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. Thi s downregulation is isotype-specific, i.e. DR-specific mAb do not affe ct the expression of DP and DQ molecules. However, antibodies binding to one DR allotype down-regulate both allotypes in heterozygous antige n-presenting cells (APC), indicating that the phenomenon is not a dire ct consequence of ligation. All down-regulating mAb identified recogni ze the first (peptide binding) domains of class II heterodimers, and s trongly inhibit the activation of class II-restricted human T cells in vitro. Conversely, non-down regulating mAb fail to inhibit T cell act ivation, and most of them (four out of five) recognize class II second domains. Down-regulating antibodies are cytotoxic for B lymphoblastoi d cell lines and for a small proportion of normal activated B cells. T heir F(ab')(2) fragments mediate both down-regulation and cytotoxicity , whereas the monovalent Fab fragments are not cytotoxic, but retain t he down-regulatory and T cell inhibitory properties. These findings ra ise the possibility of a class II major histocompatibility complex-spe cific, antibody-based immunosuppressive therapy without cytotoxic side effects.