Failure to demonstrate long-lived MHC saturation both in vitro and in vivo. Implications for therapeutic potential of MHC-blocking peptides.
Peptides that bind with high affinity to class II MHC molecules can inhibit T cell activation both in vitro and in vivo. Thus, they have been suggested as potential therapeutic agents for MHC-associated autoimmune diseases. We have constructed nonnatural peptides with high affinity for certain disease-associated MHC alleles. More specifically, a particular peptide, designated as CY-760.50, was found to have a high binding affinity for DR1, slow dissociation kinetics after binding to MHC, and prolonged stability in human serum. However, when the ability of this peptide to block peptide presentation to an influenza hemagglutinin 307-319 peptide-specific, DR1-restricted T cell clone was examined, it was found that MHC blockade could only be achieved when high concentrations of peptide were present along with Ag in the fluid phase. Thus, pretreatment of APC with MHC class II blocker, followed by removal of unbound blocker, did not result in saturation of MHC molecules, because practically immediate reacquisition of Ag-presenting capacity was observed after removal of fluid phase blocker. The pharmacokinetic behavior and the duration of blocking activity of CY-760.50 were also examined in vivo, taking advantage of the fact that the mouse MHC class II molecule I-Ab also bound CY-760.50 with high affinity. CY-760.50 administered i.v. to C57BL/6 mice was rapidly cleared from the circulation and virtually undetectable in the serum 10 min after injection. This fast clearance rate was paralleled by a similarly short duration of the MHC blockade effect. These in vivo results have implications concerning the biology of peptide-MHC interactions, and suggest that MHC blockade may not be feasible as a therapeutic approach unless effective concentrations of inhibitor can be maintained over extended periods of time in the extracellular fluids.
Ishioka
G Y
GY
Cytel, San Diego, CA 92121.
Adorini
L
L
Guery
J C
JC
Gaeta
F C
FC
LaFond
R
R
Alexander
J
J
Powell
M F
MF
Sette
A
A
Grey
H M
HM
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy; D001667:Binding, Competitive; D002460:Cell Line; D004355:Drug Stability; D015798:HLA-DR1 Antigen / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D015798:HLA-DR1 Antigen; D000949:Histocompatibility Antigens Class II; D010455:Peptides