本橋 新一郎

PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

UNLABELLED: Invariant natural killer T (iNKT) cells play an essential role in antitumor immunity by exerting cytotoxicity and producing massive amounts of cytokines. iNKT cells express invariant T-cell receptors (TCR) to recognize their cognate glycolipid antigens such as α-galactosylceramide (α-GalCer) presented on CD1d. We recently reported that iNKT cells recognize CD1d-negative leukemia cell line K562 in a TCR-dependent manner. However, it remains controversial how iNKT cells use TCRs to recognize and exhibit cytotoxic activity toward CD1d-negative tumors cells without CD1d restriction. Here, we report that iNKT cells exerted cytotoxicity toward K562 cells via a carried over anti-Vα24 TCR mAb from positive selection by magnetic bead sorting. We found that addition of the anti-Vα24Jα18 TCR mAb (6B11 mAb) rendered iNKT cells cytotoxic to K562 cells in an FcγRII (CD32)-dependent manner. Moreover, iNKT cells treated with 6B11 mAb became cytotoxic to other CD32+ cell lines (U937 and Daudi). In addition, iNKT cells treated with 6B11 mAb suppressed K562 cell growth in a murine xenograft model in vivo. These data suggest that anti-iNKT TCR mAb treatment of iNKT cells can be applied as a therapeutic strategy to treat CD32+ cancers such as leukemia, lymphoma, and lung cancer. SIGNIFICANCE: Our findings unveiled that iNKT cells recognize and kill CD1d-negative target tumors via the anti-iNKT TCR mAb bound to CD32 at the tumor site, thereby bridging iNKT cells and CD1d-negative tumors. These findings shed light on the therapeutic potential of anti-iNKT TCR mAbs in NKT cell-based immunotherapy to treat CD1d-negative CD32+ cancers.

Immune cell therapy has received attention in the clinical setting. However, current chimeric antigen receptor T cell therapies require individualized manufacturing based on patient cells, resulting in high costs and long processing times. Allogeneic immune cell therapy, which involves the use of immune cells from other donors, is emerging as a promising alternative that offers multiple advantages, including off-the-shelf availability, standardized manufacturing, and potentially stronger effector functions. Natural killer T (NKT) cells are a type of T cell that can be activated without being restricted by HLA, indicating their potential use in allogeneic cell immunotherapy. They exhibit cytotoxic activity against various cancer targets. However, their low frequency in blood limits their use in ex vivo amplification for treatment. This has led researchers to focus on allogeneic NKT cells as a potential treatment agent. In this study, we review the research on NKT cell-based immunotherapy and focus on the recent progress in clinical trials related to NKT cell-based immunotherapy worldwide. NKT cell-based therapy is not limited to specific cancer types and has been investigated in many ways worldwide over the past decade. Some clinical trials targeting NKT cells have shown promising results; however, the number of trials is low compared to those using T and natural killer cells. The use of allogeneic NKT cells may revolutionize the treatment of cancer and other diseases. However, further research and clinical trials are necessary to fully understand their efficacy, safety, and long-term benefits.

Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.

NKT細胞はHLA拘束性をもたず,直接的にがん細胞に対して抗腫瘍効果を発揮するほか,IFN-γを産生して周囲の細胞傷害活性を増強する.筆者らはNKT細胞を活性化する糖脂質抗原であるアルファガラクトシルセラミドを使用して,がん免疫治療の検討をおこなってきた.しかし,免疫能の低下したがん患者のNKT細胞の利用には,その数の少なさや機能の低下など問題がある.その問題点を解決するため,理化学研究所でiPS細胞技術を用いて作成したiPS-NKT細胞を用いて,他家移植としての免疫細胞療法を2020年に医師主導治験として開始した.開発には造腫瘍試験やGMPグレードの達成など,さまざまな非臨床試験をおこなうことでハードルを乗り越えてきた.(著者抄録)