Application of cellular gene therapy for rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of joints resulting in progressive destruction of cartilage and bone. Recently, biological agents that suppress the activities of proinflammatory cytokines have shown efficacy as antirheumatic drugs, but require frequent administration, and often result in systemic immune suppression. Thus, gene transfer approaches are being developed as an alternative approach for targeted, more efficient, and sustained delivery of inhibitors of inflammatory cytokines as well as other therapeutic agents. Several gene therapy approaches have been established in preclinical animal models. In these models, autoantigen-specific T cells have been demonstrated to be ideal gene delivery vehicles for the local delivery of “immunoregulatory molecules” because these cells have tissue-specific homing and retention properties. Indeed, bioluminescence studies in an animal model of inflammatory arthritis revealed that these cells accumulated in and remained in inflamed joints. Transfer of genetically modified dendritic cells (DCs) may also have interesting effects. We conclude that modifying antigen-specific T cells or autologous DCs by retroviral transduction for local expression of regulatory proteins is a promising therapeutic strategy for the treatment of RA

Studies of the efficacy and safety of methotrexate at dosages over 8 mg/week using the IORRA cohort database

The maximum dosage of methotrexate (MTX) for treatment of rheumatoid arthritis (RA) formally approved in Japan is 8 mg/week. We intended to examine the efficacy and safety of MTX at dosages over 8 mg/week in Japanese rheumatoid arthritis patients using the large Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort database. Among 9,122 patients registered in the IORRA database from the October 2000 survey to the October 2007 survey, 5,201 patients who had been treated with MTX were selected. We attempted to overcome the drawbacks innate to nonrandomized studies by using longitudinal analyses and multifactorial logistic regression analyses. Cross-sectional analysis of data obtained from the October 2007 survey indicated that dosages of MTX higher than 8 mg/week were used in 27.5% of patients treated with MTX. Longitudinal analyses based on data from three consecutive phases showed that final Disease Activity Score-28 (DAS28) values were significantly lower [n = 260, mean difference 0.563, 95% confidence interval (CI) 0.438–0.688, P < 2.2 × 10−22, two-sided paired t test] than initial values when MTX was increased from 8 mg/week or lower to over 8 mg/week. In addition, longitudinal analyses based on data from two consecutive phases indicated decreases in DAS28 values of 0.26 ± 1.04 (n = 690, P = 6.78 × 10−11, two-sided paired t test) when MTX dosages were increased from 8 mg/week or lower to over 8 mg/week, compared with decreases of 0.07 ± 0.89 (n = 2,125, P = 0.000307) when the dosage was maintained at 8 mg/week. The decreases in DAS28 values were significantly larger in the former than the latter (P = 2.27 × 10−6, two-sided unpaired t test). Concerning safety of MTX at dosages over 8 mg/week, we performed logistic regression analysis in which the objective variable was the existence or nonexistence of self-reported side-effects and the explanatory variable was the MTX dosage in the former phase, with adjustments made for age, sex, body mass index (BMI), steroid administration, folic acid administration, concomitant pulmonary diseases, and renal dysfunction. The results indicated that MTX dosages over 8 mg/week did not have any association with either severe or severe + moderate side-effects. These data regarding both efficacy and safety of MTX at dosages over 8 mg/week in Japanese RA patients would provide the basis for use of the drug at dosages currently not formally approved by the Japanese government

Identification of novel mast cell genes by serial analysis of gene expression in cord blood-derived mast cells

AbstractThe gene expression profile of human cord blood-derived mast cells (MCs) was investigated using serial analysis of gene expression (SAGE). A total of 22 914 tags, representing 9181 unique transcripts, were sequenced. By selecting tags that were detected more frequently in MCs than in other tissues, genes characteristic of MCs were enriched. Reverse transcription-PCR and the high-density oligonucleotide array hybridization confirmed the validity of our SAGE result. About 70% of the selected genes were previously uncharacterized. Northern blot analysis showed the MC-specific expression of selected genes. This inventory will be useful to identify novel genes with important functions in MCs

SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis

AbstractSOCS3 (CIS3/JAB2) is an SH2-containing protein that binds to the activation loop of Janus kinases, inhibiting kinase activity, and thereby suppressing cytokine signaling. During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is Epo independent. Transgene-mediated expression blocks fetal erythropoiesis, resulting in embryonic lethality. SOCS3 deletion results in an embryonic lethality at 12–16 days associated with marked erythrocytosis. Moreover, the in vitro proliferative capacity of progenitors is greatly increased. SOCS3-deficient fetal liver stem cells can reconstitute hematopoiesis in lethally irradiated adults, indicating that its absence does not disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages in JAK3-deficient mice also occurs normally. The results demonstrate that SOCS3 is critical in negatively regulating fetal liver hematopoiesis

T-systems and Y-systems in integrable systems

The T and Y-systems are ubiquitous structures in classical and quantum integrable systems. They are difference equations having a variety of aspects related to commuting transfer matrices in solvable lattice models, q-characters of Kirillov-Reshetikhin modules of quantum affine algebras, cluster algebras with coefficients, periodicity conjectures of Zamolodchikov and others, dilogarithm identities in conformal field theory, difference analogue of L-operators in KP hierarchy, Stokes phenomena in 1d Schr\"odinger problem, AdS/CFT correspondence, Toda field equations on discrete space-time, Laplace sequence in discrete geometry, Fermionic character formulas and combinatorial completeness of Bethe ansatz, Q-system and ideal gas with exclusion statistics, analytic and thermodynamic Bethe ans\"atze, quantum transfer matrix method and so forth. This review article is a collection of short reviews on these topics which can be read more or less independently.Comment: 156 pages. Minor corrections including the last paragraph of sec.3.5, eqs.(4.1), (5.28), (9.37) and (13.54). The published version (JPA topical review) also needs these correction