Cost-minimization Analysis of IgPro20, a Subcutaneous Immunoglobulin, in Japanese Patients With Primary Immunodeficiency

AbstractPurposeIgPro20, Hizentra® an L-proline−stabilized 20% human subcutaneous immunoglobulin (SCIG), has been shown in a Phase III pivotal study to be well tolerated and efficacious in adult and pediatric Japanese patients with primary immunodeficiency. Economic aspects of SCIG treatment in comparison with previous intravenous immunoglobulin (IVIG) therapy were analyzed in this Phase III study in Japan.MethodsTwenty-four Japanese patients with primary immunodeficiency on IVIG treatment were switched to IgPro20 at an equivalent dose (full analysis set). The study consisted of a screening period, an IVIG treatment period with 3 planned infusions every 3 or 4 weeks, a 12-week SCIG wash-in and wash-out period, and a 12-week SCIG efficacy period. The difference in medical cost and productivity loss resulting from changes in hospital frequency between the SCIG and IVIG treatment was evaluated. Information about treatment cost was collected as part of the Life Quality Index questionnaire. In addition, productivity loss and hospital-related absenteeism were evaluated.FindingsLife Quality Index scores for all domains were higher with SCIG than with IVIG in this patient population. In the full analysis set, the mean (SD) Life Quality Index score of the Costs domain increased from 45.1 (26.34) at Week 1 (IVIG period) to 71.9 (18.52) at Week 24 (end of the SCIG efficacy period), representing a mean change of 26.74 and a large score improvement effect size (1.01). Median productivity loss was reduced by 60% from baseline to Weeks 12 and 24. This resulted in a reduction in costs of JPY 10,875 per patient per month at Weeks 12 and 24. Subcutaneous treatment with IgPro20 also reduced hospital-related absenteeism. The number of patients, parents, or guardians who were not absent from work or housework duties and had no reduction in working time increased from 4 (17.4%) at Week 1 to 9 (39.1%) at Week 24. Similar results were obtained in the per-protocol set (n = 21).ImplicationsSwitching from IVIG to SCIG reduced markedly productivity loss and hospital-related absenteeism. The reduction in hospital visit frequency due to the use of home-based IgG therapy enabled by the change in administration route is expected to produce an important pharmacoeconomic benefit in Japan. Study Code: ZLB06_002CR, ClinicalTrials.gov identifier: NCT01199705

