Interleukin-10 (IL-10) is an ideal candidate cytokine for AdCMVhIL-10 induced a prolongation of median survival suppressing the alloimmune response in transplantation.to more than 87 days, with two of five transduced grafts To determine whether genetic modulation of the hepatic showing more than 100 days of ongoing survival, when graft with IL-10 could prolong survival following orthotopic compared with 11 days for grafts transduced with a control liver transplantation, we constructed a replication-deficient adenovirus vector carrying the E. coli -galactosidase adenovirus vector expressing human IL-10 (AdCMVhILgene (P = 0.0021) and 11 days for untreated grafts 10). Intraportal injection of this vector into a donor rat 24-(P = 0.0021). Pathological findings occurring in the 48 h before grafting resulted in efficient release of IL-10AdCMVhIL-10-transduced hepatic grafts revealed no eviinto the circulation of a recipient rat after transplantation.dence of progressive rejection reaction resulting in graft Moreover, levels of hIL-10 from the suprahepatic venafailure. These results demonstrate that hepatic grafts cava were significantly (1.48-fold) higher than those from modulated by IL-10 gene transfer make local and effective the infrahepatic vena cava (P = 0.013), indicating local ILimmunosuppression feasible in the transplantation setting. 10 production within the transduced hepatic graft.
We developed concise, accurate prediction models of the in vitro activity for 8 anticancer drugs (5-FU, CDDP, MMC, DOX, CPT-11, SN-38, TXL and TXT), along with individual clinical responses to 5-FU using expression data of 12 genes. We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes. The correlation significance of each was confirmed using expression data quantified by real-time RT-PCR, and finally 12 genes (ABCB1, ABCG2, CYP2C8, CYP3A4, DPYD, GSTP1, MGMT, NQO1, POR, TOP2A, TUBB and TYMS) were selected as more reliable predictors of drug response. Using multiple regression analysis, we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order, to predict the efficacy of the drugs by referring to the value of Akaike's information criterion for each sample. These formulae appeared to accurately predict the in vitro efficacy of the drugs. For the first clinical application model, we fixed prediction formulae for individual clinical response to 5-FU in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival, time to treatment failure and tumor growth. None of the 12 selected genes alone could predict such clinical responses.
The prolongation of survival of IL-10 cDNA transferred liver allografts might be due to inhibition of the early phase of alloimmune-response by over expression of IL-10, despite the expression of IL-2 and interferon-gamma.
Both CD4 and CD8 T cells play crucial roles in immune responses in transplantation. Immunosuppressive drugs, such as FK506 and cyclosporin A, block the priming of alloreactive CD4 T(h) cells and the subsequent induction of allospecific CD8 cytotoxic effector T cells and inhibit allograft rejection. However, the desire to minimize chronic complications that may arise from the use of immunosuppressive agents drives the search for additional strategies for immunosuppression of allograft rejection. In this study, CD4 or CD8 T cells into which the IL-10 gene is introduced using an adenovirus vector containing human IL-10 (hIL-10) cDNA (Ad-hIL-10) and into mouse T cells transgenic for the Coxsackie virus and adenovirus receptor form a model system to study the effect of administration of IL-10-secreting T cells on the survival of the allogenic skin grafts. Ad-hIL-10-infected CD4 and CD8 T cells secreted a large amount of hIL-10 for 3-4 days in culture in vitro. Ad-hIL-10-infected CD4 T cells administered in vivo could be detected in the spleen for 7 days post-transfer. Significantly prolonged survival of grafts was observed in animals that received either Ad-hIL-10-infected activated CD4 T cells or T(h)2-skewed CD4 T cells as compared with controls. Furthermore, substantial enhancement of the effect was observed in B6.C-H2(bm1)/ByJ transplants. Thus, a direct manipulation of T cells through the introduction of the immunosuppressive cytokine gene IL-10 may be a novel strategy for the control of allograft rejection.
A 69-year-old man developed obstructive jaundice 6 months after laparoscopic cholecystectomy. Endoscopic retrograde cholangiography suggested a common bile duct (CD) stone. A second operation was performed, and this revealed a CBD stone with an endoclip as a nidus. Since laparoscopic surgery has become a very common procedure, endoclips are used more frequently. Therefore, careful surveillance and strict follow-up are stressed to avoid CBD stone and various other complications caused by endoclips.
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