Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR.
Allograft rejection and immunosuppression are two major issues in transplantation medicine. The specific targeting of alloreactive T cells, the initiators and promoters of allograft rejection, would be a promising strategy to reduce unwanted T-cell responses and side effects of lifelong immunosuppression. The novel humanized monoclonal antibody GZ-αβTCR, specific for the human αβT-cell receptor, was tested in vitro and in vivo for its specificity and efficacy to modulate the αβT-cell compartment. GZ-αβTCR moderately induced apoptosis in resting αβT cells in vitro, an effect considerably amplified in activated T cells. A single dose of GZ-αβTCR significantly reduced human CD45(+)CD3(+) T cells in vivo, with a preferential modulation of CD4(+) αβT cells. Importantly, naive T cells, the T-cell subset from which alloreactivity emanates, were significantly reduced. Simultaneously, a significant, compensatory increase of γδ T cells was observed in vitro and in vivo in both humanized mouse models examined. GZ-αβTCR did not induce cytokines and was well tolerated. Thus, specificity and high efficacy make GZ-αβTCR a powerful tool to selectively eliminate putatively detrimental T-cell subsets, a major goal in transplantation medicine. At the same time, GZ-αβTCR spares γδ and natural killer cells, thus leaving the recipient's immune system competent for cell-mediated immunoregulation and cell-mediated immunity.
1] Department of General, Visceral and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany [2] Department of Pediatric Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
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G
Blank
Department of Pediatric Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
C
C
Welker
Department of Pediatric Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
J
J
Haarer
Department of Pediatric Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
M
M
Sterk
Department of General, Visceral and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany.
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S
Nadalin
NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
V A C
VA
Yañez
NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
T O
TO
Joos
Genzyme, a Sanofi Company, Framingham, MA, USA.
A
A
Menrad
Genzyme, a Sanofi Company, Framingham, MA, USA.
D
D
Snell
Genzyme, a Sanofi Company, Framingham, MA, USA.
G
G
LaCorcia
Department of General, Visceral and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany.
A
A
Königsrainer
Department of Pediatric Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
R
R
Handgretinger
Department of Pediatric Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
K
K
Schilbach
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D048708:Cell Growth Processes / Q000276:immunology; D006801:Humans; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D016693:Receptors, Antigen, T-Cell, alpha-beta