1: Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen
Science of the Month - September 2019
PNAS,
116 (29):14714-14723; 10.1073/pnas.1818907116 JUL 16 2019
Kohei Fujita, Svetoslav Chakarov, Tetsuro Kobayashi, Keiko Sakamoto, Benjamin Voisin, Kaibo Duan, Taneaki Nakagawa, Keisuke Horiuchi, Masayuki Amagai, Florent Ginhoux, and Keisuke Nagao
Dendritic cells (DCs) are immune cells that initiate acquired immunity by regulating T-cell function. They are mainly divided into conventional DC (cDC) 1 and 2, with the former primarily activating CD8 T cells and the latter activating CD4 T cells. cDC1 and cDC2 are derived from bone marrow progenitors and are dependent on the cytokine FLT3L, but the mechanisms by which their respective differentiation is maintained are not fully understood. The membrane-bound enzyme ADAM10 is essential for the differentiation of various cells, and its genetic deletion is embryonically lethal. The role of ADAM10 in DC differentiation has been unclear. In this study, we created DC-specific knockout mice (ADAM10ΔDC) and revealed that ADAM10 is essential for the differentiation and maintenance of cDC2 in the spleen. While T cells are known as a major source of FLT3L, we found that cDC2s express FLT3L and supply it in a cell-autonomous manner by shedding active FLT3L from the cell membrane via ADAM10. Abnormal differentiation of cDC2 was not observed in the skin, lungs, or their respective draining lymph nodes, suggesting that DC differentiation differs between organs and tissues. We hope that these findings will serve as a basis for therapeutic strategies in inflammation control, vaccines, and tumor immunity.
(Kohei Fujita, Department of Dentistry and Oral Surgery, '88)
2: Long-term effectiveness of oral second-generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta-analysis of direct head-to-head comparisons
Schizophrenia is a mental disorder characterized by positive symptoms such as hallucinations and delusions, and negative symptoms such as emotional blunting and avolition. The acute phase, when positive symptoms are active, is responsive to treatment, and in many cases, symptoms stabilize temporarily. However, repeated relapses, often due to medication non-adherence, can intensify negative symptoms and cognitive impairment, leading to a decline in social functioning. Therefore, maintenance phase treatment is crucial. Over 80 antipsychotic drugs have been developed to date, including about 30 second-generation antipsychotics developed primarily to reduce side effects. Although these are sometimes discussed collectively as new-generation drugs, they have been shown to have different effects and side effects, necessitating a consolidation of information.
This paper is a meta-analysis of randomized controlled trials comparing 13 representative second-generation antipsychotics for the maintenance treatment of schizophrenia. It examined 15 outcomes, including drug continuation rates and relapse rates, and the analysis included data from 59 trials and just under 46,000 individuals. While the detailed results are omitted here, the efficacy and side effect profiles varied significantly among the drugs. This reaffirms the need to select drugs appropriate for each individual patient's condition. Our team has been extracting, accumulating, and analyzing data for this research for over 10 years. This paper aims to deliver a vast amount of information in an easy-to-understand format for busy clinicians, and we hope it will be utilized by psychiatrists around the world.
(Toshiro Kishimoto, Department of Neuropsychiatry, '79)