He, Donggou
Wu, Lizhi
Kim, Hee Kyung
Li, Hui
Elmets, Craig A.
Xu, Hui
Hapten-induced contact hypersensitivity (CHS) in the skin is a delayed type cellular immune response that can be mediated by CD8(+) T cells that produce IFN-gamma or IL-17. However, mechanisms for these cytokines in the elicitation of CHS remain to be fully elucidated. In this study, we show that adoptive transfer of CHS with hapten-primed wild-type (WT) CD8(+) T cells is reduced in IFN-gamma R(-/-) or IL-17R(-/-) mice compared with WT controls. The infiltration of granulocytes and macrophages in the hapten challenged skin of IL-17R(-/-) recipients is significantly reduced whereas it is less affected in IFN-gamma R(-/-) recipients although CD8(+) T cell infiltration is inhibited in both recipients. In contrast, the activity of reactive oxidative species is significantly inhibited in IFN-gamma R(-/-) but is less affected in IL-17R(-/-) recipients. Further analysis reveals that the expression of chemokines and cytokines is differentially regulated in the hapten-challenged skin of IFN-gamma R(-/-) or IL-17R(-/-) recipients compared with WT controls. Interestingly, injection of rIL-17 in the skin induces inflammation with a high level of leukocyte infiltration whereas injection of IFN-gamma induces inflammation with a high level of reactive oxidative species. Moreover, neutralization of IL-17 in IFN-gamma R(-/-) or IFN-gamma in IL-17R(-/-) mice further suppresses the adoptive transfer of CHS by hapten-primed WT CD8(+) T cells. The study demonstrates that IFN-gamma and IL-17 mediate the elicitation of CHS by different mechanisms and that both cytokines are required for optimal responses. This outcome improves understanding of pathogenesis and provides new insights into therapeutic strategies for CHS. The Journal of Immunology, 2009, 183: 1463-1470.
A body of evidence indicates that expression of the programmed cell death 1 (PD-1) receptor by activated T cells plays an important role in the down-regulation of immune responses; however, the functions of its known ligands, B7-H1 (PD-L1) and B7-dendritic cell (DC; PD-L2), at the effector phase of immune responses are less clear. In the current study, we investigated the roles of B7-H1 in DC-mediated regulation of hapten-activated T cells and the delayed-type contact hypersensitivity response in primed animals. We found that the expression of B7-H1 and B7-DC was induced on activation of DC by hapten stimulation. Blockade of B7-H1, but not B7-DC, enhanced the activity of hapten-specific T cells. Interaction with a DC line that expresses high cell-surface levels of B7-H1 (B7-H1/DC) suppressed the proliferation of, and cytokine production by, activated T cells. In vivo administration of hapten-carrying B7H1/DC desensitized the response of sensitized animals to hapten challenge, and this desensitization was hapten-specific. These data indicate that B7-H1 expressed by DC mediates inhibitory signals for activated T cells and suppresses the elicitation of immune responses. The ability of B7-H1/DC to inhibit the function of preactivated T cells in vivo suggests novel strategies for the treatment of immune response-mediated disorders.
Kim, Hee Kyung
Laor, Tal
Horn, Paul S.
Wong, Brenda
Objective: To determine the feasibility of using T2 mapping as a quantitative method to longitudinally follow the disease activity in children with Duchenne muscular dystrophy (DMD) who are treated with steroids. Materials and Methods: Eleven boys with DMD (age range: 5-14 years) underwent evaluation with the clinical functional score (CFS), and conventional pelvic MRI and T2 mapping before and during steroid therapy. The gluteus muscle inflammation and fatty infiltration were evaluated on conventional MRI. The histograms and mean T2 relaxation times were obtained from the T2 maps. The CFS, the conventional MRI findings and the T2 values were compared before and during steroid therapy. Results: None of the patients showed interval change of their CFSs. On conventional MRI, none of the images showed muscle inflammation. During steroid treatment, two boys showed increased fatty infiltration on conventional MRI, and both had an increase of the mean T2 relaxation time (p < 0.05). The remaining nine boys had no increase in fatty infiltration. Of these, three showed an increased mean T2 relaxation time (p < 0.05), two showed no change and four showed a decreased mean T2 relaxation time (p < 0.05). Conclusion: T2 mapping is a feasible technique to evaluate the longitudinal muscle changes in those children who receive steroid therapy for DMD. The differences of the mean T2 relaxation time may reflect alterations in disease activity, and even when the conventional MRI and CFS remain stable.
Kim, Seung Tae
Kim, Hee Kyung
Lee, Jeeyun
Park, Se Hoon
Lim, Ho Yeong
Park, Young Suk
Kang, Won Ki
Park, Joon Oh
Purpose: We aimed to evaluate the effect of bevacizumab in metastatic CRC (colorectal cancer) regarding to microsatellite instability (MSI) and the sidedness of the primary tumor. Materials and Methods: A total of 140 CRC patients were retrospectively analyzed, who received bevacizumab-containing chemotherapy between April 2008 and January 2013. MSI status and Kirsten RSAS (KRAS) mutational status were available in all 140 patients, but BRAF (the gene for the B-type Raf kinase) mutational status was only available in 74 patients (52.9%). Results: MSI-high (MSI-H) was detected in 4.3% of analyzed patients. Characteristics of patients, with the exception of BRAF mutational status, were generally similar between those with right- (RC) and left-sided colon cancer (LC). Right-sided tumors were significantly associated with a BRAF mutation (p=3D0.025). In addition, patient characteristics with a microsatellite stable (MSS) tumor were not different from those with an MSI-H tumor. For all 140 patients, the most commonly used regimen with bevacizumab was capecitabine plus oxaliplain (XELOX), irrespective of treatment line, followed by 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI), 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), intravenous 5-fluorouracil (5-FU) and capecitabine plus irinotecan (XELIRI). There was no significant difference between the MSI-H and MSS groups in treatment efficacy, including response rate (RR) and disease control rate (DCR). There was also no difference in RR and DCR according to the sidedness of the primary tumor. No significant difference in progression-free survival (PFS) was observed between MSI-H and MSS groups (5.93 months vs. 7.37 months; p=3D0.801) or between LC and RC groups (7.37 months vs. 5.83 months; p=3D0.801). Conclusions: The effect of bevacizumab was not different between LC and RC and between MSS and the MSI-H tumors.