EBV感染におけるT細胞の活性化と細胞死のメカニズムに関する研究

金沢大学医学部・附属病院本研究では,EBV初感染伝染性単核症(IM)を一つのモデルとして活性化に伴うT細胞の生理的細胞死の背景を検討,以下の成績が得られた.1)IM活性化T細胞は,健康者メモリーT細胞とCD45RO抗原やアポトーシス媒介性細胞表面分子のFas抗原発現は大差ないが,健康者メモリーT細胞と異なりIM活性化T細胞は試験官内で容易に著明なアポトーシスが起こす.T細胞のアポトーシス誘導には細胞の内的条件が重要と考えられ,T細胞のアポトーシスに関わる新たな細胞膜分子を同定する意味で,IM患者リンパ球を免疫原に単クローン抗体IMN3.1抗体を得た.2)アポトーシス抑制遺伝子産物のBcl-2は,健康者メモリーT細胞で強く発現するが,IM活性化T細胞では欠如する.Bcl-2発現の欠損ないし減弱は,顆粒球や単球のような半減期の短い白血球でも観察される.顆粒球や単球ではFas抗原の構成的発現がみられ,Bcl-2微弱発現に対応して顆粒球や単球が抗Fas抗体によりアポトーシスが促進された.これらの結果は,Bcl-2発現の強弱がFas/リガンドに対する細胞の感受性に一部関係すること,Fas/リガンド系が免疫反応のみならず炎症に関わる血液系細胞をも標的として作用すること示した.3)癌遺伝子産物のp53は細胞のアポトーシス誘導を促進する作用があり,点突然変異により生じた変異p53はその作用がなく,癌細胞の生成や不死化を導く.伝染性単核症活性化T細胞ではp53発現はないが,正常者リンパ球を放射線照射によりアポトーシス死を誘導した場合にp53発現が誘導される.放射線照射性アポトーシスに付随したp53発現が,CD4^+T細胞,CD8^+T細胞やB細胞でみられるのに反して,NK細胞やγδ型のT細胞抗原受容体をもつT細胞ではp53発現を伴わないことを示し,リンパ球のアポトーシス誘導に関わる細胞内条件としてのp53の役割には多様性のあることを明かにした.We employed EBV-induced infectious mononucleosis (IM) as a model of activated T cell death to elucidate cellular requirements for induction of T cell death by activation with viral infection. Obtained results are as follows :1)Both activated T cells in acute IM patients and memory T cells in normal persons express CD45RO and Fas antigen, which can mediate apoptosis. Unlike memory T cells, activated T cells in IM easily undergo apoptotic cell death after on a simple incubation in vitro. By immunizing mice with IM cells, we obtained a novel mouse monoclonal antibody, termed IMN3.1, which was marked to react with apoptosis-prone T cells. Molecular cloning of IMN3.1-identified antigen is in progress.2)Seemingly supporting their susceptibility to apoptosis, activated T cells in IM lacked expression of Bcl-2, which have a preventive function against apoptotic cell death. Low or absent expression of Bcl-2 was observed on granulocytes and monocytes, both of which have shorter life-spans. The important finding was that anti-Fas antibody could accelerated apoptotic cell death in granulocytes and monocytes. These observations suggest that the Fas antigen/ligand system may play a key role in resolution of inflammatory and immune responses.3)The mutation of the p53 oncogene is thought to lead to oncogenosis in human malignancies. Expression of p53 was not found in activated T cells in IM patients, although they were sucseptible to apoptosis. Ionizing irradiation could induce p53 expression on the whole population of peripheral blood lymphocytes, concomitant with marked apoptosis. However, we found a marked difference of lymphocyte subpopulations regarding p53 induction. Induction of p53 in CD4^+ T,CD8^+ T and B cells after irradiation was prominent. In contrast, neither TCR-gamma/delta^+ T cells nor NK cells showed identifiable levels of p53. The results suggest that radiation-induced lymphocytic apoptosis may be mediated by p53-dependent or-independent mechanisms.研究課題/領域番号:05454284, 研究期間(年度):1993 – 1994出典：研究課題「EBV感染におけるT細胞の活性化と細胞死のメカニズムに関する研究」課題番号05454284（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-05454284/054542841994kenkyu_seika_hokoku_gaiyo/）を加工して作

