41 research outputs found
VĪ±14 NK T cellātriggered IFN-Ī³ production by Gr-1+CD11b+ cells mediates early graft loss of syngeneic transplanted islets
Pancreatic islet transplantation is a highly promising approach for the treatment of insulin-dependent diabetes mellitus. However, the procedure remains experimental for several reasons, including its low efficiency caused by the early graft loss of transplanted islets. We demonstrate that Gr-1+CD11b+ cells generated by transplantation and their IFN-Ī³ production triggered by VĪ±14 NKT cells are an essential component and a major cause of early graft loss of pancreatic islet transplants. Gr-1+CD11b+ cells from VĪ±14 NKT cellādeficient (JĪ±281ā/ā) mice failed to produce IFN-Ī³, resulting in efficient islet graft acceptance. Early graft loss was successfully prevented through the repeated administration of Ī±-galactosylceramide, a specific ligand for VĪ±14 NKT cells, resulting in dramatically reduced IFN-Ī³ production by Gr-1+CD11b+ cells, as well as VĪ±14 NKT cells. Our study elucidates, for the first time, the crucial role of Gr-1+CD11b+ cells and the IFN-Ī³ they produce in islet graft rejection and suggests a novel approach to improving transplantation efficiency through the modulation of VĪ±14 NKT cell function
Clinical significance of side population in ovarian cancer cells
Recently, accumulating evidence has suggested that tumors, including ovarian cancer, are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. The emergence of drug resistance is one of the most difficult problems in the treatment of ovarian cancer, which has been explained recently by the potential of CSCs to have superior resistance against anti-cancer drugs than conventional cancer cells. In this study, we expanded this line of study to examine whether this phenomenon is also observed in clinical specimens of ovarian cancer cells. In total we could analyze 28 samples out of 60 obtained from ovarian cancer patients. The clinical samples were subjected to testing of the expression of side population (SP) as a CSC marker, and according to the presence of SP (SP+) or absence of SP (SPā), clinicopathological significances were analyzed. Although there was no statistical significance, there were more SP+s in recurrent cases as well as in ascitic and peritoneal dissemination than in primary tumor of the ovary. There was no correlation between SP status and FIGO staging. In 19 cases of those who could be followed more than 6Ā months from initial therapy, there were 8 cases of recurrence or death from disease, and all of these were SP+. On the other hand, in 11 cases of disease-free survivors, 6 were SP+. There was a significant difference in prognosis between SP+ and SPā (pĀ =Ā 0.017). Although this study was limited, it revealed that SP could be contained more in recurrent or metastatic tumors than in primary tumors, and also that the presence of SP could be a risk factor of recurrence in ovarian cancer. Therefore, a novel therapeutic strategy targeting SP could improve the prognosis of ovarian cancer
Dysfunction of T cell receptor AV24AJ18+, BV11+ double-negative regulatory natural killer T cells in autoimmune diseases
Mouse models of human INAD by Pla2g6 deficiency
Infantile neuroaxonal dystrophy (INAD) is a
severe neurodegenerative disease characterized by its
early onset. PLA2G6, which encodes a phospholipase
A2, iPLA2Ć, has been identified as a causative gene of
INAD. iPLA2Ć has been shown to be involved in various
physiological and pathological processes, including
immunity, cell death, and cell membrane homeostasis.
Gene targeted mice with a null mutation of Pla2g6
develop the INAD phenotype as late as approximately 1
to 2 years after birth. Recently, another INAD mouse
model, Pla2g6-INAD mice line, has been established.
The Pla2g6-INAD mice bear a point mutation in the
ankyrin repeat domain of Pla2g6 generated by N-ethylN-nitrosourea
mutagenesis. These mutant mice develop
severe motor dysfunction and hematopoietic abnormality
in a manner following Mendelian law. The mice showed
the abnormal gait and poor performance as early as 7 to
8 weeks of age, detected by hanging grip test.
Neuropathological examination revealed widespread
formation of spheroids containing tubulovesicular
membranes similar to human INAD. Molecular and
biochemical analysis revealed that the mutant mice
expressed Pla2g6 mRNA and protein, but the mutated
Pla2g6 protein had no glycerophospholipid-catalyzing
enzyme activity. When analyzed the offspring which
bear Pla2g6 knockout allele and Pla2g6-INAD allele,
abnormal gait appeared slightly later than Pla2g6-INAD
homozygotes but with earlier onset than the Pla2g6
knockout homozygotes. This result suggests that mutant
Pla2g6 protein contributes to early onset of INAD
symptoms in the absence of intact Pla2g6 protein. The
analysis of various INAD mouse models may help to
understand the pathogenesis of neurodegenerative
diseases, including INAD
Suppression of IgE antibody responses by NKT cellsāmechanisms of NKT cell-mediated regulatory function
Author Correction:Runx/CbfĪ² complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation (Nature Communications, (2019), 10, 1, (447), 10.1038/s41467-019-08365-0)
The original version of this Article contained an error in the author affiliations.Ā Affiliation 5 incorrectly read āLaboratory for Prediction of Cell Systems Dynamics, RIKEN Center for Biosystems Dynamics Research (BDR), Suite, Hyogo 565-0874, Japan.āĀ This has now been corrected in both the PDF and HTML versions of the Article
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Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity.
CCL5 is a unique chemokine with distinct stage and cell-type specificities for regulating inflammation, but how these specificities are achieved and how CCL5 modulates immune responses is not well understood. Here we identify two stage-specific enhancers: the proximal enhancer mediates the constitutive CCL5 expression during the steady state, while the distal enhancer located 1.35āMb from the promoter induces CCL5 expression in activated cells. Both enhancers are antagonized by RUNX/CBFĪ² complexes, and SATB1 further mediates the long-distance interaction of the distal enhancer with the promoter. Deletion of the proximal enhancer decreases CCL5 expression and augments the cytotoxic activity of tissue-resident T and NK cells, which coincides with reduced melanoma metastasis in mouse models. By contrast, increased CCL5 expression resulting from RUNX3 mutation is associated with more tumor metastasis in the lung. Collectively, our results suggest that RUNX3-mediated CCL5 repression is critical for modulating anti-tumor immunity