Down-regulation of class II major histocompatibility complex molecules on antigen-presenting cells by antibody fragments.
Certain HLA class II-specific monoclonal antibodies (mAb) cause up to 90% decrease in the cell surface expression of class II molecules. This down-regulation is isotype-specific, i.e. DR-specific mAb do not affect the expression of DP and DQ molecules. However, antibodies binding to one DR allotype down-regulate both allotypes in heterozygous antigen-presenting cells (APC), indicating that the phenomenon is not a direct consequence of ligation. All down-regulating mAb identified recognize the first (peptide binding) domains of class II heterodimers, and strongly inhibit the activation of class II-restricted human T cells in vitro. Conversely, non-down-regulating mAb fail to inhibit T cell activation, and most of them (four out of five) recognize class II second domains. Down-regulating antibodies are cytotoxic for B lymphoblastoid cell lines and for a small proportion of normal activated B cells. Their F(ab')2 fragments mediate both down-regulation and cytotoxicity, whereas the monovalent Fab fragments are not cytotoxic, but retain the down-regulatory and T cell inhibitory properties. These findings raise the possibility of a class II major histocompatibility complex-specific, antibody-based immunosuppressive therapy without cytotoxic side effects.
Vidović
D
D
Department of Inflammation and Autoimmune Diseases, Preclinical Research, Hoffmann-La Roche, Inc., Nutley, NJ 07110-1199, USA.
Falcioni
F
F
Siklodi
B
B
Belunis
C J
CJ
Bolin
D R
DR
Ito
K
K
Nagy
Z A
ZA
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D000939:Epitopes / Q000032:analysis; D006684:HLA-DR Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D007140:Immunoglobulin Fab Fragments