新生児NaiveT細胞の機能的特異性とMemoryT細胞への分化・成熟

金沢大学医学部附属病院平成2、3年の本研究で得られた結果の概要は以下の通りである。1.新生児T細胞はCD45RO陰性、CD45RA陽性のnaiveT細胞の形質及び機能的性状をもつが、強いサプレッサ-活性、刺激培養の結果CD45RA陽性からCD45RO陽性に形質転換したmemory様細胞にあっても、ヘルパ-活性はなお不良であるなど、成人naiveT細胞と異なる。2.Tγδ細胞の比率は加齢につれ増し、これは主としてCD45RO抗原陽性、抗原応答性をもつBB3陽性サブセットの増加による。が、末梢血の小集団のδTCSー1陽性細胞はCD45RO陰性のnaiveT細胞の性状を示す。3.抗CD2抗体によるmemory CD4^+T細胞の増殖反応は単球非存在下でも良好で、ILー2のみならずILー6を産生。他方、naive CD4^+T細胞の抗CD2抗体反応性は微弱であり、ILー6産生欠如が要因である。4.伝染性単核症では、CD8^+のみならずCD4^+T細胞がCD45RO抗原を強く発現、CD45RO発現は本症における両T細胞サブセットのEBウイルス感染による活性化状態を示唆する。5.抗原応答性というmemoryT細胞の本来の機能に関連して、末梢血memoryT細胞はILー2Rを構成する2つのサブユニット(α、β鎖)を発現。つまり、memory CD4^+T細胞はILー2Rα鎖を、memory CD8^+T細胞はILー2Rβ鎖を発現、ILー2Rサブユニット発現に対応して、memoryT細胞サブセットはILー2添加に強く反応、増殖する。6.新生児、小児末梢血CD4^+T細胞の中に、naive形質をもつが、ILー2Rα鎖を発現、memory細胞としてのサイトカイン遺伝子発現能を有する、naiveからmemoryT細胞へ分化途上の小細胞集団が存在する。7.全血法により、成熟新生児ではILー6産生能は成人に匹敵するが、未熟児のILー6産生能は未成熟であり、ことに細菌刺激に対するILー6産生が不良であることを明かとした。Naive and memory T cell populations can be discriminated by differential expression of CD45 isoforms. These studies were undertaken to elucidate some functional characteristics of neonatal inherently naive T cells and their maturation steps into memory T cells following increased antigenic exposure after birth. Obtained results are follow as.1) Although neonatal T cells share with adult naive T cells in terms to CD45RA expression, they have strong suppressor activity and less helper activity for B cell differentiation even after memory cells-like phenotypic changes by activation.2) BB3^+ subsets within T-gamma/delta^+ T cells, but not deltaTCS-1^+ cells, express CD45RO and have the ability to respond to the antigen.3) Naive CD4^+ T cells, unlike memory ones, are hyporesponsive to anti-CD2 stimulation, based on their inability to produce IL-6.4) Both CD4^+ and CD8^+ T cell populations express CD45RO as well as HLA-DR antigens, indicating strong stimulation with Epstein-Barr infection.5) Memory T cells express IL-2 receptor subunits (alpha or chains) and respond well to exogenous IL-2.6) A novel population of CD4^+ T cells with naive (CD45RA^+, CD45RO^-) phenotype expressing IL-2R alpha-chain, which express memory-like functions, are identifiable in the blood of newborns and young children. This population represents the cells at the transitional stage from naive to memory T cells.7) Full-term newborns can produce IL-6 in response to bacterial pathogens, but IL-6-producing capabilities of preterm babies are still immature.研究課題/領域番号:02454268, 研究期間(年度):1990 – 1991出典：研究課題「新生児NaiveT細胞の機能的特異性とMemoryT細胞への分化・成熟」課題番号02454268（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-02454268/024542681991kenkyu_seika_hokoku_gaiyo/）を加工して作

EBV感染B細胞の自己増殖因子と調節機構

金沢大学医学部附属病院ヒトB細胞はEpstein-Barrウイルス(EBV)の感染を受けると形質転換れ、半永久的に培養・維持可能なリンパ芽球様細胞に株化される。このようなEBV感染B細胞の増殖は自ら産生する増殖因子により調節されるものと考えられている。本研究では、EBV感染B細胞株における自己増殖因子としてのインタ-ロイキン6(IL-6)の意義を検討し、以下の結果が得られた。1.EBV感染B細胞のIL-6レセプタ-(R)の発現:阪大細胞工学センタ-にて開発された抗IL-6R単クロ-ン抗体(MT18)にて確認した。2.IL-6によるEBV感染B細胞の増殖促進:レコンビナントIL-6の添加によりEBV感染B細胞の増殖が促された。この増殖促進は細胞密度が低い場合により顕著であった。3.EBV感染B細胞のIL-6産生、各種細胞株の培養上清中にIL-6依存生マウス・ハイブリド-マの増殖を促す活性が見だされた。この増殖活性は抗IL-6抗体により中和されること、さらに抗IL-6抗体を用いたウエスタンブロット法により23kdを主としたIL-6蛋白が同定された。4.EBV感染B細胞のIL-6遺伝子発現ノ-ザンブロット法によりIL-6mRNA発現が確認されたが、エンドトキシンなどの刺激をうけた単球に比べて微弱であり、これは単球と異なりEBV感染B細胞のIL-6mRNA発現が個々の細胞間での違いを示唆した。このことは、RNAリボプロ-プを用いたin situ hybridization法により確認された。以上、EBV感染B細胞株が、1)IL-6Rを発現IL-6に反応し増殖すること、2)IL-6mRNAを発現すること、3)IL-6蛋白を産生することより、IL-6が自己増殖因子として機能することが示された。しかし、この細胞株にあって、IL-1もまた増殖促進効果発揮また産生することを観察していて、EBV感染B細胞の自己増殖因子の多様性が窺われた。研究課題/領域番号:01570518, 研究期間(年度):1989出典：研究課題「EBV感染B細胞の自己増殖因子と調節機構」課題番号01570518（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-01570518/）を加工して作

