NAKAO Atsuto Yamanashi University, School of Medicine, Professor, 医学部, 教授 (80317445)
NAGATA Satoru Juntendo University, School of Medicine, Dept.of Pediatrics, Lecturer, 医学部, 講師 (70266055)
SHIMIZU Toshiaki Juntendo University, School of Medicine, Dept.of Pediatrics, Associate Professor, 医学部, 助教授 (30260889)
|Budget Amount *help
¥3,600,000 (Direct Cost : ¥3,600,000)
Fiscal Year 2005 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 2004 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 2003 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Helper T cells are classified mainly into three broad types according to their cytokine production profile : Th1,Th2, and Th3 cells. Thi1 cells produce IL-2,IFN-γ and TNF-α and mainly involve cell-mediated immunological reactions. Th2 cells produce IL-4,IL-5,IL-9,IL-10, and IL-13, which promote eosinophilia and generally boost antibody responses including IgE-mediated allergic patients. Lastly, Th3 cells regulate Th1 and Th2 cytokine production by producing TGF-β. TGF-β has a broad spectrum of activities in regulation, including induction of oral tolerance, potent anti-inflammatory effects, mucosal IgA expression, and effects on epithelial cell proliferation and differentiation. TGF-β signals through a receptor serine kinase that then phosphorylates and thereby activates transcription factors Smad2 and Smad3. Smad4, a common mediator, then binds to these activated molecules and can send signals to the nucleus. The Smad7 molecule may also function as an antagonistic Smad, and may inhibi
t TGF-β-mediated Smad3 phosphorylation to attenuate TGF-β signaling to the nucleus. In this project, we organized a series of studies to examine the effects of TGF-β in chronic inflammatory diseases. We have also investigated the immunological development if TGF-β signaling in early infancy.
We have first investigated a girl with atopic dermatitis, nephrotic syndrome, insulin dependent diabetes mellitus, and Harada's disease. Since Th1- and Th2-mediated chronic inflammatory diseases are present in a single patient, a TGF-β/Smad regulatory signal was investigated. Enhanced expression of Smad7, an antagonist for TGF-β signaling, was confirmed, suggested that lack of regulatory signaling might contribute chronic inflammatory diseases including her disease status.
To evaluate the immunological development of preterm infants, we examined the serum cytokine levels and the expression of Th2 and Th1 chemokine receptors, CCR4 and CCR5, on day 0, 14, and 28 in preterm infants. Serum IL-4 levels exhibited an increase on day 14, but decreased to the initial level on day 28. The significant elevation of serum TGF-β_1 levels was confirmed on day 14 but decreased to the initial level on day 28. The RT-PCR confirmed the expression of CCR5-mRNA soon after birth, while there was no expression of CCR4-mRNA. Thereafter, the expression of CCR4-mRNA increased significantly and reached the level of CCR5-mRNA expression on day 28. Thus, CCR4^+CD4^+ cells were significantly increased from day 0 to 28, while CCR5^+CD4^+ cells were not analyzed by FACS. Increased IL-4 and TGF-β_1 synthesis as well as increased CCR4^+CD4^+ cells suggest that, under extra-maternal circumstances, there is a shift in bias toward Th2 responses even in preterm infants soon after delivery, while they may be capable of developing Th1 mediated responses soon after birth.
We, then, examined the effect of probiotics, Bifidobacterium breve, on the immunological system of preterm infants. Serum TGF-β_1 level was elevated on day 14 and remained elevated on day 28 in the B.breve group. Level of mRNA expression was enhanced for Smad3 and reduced for Smad7 (antagonistic Smad) after B.breve administration relative to levels in Controls on day 28. These results demonstrated that the administration of B.breve to preterm infants can up-regulate TGF-β1 signaling and may possibly be beneficial in attenuating inflammatory and allergic reactions in these infants. Less