Lethal effect of CD3-specific antibody in mice deficient in TGF-beta1 by uncontrolled flu-like syndrome.
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-beta1(-/-) mice. The death of TGF-beta1(-/-) mice was associated with occurrence of this uncontrolled flu-like syndrome, as demonstrated by a sustained storm of systemic inflammatory TNF and IFN-gamma cytokines. We present evidence that deficiency of professional phagocytes to produce TGF-beta1 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-beta1 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-beta1(-/-) mice.
Perruche
Sylvain
S
Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Zhang
Pin
P
Maruyama
Takashi
T
Bluestone
Jeffrey A
JA
Saas
Philippe
P
Chen
WanJun
W
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology*; D002423:Cause of Death; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000209:etiology* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010586:Phagocytes / Q000473:pathology; D013577:Syndrome; D013601:T-Lymphocytes / Q000473:pathology; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D017252:CD3 Complex; D016207:Cytokines; D053773:Transforming Growth Factor beta1