Interleukin-4 Cellular Gene Therapy and Osteoprotegerin Decrease Inflammation-Associated Bone Resorption in Collagen-Induced Arthritis

To evaluate the respective action of IL-4, an anti-inflammatory cytokine, and OPG, an inhibitor of bone resorption, on the inflammatory process and the associated bone resorption in collagen-induced arthritis (CIA). After CIA induction, DBA/1 mice were treated with OPG or with IL-4 DBA/1 transfected fibroblasts or both OPG + IL-4. CIA significantly improved in IL-4 groups. OPG had no effect on arthritis clinical scores but histologic scores were reduced in OPG, IL-4, and OPG + IL-4 groups vs. nontreated CIA mice. OPG increased significantly BMD and decreased by 45% D-pyridinolin levels. Moreover association of IL-4 and OPG exerted an additive effect of BMD and resorption marker (-68%). Production of IFN-gamma in the supernatants of spleen cells was reduced in IL-4 treated mice. OPG had a moderate effect on IFN-gamma, but potentiated the inhibitory effect of IL-4. OPG and IL-4 prevent bone loss in CIA-mice model and could have additive effects on IFN-gamma secretion.     

Quantitative Studies on the Proliferation and Differentiation of Antibody-Forming Cells in Lymph

The transforming cells that appear in the efferent lymph from a lymph node responding to an antigenic challenge are part of a heterogeneous population which changes as the response progresses. Some cells containing small amounts of antibody appear early in the response and these cells have the cytologic characteristics of small and medium lymphocytes. They are, however, actively synthesizing DNA. As the immune response progresses, the antibody content of the cells in lymph increases. When incubated in vitro, cells in lymph appearing late in the response released 20 times more antibody per cell than those appearing early in the response. Large blast cells are the predominant antibody-forming cell in lymph. At the peak of a secondary challenge with horseradish peroxidase, up to 40% of the cells in lymph may be blast cells and, of these, two-thirds may contain specific antibody. It seems probable that most if not all of the blast cells responding to the antigen are involved directly in antibody and DNA synthesis. Cells in all stages of ultrastructural differentiation, and even mature plasma cells, were found to incorporate ³H-thymidine into their nuclear DNA.     

Activation of invariant NK T cells protects against experimental rheumatoid arthritis by an IL-10-dependent pathway

Invariant natural killer T (iNKT) cells are a unique lymphocyte subtype implicated in the regulation of autoimmunity and a good source of protective Th2 cytokines. Agonist alpha-galactosylceramide (alpha-GalCer) of iNKT cells exert a therapeutical effect in type 1 diabetes. We investigated whether iNKT activation with alpha-GalCer was protective in collagen-induced arthritis (CIA) in DBA/1 mice, a standard model of rheumatoid arthritis. Here, we have shown that in vivo iNKT cell function was altered in DBA/1 mice since stimulation with alpha-GalCer led to decreased IL-4 and IFN-gamma levels in sera, as compared with C57BL/6 mice. alpha-GalCer induced a clear-cut diminution of clinical and histological arthritides. An anti-IL-10 receptor antibody abrogated the protective effect of alpha-GalCer, suggesting a key role for IL-10 in the protection against CIA by activated iNKT cells. Confirming these data, disease protection conferred by alpha-GalCer correlated with the ability of LN CD4+ cells to secrete larger amounts of IL-10. These findings suggest that in CIA susceptibility to autoimmunity is associated with dysfunctions of iNKT cells. Our demonstration that iNKT cell activation by alpha-GalCer remains efficient in CIA-prone DBA/1 mice to provide protective IL-10 suggests that this could be used therapeutically to treat autoimmune arthritis.     

Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case.

BACKGROUND: The potential of hyperechogenic fetal bowel to act as a hallmark for prenatal cystic fibrosis screening in the general population is controversial. METHODS: Our goal was to evaluate the incidence of cystic fibrosis in 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. The diagnosis of cystic fibrosis was based on prenatal screening for the eight mutations most frequently observed in France (deltaF508, deltaI507, 1717-1G-->A, G542X, G551D, R553X, W1282X, N1303K) and at postnatal follow up. RESULTS: The overall incidence of cystic fibrosis was 7/209 (3.3%) which is 84 times the estimated risk of CF in the general population (112500). Of these seven cases, six were diagnosed prenatally based on DNA analysis (deltaF508/deltaF508, n=5; deltaF508/G542X, n=1). One case in which only one mutation had been recognised was diagnosed clinically after birth (deltaF508/unidentified mutation). Of the seven cases, none was diagnosed at 16-19 weeks, four at 16-24 weeks, and three after this. The incidence of heterozygous fetuses (15/209, 7%) was not significantly higher than the 5% expected in the general population. The mutations involved in these heterozygous cases were deltaF508 (n=13), G542X (n=1), and G551D (n=1). CONCLUSIONS: Screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography. This underlines the need to review genetic counselling in this situation where the fetus is the index case for a genetic disease.     

Calculation of direct standard costs in the evaluation of new technologies: application to the treatment of acute myeloblastic leukemias

Financial incidence of new technology can be approached through the utilization of "direct standard cost". This method allows actualization of prices and permits the integration of new procedures. It is applied to acute non lymphoblastic leukemia.     

Treatment of Gorlin syndrome (nevoid basal cell carcinoma syndrome) with methylaminolevulinate photodynamic therapy in seven patients,including two children: interest of tumescent anesthesia for pain control in children

Objective To report our experience of methylaminolevulinate photodynamic therapy (MAL‐PDT) in the treatment of multiple basal cell carcinoma (BCC) in adults and children with Gorlin syndrome (GS). Design Report of cases. Setting University of Montpellier, Department of Dermatology. Patients Seven Gorlin patients (41 superficial or nodular carcinomas), including two children. Interventions Prior superficial curettage for superficial BBCs or debulking for nodular BCCs was systematically performed. Methylaminolevulinic acid was applied topically to lesions 3 h before illumination with 635 nm red light for 10 min (37 J/cm²). To prevent treatment discomfort, analgesics and/or cooling by sprayed water were most often provided, and occasionally 1% lidocaine local anesthesia. A ropivacaine‐lidocaine tumescent anesthesia was performed on the youngest patient. Main outcome measures The initial response rate; tolerance, particularly in children; cosmetic outcome. Results Overall clearance in patients was 60% after one session of MAL‐PDT and 78% after three sessions. Resolution of the lesions was accompanied by an excellent cosmetic outcome in all patients. Treatments were well tolerated in adults with moderate pain sensation during illumination. In a child, tumescent anesthesia assured excellent tolerance in all treatment stages. Conclusion We add our experience to previous articles that consider PDT as an interesting option in the treatment of GS. To our knowledge, this study is the first report of MAL‐PDT in GS children using tumescent anesthesia. Specific guidelines for adult and pediatric patients remain to be established.     

Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.