The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published 18 April 2005. doi:10.1084/jem.20040912
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 8, 1293-1305
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ARTICLE

 An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells

Silvia Gregori1, Patrizia Mangia2, Rosa Bacchetta1, Eleonora Tresoldi1, Frank Kolbinger4, Catia Traversari2, Josè M. Carballido5, Jan E. de Vries5, Ulf Korthäuer5, and Maria-Grazia Roncarolo1,3

1 San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy
2 Molmed S.p.A., 20132 Milan, Italy
3 Vita-Salute San Raffaele University, 20132 Milan, Italy
4 Novartis Institutes for Biomedical Research, Discovery Technologies, CH-4002 Basel, Switzerland
5 Novartis Institutes for Biomedical Research, Dermatology/Immunopathology, A-1235 Vienna, Austria

CORRESPONDENCE Maria Grazia Roncarolo: m.roncarolo{at}hsr.it

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/RBhigh 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.

Abbreviations used: {Delta}{psi}m, value of change in mitochondria transmembrane potential; chA6, chimeric A6; MLP, mixed lymphocyte-peptide; MP, matrix protein-derived peptide; PTPase, protein tyrosine phosphatase; T reg, regulatory T; TT, tetanus toxoid.


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