Recurrent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults

<p>Abstract</p> <p>Background</p> <p>X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK) gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood.</p> <p>Methods</p> <p>Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, <5 mg/dl). He had suffered from frequent pneumonia since age 25 but had no history of frequent infections in his childhood or in adolescence. Sequencing of the BTK cDNA obtained from an Epstein–Barr virus-transformed B lymphoblastoid cell line derived from the bone marrow of the patient was performed to confirm a genetic defect.</p> <p>Results</p> <p>Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT), resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain.</p> <p>Conclusions</p> <p>This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients.</p

Flow Cytometric Assessment of Neutrophil Oxidative Metabolism in Chronic Granulomatous Disease on Small Quantities of Whole Blood: Heterogeneity in Female Patients

A rapid and sensitive flow cytometric assay is presented for the quantitative estimation of the oxidative metabolic activity of individual polymorphonuclear leukocytes (PMN) on less than 100 td of whole blood. This procedure is a simplified version using whole blood of the method of Bass et al (J. Immunol. 130:1910, 1983) that estimated the metabolic burst activity of phorbol myristate acetate (PMA)-stimulated individual PMN as the intracellular generation of a fluorescence product by a flow cytometric assay. With this method, almost all the PMN from normal subjects responded to PMA as a single cell population generating bright intracellular fluorescence. PMN from a boy with chronic granulomatous disease (CGD), could not respond to PMA with any increase of their fluorescence intensity. His mother had two distinct PMN populations one functionally normal and the other defective, indicating a random lyonization in the carrier mother and the X-linked recessive mode of inheritance. In two female patients with CGD from unrelated families, their PMN responded to PMA, as a whole, with a minimal increase in the fluorescence intensity, but the metabolic defects in their PMN were not so complete as seen in a classical X-linked CGD boy. But, PMN from two female sibling patients from the other family responded to PMA as a single uniform cell population with a weak but definite fluorescence intensity. However, the genetic background of these female patients with CGD remains unclear, since PMN dysfunction could not be identified in their mothers with this method.This work was supported in part by a grant (No. 58440046) from the Ministry of Education of Japan

Differential expression of CD45RO (UCHL1) and its functional relevance in two subpopulations of circulating TCR-γ/δ+ lymphocytes

金沢大学大学院医学系研究科血管病態制御学We examined the developmental profile of TCR-γ/δ+ cells with respect to CD45RO expression. Although total TCR-γ/δ+ cells were negligible in the neonatal blood and increased with advancing age, most blood TCR-γ/δ+ cells markedly expressed CD45RO without a distinction of age, probably reflecting a different CD45RO expression of two subsets defined by BB3 and δTCS1 mAbs. The vast majority of BB3+ cells expressed CD45RO, whereas expression of CD45RO was virtually absent in the δTCS1+ population. Functional studies revealed that, while both TCR-γ/δ+ cell subsets showed CD3-mediated activation, only BB3+ (or TiγA+) cells, but not δTCS1+ cells, appeared to proliferate in response to PPD in PPD-reactive individuals. The results suggested that the CD45RO+ (BB3+ or TiγA+) subset among blood TCR-γ/δ+ cells may be mainly involved in the memory or primed component of the immune system responding to some foreign antigens

