An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells.
The effects of a chimeric monoclonal antibody (chA6 mAb) that recognizes both the RO and RB isoforms of the transmembrane protein tyrosine phosphatase CD45 on human T cells were investigated. Chimeric A6 (chA6) mAb potently inhibited antigen-specific and polyclonal T cell responses. ChA6 mAb induced activation-independent apoptosis in CD4(+)CD45RO/RB(high) T cells but not in CD8(+) T cells. In addition, CD4(+) T cell lines specific for tetanus toxoid (TT) generated in the presence of chA6 mAb were anergic and suppressed the proliferation and interferon (IFN)-gamma production by TT-specific effector T cells by an interleukin-10-dependent mechanism, indicating that these cells were equivalent to type 1 regulatory T cells. Similarly, CD8(+) T cell lines specific for the influenza A matrix protein-derived peptide (MP.58-66) generated in the presence of chA6 mAb were anergic and suppressed IFN-gamma production by MP.58-66-specific effector CD8(+) T cells. Furthermore, chA6 mAb significantly prolonged human pancreatic islet allograft survival in nonobese diabetic/severe combined immunodeficiency mice injected with human peripheral blood lymphocytes (hu-PBL-NOD/SCID). Together, these results demonstrate that the chA6 mAb is a new immunomodulatory agent with multiple modes of action, including deletion of preexisting memory and recently activated T cells and induction of anergic CD4(+) and CD8(+) regulatory T cells.
Gregori
Silvia
S
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
Mangia
Patrizia
P
Bacchetta
Rosa
R
Tresoldi
Eleonora
E
Kolbinger
Frank
F
Traversari
Catia
C
Carballido
Josè M
JM
de Vries
Jan E
JE
Korthäuer
Ulf
U
Roncarolo
Maria-Grazia
MG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006085:Graft Survival; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008840:Microfilament Proteins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D011505:Protein-Tyrosine Kinases; D013745:Tetanus Toxoid / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D008840:Microfilament Proteins; C485188:TWF1 protein, human; D013745:Tetanus Toxoid; D011505:Protein-Tyrosine Kinases; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1