Objective. Sphingosine 1-phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P 1 signaling in the pathogenesis of rheumatoid arthritis (RA).Methods. We examined S1P 1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting. We also performed S1P 1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST-1 assay, and its effects on tumor necrosis factor ␣ (TNF␣)-or interleukin
Increased T Reg frequencies in peripheral blood were related to low peripheral blood CD4 T-cell counts and polarization toward Th2 immune responses in HIV-infected patients.
Although embryonic stem (ES) cell-like induced pluripotent stem (iPS) cells have potential therapeutic applications in humans, they are also useful for creating genetically modified human disease models in nonhuman primates. In this study, we generated common marmoset iPS cells from fetal liver cells via the retrovirus-mediated introduction of six human transcription factors: Oct-3/4, Sox2, Klf4, c-Myc, Nanog, and Lin28. Four to five weeks after introduction, several colonies resembling marmoset ES cells were observed and picked for further expansion in ES cell medium. Eight cell lines were established, and validation analyses of the marmoset iPS cells followed. We detected the expression of ES cell-specific surface markers. Reverse transcription-PCR showed that these iPS cells expressed endogenous Oct-3/4, Sox2, Klf4, c-Myc, Nanog and Lin28 genes, whereas all of the transgenes were silenced. Karyotype analysis showed that two of three iPS cell lines retained a normal karyotype after a 2-month culture. Both embryoid body and teratoma formation showed that marmoset iPS cells had the developmental potential to give rise to differentiated derivatives of all three primary germ layers. In summary, we generated marmoset iPS cells via the transduction of six transcription factors; this provides a powerful preclinical model for studies in regenerative medicine.
Summary. Angiogenesis is a crucial process in the progression of multiple myeloma (MM). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are multifunctional cytokines that potently stimulate angiogenesis including tumour neovascularization. Serum levels of VEGF and HGF were measured in 52 patients with MM by enzyme‐linked immunosorbent assay (ELISA). Serum levels of VEGF and HGF were elevated in MM patients compared with healthy controls (VEGF: mean 0·31 ng/ml and 0·08 ng/ml respectively, P < 0·01; HGF: mean 2·17 ng/ml and 0·45 ng/ml, respectively, P < 0·001). In serial samples taken after chemotherapy, serum VEGF and HGF levels were correlated with M‐protein levels. Serum levels of VEGF were higher in patients with extramedullary plasmacytomas than in patients without them (P < 0·05). They were also significantly higher in a group of patients who showed poor response to chemotherapy (P < 0·01). Serum levels of HGF were higher in patients with complications such as anaemia, hypercalcaemia and amyloidosis than in patients without these complications (P < 0·01, P < 0·05, P < 0·05 respectively). Both serum VEGF and HGF levels were significant predictors of mortality (P = 0·01, P = 0·02, respectively, log‐rank test). The present study demonstrated that serum levels of VEGF and HGF are significantly elevated and dependent on the severity of MM, suggesting that measurement of VEGF and HGF may be useful for assessing disease progression and for predicting the response to chemotherapy in MM patients.
We report a 15-year-old Japanese girl with severe systemic Weber-Christian disease (WCD) who presented with acute onset of high fever associated with tender subcutaneous nodules. Laboratory tests showed an elevated serum concentration of lactate dehydrogenase (LDH), leukopenia, and coagulation abnormalities. The anti-nuclear and anti-DNAantibodies were negative, and the serum pancreatic enzymesand alpha 1-antitrypsin levels were normal. Pulse steroid therapy was not effective, and eventually cerebellar hemorrhage occurred. After initiation of oral cyclosporin A (CyA) therapy, fever came down and her clinical condition improved markedly. Extremely high serum concentrations of interferon-gamma (IFN-y) and soluble interleukin-2 receptor (SIL-2R) in this patient returned to normal with CyA therapy. These findings suggest that T-cell immuneresponses are involved in the pathogenesis ofWCD, and that CyAis effective against the disease via suppression of T-cell reactions.
Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT). When GVHD is controlled by T-cell-depleted grafts or immunosuppressants, BM transplant recipients often suffer from an increased rate of leukemic relapse and impaired reconstitution of immunity. Using a mouse BMT model, we investigated the effects of hepatocyte growth factor (HGF) gene transfection on the severity of GVHD, the graft-versus-leukemia effect, and the reconstitution of T cells after BMT. After HGF gene transfer, acute GVHD was reduced, while mature donor T-cell responses to host antigens were preserved, resulting in a significant improvement of leukemia-free survival. HGF gene transfer promoted regeneration of bone marrowderived T cells and the responsiveness of these cells to alloantigens. Furthermore, HGF preserved the thymocyte phenotype and thymic stromal architecture in mice with GVHD. This suggested that HGF exerts a potent protective effect on the thymus, which in turn promotes reconstitution of bone marrow-derived T cells after allogeneic BMT. These results indicate that HGF gene transfection can reduce acute GVHD preserving the graftversus-leukemia effect, while promoting thymic-dependent T-cell reconstitution after allogeneic BMT.
IntroductionDonor T cells contaminating hematopoietic stem cells (HSCs) contribute both positively and negatively to the outcome of allogeneic bone marrow transplantation (BMT). Donor T cells play a positive role by facilitating engraftment of the allograft and contributing to antitumor immunity, but are also primarily responsible for graft-versus-host disease (GVHD). [1][2][3][4][5][6][7][8] To date, approaches to control acute GVHD have employed methods that attempt to remove or suppress the function of all T cells regardless of their immunologic specificity. Although the administration of immunosuppressants achieves an acceptable rate of engraftment with reasonable control of GVHD, these drugs induce a generalized decrease of immunocompetence with its attendant morbidity and mortality. Immunosuppressants also often have significant acute and chronic adverse effects on organ function. 9,10 Ex vivo T-cell depletion of donor HSCs appears to be more effective at ameliorating or even eliminating GVHD, but this approach is complicated by an unacceptable incidence of graft failure, profound and protracted immunodeficiency, and loss of antitumor immunity. [5][6][7][8] New methods of reducing toxicity while retaining the antitumor potential of BMT, including donor lymphocyte infusion and nonmyeloablative conditioning, have led to a significant decrease in the occurrence of acute GVHD. Unfortunately, along with the decline of acute GVHD, chronic GVHD has begun to emerge as a major complication of BMT. 11 An important cause of impaired reconstitution of immunity after allogeneic BMT is the thymic damage initiated by hostreactive donor T cells, because reconstitution of T-cell immunity depends on the differentiation of donor HSCs in the thymus. 12,13 It is likely tha...
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