Vidović D, Falcioni F, Siklodi B, Belunis C J, Bolin D R, Ito K, Nagy Z A
Department of Inflammation and Autoimmune Diseases, Preclinical Research, Hoffmann-La Roche, Inc., Nutley, NJ 07110-1199, USA.
Eur J Immunol. 1995 Dec;25(12):3349-55. doi: 10.1002/eji.1830251222.
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.
某些HLA II类特异性单克隆抗体（mAb）可使II类分子的细胞表面表达降低多达90%。这种下调是同种型特异性的，即DR特异性mAb不影响DP和DQ分子的表达。然而，与一种DR同种异型结合的抗体可下调杂合抗原呈递细胞（APC）中两种同种异型的表达，这表明该现象并非连接的直接后果。所有已鉴定的下调mAb均识别II类异二聚体的第一个（肽结合）结构域，并在体外强烈抑制II类限制性人T细胞的活化。相反，非下调mAb不能抑制T细胞活化，其中大多数（五分之四）识别II类第二个结构域。下调抗体对B淋巴母细胞系和一小部分正常活化B细胞具有细胞毒性。它们的F(ab')2片段介导下调和细胞毒性，而单价Fab片段无细胞毒性，但保留下调和T细胞抑制特性。这些发现增加了一种基于抗体的、无细胞毒性副作用的II类主要组织相容性复合体特异性免疫抑制疗法的可能性。
