Mesenchymal stromal cells (MSCs) derived from adipose tissue have immunomodulatory effects, suggesting that they may have therapeutic potential for crescentic GN. Here, we systemically administered adipose-derived stromal cells (ASCs) in a rat model of anti-glomerular basement membrane (anti-GBM) disease and found that this treatment protected against renal injury and decreased proteinuria, crescent formation, and infiltration by glomerular leukocytes, including neutrophils, CD8 + T cells, and CD68 + macrophages. Interestingly, ASCs cultured under low-serum conditions (LASCs), but not bone marrow-derived MSCs (BM-MSCs), increased the number of immunoregulatory CD163 + macrophages in diseased glomeruli. Macrophages cocultured withASCs, but not with BM-MSCs, adopted an immunoregulatory phenotype. Notably, LASCs polarized macrophages into CD163 + immunoregulatory cells associated with IL-10 production more efficiently than ASCs cultured under high-serum conditions. Pharmaceutical ablation of PGE 2 production, blocking the EP 4 receptor, or neutralizing IL-6 in the coculture medium all significantly reversed this LASC-induced conversion of macrophages. Furthermore, pretreating LASCs with aspirin or cyclooxygenase-2 inhibitors impaired the ability of LASCs to ameliorate nephritogenic IgG-mediated renal injury. Taken together, these results suggest that LASCs exert renoprotective effects in anti-GBM GN by promoting the phenotypic conversion of macrophages to immunoregulatory cells, suggesting that LASC transfer may represent a therapeutic strategy for crescentic GN.

UL16-binding protein 2 (ULBP2) is one of the ligands for NKG2D (NKG2DL). ULBP2 expression is induced in transformed cells and is recognized by immune effector cells via the activating NKG2D immunoreceptor. Soluble forms of NKG2DL have been reported in the serum of patients with several types of cancer. The present study investigated the diagnostic and prognostic significance of serum-soluble ULBP2 (sULBP2) in lung cancer patients. We used flow cytometry to evaluate the surface expression of NKG2DL by various lung cancer cells, while sULBP2 was measured using our original ELISA. In addition, the immunological effect of sULBP2 on peripheral blood mononuclear cells (PBMC) was examined by the 51 Cr release assay. We found that ULBP2 was highly expressed and that the sULBP2 level was elevated in supernatants of cultured non-small-cell lung cancer (NSCLC) cells as well as in the serum of NSCLC patients. ULBP2 levels were especially high in squamous cell carcinoma (SQ) patients. Clinical stage IIIB and IV NSCLC patients with a sULBP2 level ! 8.7 pg/mL showed significantly shorter survival than patients with sULBP2 <8.7 pg/mL. In multivariate analysis, a sULBP2 level ! 8.7 pg/mL (hazard ratio [HR], 2.13; P = 0.038) and clinical stage IV (HR, 2.65; P = 0.019) were independent determinants of a poor outcome. As a possible mechanism, we demonstrated that sULBP2 directly suppresses the cytolytic activity of PBMC. In conclusion, ULBP2 is the most significant NKG2DL for lung cancer, and sULBP2 is useful in the diagnosis of SQ and as a prognostic indicator for patients with advanced NSCLC. (Cancer Sci 2012; 103: 1405-1413

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Background Statins are associated with muscle complaints ranging from myalgia to rhabdomyolysis. We studied the genetic contribution to the risk of the statin‐induced myopathy by comparing frequencies of mutant alleles of candidate genes in case and control groups. Methods We studied ten Japanese patients with abnormal increase in plasma creatinine kinase or severe muscle complaints, in comparison with control patients (n=26) who received statins but had no myopathy. DNA samples were genotyped for 152 SNPs/mutations in eight candidate genes selected from genes responsible for inherited rhabdomyolysis and those involved in the metabolism or transport of stains. Results No mutations or SNPs were detected in the genes of inherited rhabdomyolysis except for 128G>A in VLCAD, of which frequency was almost the same as that of the controls. For CYP3A4 and MRP2, one and two SNPs were detected respectively, but there was no significant difference between the groups. However, we found a significant association between OATP‐C*15 and pravastatin‐ or atorvastatin‐induced myopathy (P<0.01). An odds ratio of 11.3 (95%CI=1.6–80.3, P<0.05) was obtained when the possession of one or more OATP‐C*15 was compared. In addition, an association between 2677G>A in MDR1 and simvastatin‐ or atorvastatin‐incuced myopathy was also observed (P<0.05). Conclusions The results suggest that OATP‐C*15 is one of the susceptible factors for development of myopathy in patients taking pravastatin or atorvastatin. Clinical Pharmacology & Therapeutics (2005) 77, P21–P21; doi: