Regulation of encephalitogenic T cells with recombinant TCR ligands.
We have previously described recombinant MHC class II beta1 and alpha1 domains loaded with free antigenic peptides with potent inhibitory activity on encephalitogenic T cells. We have now produced single-chain constructs in which the peptide Ag is genetically encoded within the same exon as the linked beta1 and alpha1 domains, overcoming the problem of displacement of peptide Ag from the peptide binding cleft. We here describe clinical effects of recombinant TCR ligands (RTLs) comprised of the rat RT1.B beta1alpha1 domains covalently linked to the 72-89 peptide of guinea pig myelin basic protein (RTL-201), to the corresponding 72-89 peptide from rat myelin basic protein (RTL-200), or to cardiac myosin peptide CM-2 (RTL-203). Only RTL-201 possessed the ability to prevent and treat active or passive experimental autoimmune encephalomyelitis. Amelioration of experimental autoimmune encephalomyelitis was associated with a selective inhibition of proliferation response and cytokine production by Ag-stimulated lymph node T cells and a drastic reduction in the number of encephalitogenic and recruited inflammatory cells infiltrating the CNS. The exquisitely selective inhibition could be observed between molecules that differ by a single methyl group (the single amino acid residue difference between RTL-200 (threonine) and RTL-201 (serine) at position 80 of the myelin basic protein peptide). These novel RTLs provide a platform for developing potent and selective human diagnostic and therapeutic agents for treatment of autoimmune disease.
Burrows
G G
GG
Department of Neurology, Biochemistry and Molecular Biology, and Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland 97201, USA. ggb@ohsu.edu
Adlard
K L
KL
Bebo
B F
BF
Chang
J W
JW
Tenditnyy
K
K
Vandenbark
A A
AA
Offner
H
H
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005452:Fluoresceins / Q000032:analysis; D006168:Guinea Pigs; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology*; D013194:Staining and Labeling; D013388:Succinimides / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000637:transplantation
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D006649:Histocompatibility Antigens; D007166:Immunosuppressive Agents; D008024:Ligands; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D013388:Succinimides; C038353:histocompatibility antigens RT, rat