Therapeutic Strategy for Rheumatoid Arthritis by Induction of Myeloid-Derived Suppressor Cells with High Suppressive Potential.

Combination treatment using fingolimod (FTY720), an immunomodulator, and a pathogenic antigen prevents the progression of glucose-6-phosphate isomerase (GPI)325-339-induced arthritis. In this study, we focused on myeloid-derived suppressor cells (MDSCs; CD11b+Gr-1+ cells) and investigated the effects of the combination treatment on these cells. DBA/1J mice with GPI325-339-induced arthritis were treated using FTY720 and/or GPI325-339 for five days. The expanded CD11b+Gr-1+ cell population and its inhibitory potential were examined. The percentage of CD369+CD11b+Gr-1+ cells effectively increased in the combination-treated mice. The inhibitory potential of CD369+CD11b+Gr-1+ cells was higher than that of cells not expressing CD369. Among bone marrow cells, the expression of CD369 in CD11b+Gr-1+ cells increased following stimulation with granulocyte-macrophage colony-stimulating factor, and the expression of CD11c increased accordingly. The increased CD11c expression indicated a decrease in the potential to suppress T cell proliferation based on the results of the suppression assay. The percentage of CD11c-CD369+ cells in CD11b+Gr-1+ cells that were induced by the combination treatment also increased, and these cells tended to have a higher capacity to inhibit T cell proliferation. In conclusion, the combination treatment using FTY720 and the pathogenic antigen effectively induces MDSC, which demonstrates a high potential for suppressing T cell proliferation in the lymph nodes, thereby establishing an immune-tolerant state.

Characterization of an Expanded IL-10-Producing-Suppressive T Cell Population Associated with Immune Tolerance.

An increase in the number of glucocorticoid-induced tumor necrosis factor receptor-family related gene/protein (GITR)+CD25- (or fork-head box protein 3: Foxp3-) CD4+ T cells, after treating a mouse model of arthritis with fingolimod (FTY720), and a pathogenic antigen may play a key role in the establishment of immune tolerance. In this study, we characterized a specific expanded T cell subset in this population. Mice with glucose-6-phosphate isomerase peptide (GPI325-339)-induced arthritis were treated with FTY720 (1 mg/kg, per os) and GPI325-339 (10 µg/mouse, intravenously) for five days, starting from the onset of symptoms. The expanded GITR+CD25- (or Foxp3-) CD4+ T cell population and its cytokine production were examined using flow cytometry. Furthermore, time-dependent changes in T-bet and/or early growth response gene 2 (Egr-2) expression in this T cell subset were examined. The density of T cell immunoreceptors with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)+CD39+ cell subset in the GITR+Foxp3-CD4+ T cell population was significantly increased only in the combined treatment group, compared to that in the untreated and single-treatment groups. In the TIGIT+CD39+GITR+Foxp3-CD4+ T cell population, T-bet+Egr-2+/T-bet+Egr-2- cell ratio increased in the latter stage of the treatment. Furthermore, this T cell subset, which corresponded to a T helper 1 (Th1) response, produced high levels of both interleukin (IL)-10 and interferon (IFN)-γ. In conclusion, expanded TIGIT+CD39+GITR+Foxp3-CD4+ T cells shifted from an effector Th1 to IL-10-producing-suppressor T cell phenotype, which may promote an immune-tolerant state.

[A Case of Prostate Cancer with High Levels of Prostate-Specific Antigen Undetected by Prostate Biopsy].

A 79 year-old-man visited our hospital with right back pain. Computed tomography suggested external iliac and para-aortic lymphadenopathy. Serum prostate specific antigen (PSA) increased to 335 ng/ml and prostate cancer was highly suspected. We performed transperineal prostate biopsies two times, but could not detect prostate carcinoma cells. Multiparametric magnetic resonance imaging (MRI) indicated no suspicious malignant lesions in the prostate. Laparoscopic biopsy of the right obturator lymph nodes was performed and histological examination, including immunohistochemical staining with PSA, confirmed lymphnode metastasis from prostate cancer. After endocrine therapy was started, serum PSA levels declined and lymph nodes shrunk. In cases of negative prostate biopsies despite high serum PSA levels, aggressive indication for biopsy of metastatic lesion and histological inspection is highly recommended.

Reimbursement pricing for new medical devices in Japan: Is the evaluation of innovation appropriate?

OBJECTIVES: In Japan, strong reimbursement pricing control measures for existing medical device products have rendered new medical device reimbursement pricing critical for manufacturers. Few studies have been conducted on this aspect; therefore, this paper (1) clarifies whether evaluation of innovation is appropriate or not and (2), if not, investigates its background. METHODS: In this research, 319 C1/C2 government decisions for new medical devices in the 10 years from April 2008 to March 2018 were analyzed. Evaluation of innovation was considered in terms of the reimbursement price, as well as the foreign average price ratio. RESULTS: Considering the degree of evaluation of innovation, the average premium rate for the similar function category comparison method was 10.2% during 2008 to 2010 (this means the newly set reimbursement price was 10.2% higher than that of corresponded exiting categories); it declined consistently thereafter, to 3.2% during 2016 to 2018. Moreover, evaluation of innovation by the foreign average price (FAP) ratio was 1.04 in 2008 to 2010, consistently decreasing to 0.88 in 2016 to 2018. The period from product approval to the non-Special Designated Treatment Material (non-STM) (a part of technical fee) price listing is much longer than that of the STM (own reimbursement price) listing. CONCLUSION: Several reasons were considered for the decline in innovation evaluation: (1) the lowering of the FAP upper limit ratio, (2) the possibility that there was not enough evidence at the time of price listing, (3) and the more rigorous standards to create a new separate functional category. However, some aspects were attributable to reimbursement system reform.