHC blockade is not the only mechanism of action of these peptides. Moreover, both analogues inhibited the ability of p195-212 to prime lymph node cells for proliferative responses even when the analogues were administered in a soluble form. Thus the altered peptide ligands 207ALA and 204GLY can modulate T-cell responses both in vitro and in vivo and may have therapeutic potential for the treatment of MG.
Kirshner
S L
SL
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Zisman
E
E
Fridkin
M
M
Sela
M
M
Mozes
E
E
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D002478:Cells, Cultured; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology*; D011485:Protein Binding; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D007376:Interleukin-2; D010446:Peptide Fragments; D011950:Receptors, Cholinergic; D015847:Interleukin-4