Antioxidant α-tocopherol ameliorates glycemic control of GK rats, a model of type 2 diabetes

AbstractWe have shown recently that oxidative stress by chronic hyperglycemia damages the pancreatic β-cells of GK rats, a model of non-obese type 2 diabetes, which may worsen diabetic condition and suggested the administration of antioxidants as a supportive therapy. To determine if natural antioxidant α-tocopherol (vitamin E) has beneficial effects on the glycemic control of type 2 diabetes, GK rats were fed a diet containing 0, 20 or 500 mg/kg diet α-tocopherol. Intraperitoneal glucose tolerance test revealed a significant increment of insulin secretion at 30 min and a significant decrement of blood glucose levels at 30 and 120 min after glucose loading in the GK rats fed with high α-tocopherol diet. The levels of glycated hemoglobin A1c, an indicator of glycemic control, were also reduced. Vitamin E supplementation clearly ameliorated diabetic control of GK rats, suggesting the importance of not only dietary supplementation of natural antioxidants but also other antioxidative intervention as a supportive therapy of type 2 diabetic patients

Increased production of intestinal immunoglobulins in Syntenin-1-deficient mice

AbstractSyntenin-1 is an intracellular PDZ protein that binds multiple proteins and regulates protein trafficking, cancer metastasis, exosome production, synaptic formation, and IL-5 signaling. However, the functions of Syntenin-1 have not yet been clearly characterized in detail, especially in vivo. In this study, we generated a Syntenin-1 knock out (KO) mouse strain and analyzed the role(s) of Syntenin-1 in IL-5 signaling, because the direct interaction of Syntenin-1 with the cytoplasmic domain of the IL-5 receptor α subunit and the regulation of IL-5 signaling by Syntenin-1 have been reported. Unexpectedly, the number of IL-5-responding cells was normal and the levels of fecal immunoglobulins were rather higher in the Syntenin-1 KO mice. We also found that IgA and IgM production of splenic B cells stimulated in vitro was increased in Syntenin-1 KO mice. In addition, we showed that a distribution of intestinal microbial flora was influenced in Syntenin-1 KO mice. Our data indicate that Syntenin-1 negatively regulates the intestinal immunoglobulin production and has a function to maintain the intestinal homeostasis in vivo. The analysis of Syntenin-1 KO mice may provide novel information on not only mucosal immunity but also other functions of Syntenin-1 such as cancer metastasis and neural development

Role of interleukin 6 for differential responsiveness of naive and memory CD4+ T cells in CD2-mediated activation

金沢大学大学院医学系研究科血管病態制御学The present study was undertaken to elucidate different requirements for CD2-mediated activation of naive (CD45RO-) and memory (CD45RO+) CD4+ T cells. A mitogenic combination of anti-CD2 (anti-T112 and anti-T113) mAbs could effectively induce the proliferation of memory CD4+ T cells even in the absence of monocytes. In marked contrast, naive CD4+ T cells did not disclose any proliferative responses to antiCD2 mAbs, when monocytes were absent in culture. This differential responsiveness of naive and memory CD4+ T cells appeared to be related largely to a difference in IL-6 - producing ability between both populations. IL-6 among monocyte-derived cytokines could correct unresponsiveness of naive CD4+ T cells to anti-CD2 stimulation. Unlike naive CD4+ T cells, memory CD4+ T cells produced IL-6 by themselves, with its mRNA being expressed on anti-CD2 stimulation. Anti-IL-6R mAb significantly inhibited proliferation of memory CD4+ T cells seen in the anti-CD2-stimulated cultures without monocytes, indicating the involvement of their own production of IL-6 in CD2-mediated activation. The results suggest an essential role of IL-6 for triggering of CD4+ T cells via the CD2 molecule