制御性T細胞は早期新生児期に著明に増加する

審査の要旨 , 内容の要旨広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Thymic Alterations in GM2 Gangliosidoses Model Mice

BACKGROUND: Sandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies. METHODOLOGY/PRINCIPAL FINDINGS: In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb(-/-) mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4(+)/CD8(+) T cells and a significantly increased number of CD4(+)/CD8(-) T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcRγ additionally disrupted Hexb(-/-) mice. CONCLUSIONS/SIGNIFICANCE: These results suggest that the FcRγ chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Repair process of the rat Achilles tendon after tenotomy

アキレス腱の修復能力と修復過程について詳細に調べるために,ラットのアキレス腱を切断して,後肢を固定せずに,最長6カ月後まで修復過程を観察した.3日後には腱の断端間(修復部)は,柔らかい結合組織で充たされ,1週後には断端が索状の結合組織で連絡していた.切断した腱の残存部には,線状の細い核を持ち細胞質が乏しい線維芽細胞(腱細胞)に混じって,核が楕円形で細胞質が豊富な線維芽細胞(腱芽細胞)が,3日後に少数出現し,1,2週後には増加したが,4週後以降は減少した.血管は,3日後には修復部の周辺に少数観察され,次第に増加して分布も広がり,2週後には修復部や切断された腱の内部にも多数観察されたが,4週後以降は減少した.修復部の線維芽細胞と膠原線維は,3日後には乏しかったが,1,2週後には増加し,4週後には多数が長軸に沿って配列して腱の断端と再生した腱との区別は困難だった.4週後以降には一部の再生腱で軟骨が見られ,3,6カ月後にはすべての再生腱で骨が観察された. 本実験で,アキレス腱の修復には腱内部と周囲結合組織の線維芽細胞が関わり,2週後に最も修復が盛んになることが示唆された.また,4週後ないし遅くとも6週後までに腱はおおむね修復されることが明らかになった.ラットとヒトでは異なるが,アキレス腱が高い修復能力を持ち比較的短期間に修復が進むことは,アキレス腱断裂に対する治療法を選択するうえで参考になり,リハビリテーションの開始時期を早めることができる可能性を示唆する.To investigate the regenerating ability and healing process of the rat Achilles tendon, the tendon was cut and its repair process was observed up to 6 months without hindlimb casting. The gap between severed tendons was filled with soft connective tissue at 3 days postoperatively and bridged by fibrous connective tissue at 1 week. By light microscopy, tendons showed a small number of tenoblasts with an ovoid nucleus and rich cytoplasm among tenocytes which contained a thin nucleus and scanty cytoplasm at 3 days. Tenoblasts increased in number at 1 and 2 weeks, and decreased at 4 weeks onward. Blood vessels were located at the peripheries of the regenerating portion at 3 days, increased in number and distribution throughout the regenerating portion and tendon at 2 weeks, and decreased at 4 weeks afterwards. Fibroblasts and collagen fibers at the regenerating portion were small in number at 3 days, increased at 1 and 2 weeks, and oriented along the long axis of tendon at 2 and 4 weeks. It was difficult to discriminate between severed tendon and the regenerated portion at 4 weeks. Cartilage was observed in some specimens at 4 weeks, and bones were found in all specimens at 3 and 6 months. These findings indicate that fibroblasts derived from both tendon and surrounding connective tissues are involved in repair, and that the repair process of tendon seems most active at 2 weeks after surgery. Regenerated tendons are considered to restore principal tendon structure at 4 or, at the latest, 6 weeks. Thus, Achilles tendon has an intrinsic ability to repair within several weeks, which provides a rationale for consideration of medical treatment and planning of early rehabilitation

Relative Dose Intensity of Induction-Phase Pazopanib Treatment of Soft Tissue Sarcoma: Its Relationship with Prognoses of Pazopanib Responders

The approved standard dose of pazopanib is 800 mg per day, but the appropriate dose of pazopanib to treat soft tissue sarcoma (STS) patients in real-world practice is controversial. Of 124 STS patients treated with pazopanib, we retrospectively analyzed the cases of STS patients who achieved progression-free survival at 12 weeks by pazopanib treatment as pazopanib responders, and we evaluated their relative dose intensity (RDI) in the initial 12 weeks (12W-RDI). We enrolled 78 STS patients in the analyses as pazopanib responders, and 54 patients of the 78 pazopanib responders (69%) were able to maintain 12W-RDI ≥80%. In landmark analyses, patients with 12W-RDI of 80% ≥80% had significantly longer progression-free survival compared to those with 12W-RDI <80% (30.7 weeks vs. 22.0 weeks, hazard ratio [HR]: 0.56 [95%CI: 0.33–0.94], p = 0.026). The most frequently observed reasons of treatment interruption and/or dose reduction of pazopanib during the initial 12 weeks were anorexia and liver function disorders. Liver toxicity was the adverse event most frequently observed in the 12W-RDI <80% patients throughout the treatment periods. Based on our results, it appears that maintaining as high a dose intensity as possible that is tolerable—at least during the initial 12 weeks—is likely to be the better option in pazopanib treatment for STS patients