TY - JOUR
T1 - Lethal effect of CD3-specific antibody in mice deficient in TGF-β1 by uncontrolled flu-like syndrome
AU - Perruche, Sylvain
AU - Zhang, Pin
AU - Maruyama, Takashi
AU - Bluestone, Jeffrey A.
AU - Saas, Philippe
AU - Chen, Wan Jun
PY - 2009/7/15
Y1 - 2009/7/15
N2 - CD3-specific Ab therapy results in a transient, self-limiting, cytokine-associated, flu-like syndrome in experimental animals and in patients, but the underlying mechanism for this spontaneous resolution remains elusive. By using an in vivo model of CD3-specific Ab-induced flu-like syndrome, we show in this paper that a single injection of sublethal dose of the Ab killed all TGF-β1-/- mice. The death of TGF-β1-/- mice was associated with occurrence of this uncontrolled flu-like syndrome, as demonstrated by a sustained storm of systemic inflammatory TNF and IFN-γ cytokines. We present evidence that deficiency of professional phagocytes to produce TGF-β1 after apoptotic T cell clearance may be responsible, together with hypersensitivity of T cells to both activation and apoptosis, for the uncontrolled inflammation. These findings indicate a key role for TGF-β1 and phagocytes in protecting the recipients from lethal inflammation and resolving the flu-like syndrome after CD3-specific Ab treatment. The study may also provide a novel molecular mechanism explaining the early death in TGF-β1-/- mice.
AB - CD3-specific Ab therapy results in a transient, self-limiting, cytokine-associated, flu-like syndrome in experimental animals and in patients, but the underlying mechanism for this spontaneous resolution remains elusive. By using an in vivo model of CD3-specific Ab-induced flu-like syndrome, we show in this paper that a single injection of sublethal dose of the Ab killed all TGF-β1-/- mice. The death of TGF-β1-/- mice was associated with occurrence of this uncontrolled flu-like syndrome, as demonstrated by a sustained storm of systemic inflammatory TNF and IFN-γ cytokines. We present evidence that deficiency of professional phagocytes to produce TGF-β1 after apoptotic T cell clearance may be responsible, together with hypersensitivity of T cells to both activation and apoptosis, for the uncontrolled inflammation. These findings indicate a key role for TGF-β1 and phagocytes in protecting the recipients from lethal inflammation and resolving the flu-like syndrome after CD3-specific Ab treatment. The study may also provide a novel molecular mechanism explaining the early death in TGF-β1-/- mice.
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U2 - 10.4049/jimmunol.0804076
DO - 10.4049/jimmunol.0804076
M3 - Article
C2 - 19561097
AN - SCOPUS:70249136213
VL - 183
SP - 953
EP - 961
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -