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关键词： BK virus   Hemorrhagic Cystitis   Mycophenolate Mofetil   Post-transplant Cyclophosphamide   Sirolimus  

摘要： BACKGROUND:BK hemorrhagic cystitis (BK-HC) is a common complication following hematopoietic stem cell transplantation (HSCT), particularly when posttransplant cyclophosphamide (PTCy) is used as graft-versus-host disease (GVHD) prophylaxis. However, comparative studies of BK-HC incidence in matched sibling donors (MSD) and unrelated donors (MUD) often include small haploidentical (HAPLO) donor cohorts and usually lack detailed information on disease evolution, coinfections, management and impact on outcomes. OBJECTIVES:This study aimed to evaluate the incidence, risk factors, and outcomes in patients with hematologic malignancies undergoing HSCT from MSD, MUD, HAPLO donors using PTCy as GVHD prophylaxis. Furthermore, we analyze risk factors for BK-HC and its impact on renal function and transplant outcomes. STUDY DESIGN:Retrospective analysis of BK-HC episodes in patients undergoing HSCT from 167 MSD, 129 MUD and 103 HAPLO from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus and mycophenolate mofetil was given, irrespective of donor type or conditioning intensity, and mesna was used prophylactically with PTCy. RESULTS:The incidence of grade 2-4 BK-HC was 23%, with a higher prevalence of grades 3-4 in HAPLO (19%), compared to MSD (11%) and MUD (8%) recipients (p=0.02). BK-HC was diagnosed at a median of 29 days after HSCT and symptoms persisted for a median of 27 days, with longer duration in grade 3-4 cases (p=0.02). Additionally, higher grades were associated with a greater transfusion burden (p<0.001). JC virus coinfection was detected in 24%, and cytomegalovirus viruria in 17%, which was not treated. BK antiviral treatment beyond supportive care was used in only two patients, while antibacterial treatments were prescribed in 28% for urinary symptoms and in 57% for concomitant infections in other sites. Younger age and HAPLO donors were significant risk factors for developing higher-grade BK-HC. No interaction was seen between age and conditioni

关键词： Human artificial chromosome   Rejuvenated mesenchymal stem cells   Ulcerative colitis  

摘要： Ulcerative colitis (UC) is an incurable intestinal disease, with current treatments mainly focused on inflammation control and, in severe cases, surgical resection. Recent studies have highlighted the need for new therapies that promote tissue regeneration. R-spondin-1 (RSPO1) and interleukin-22 (IL-22) have shown anti-inflammatory and regenerative effects in UC models, but have short half-lives and poor targeting abilities. Another therapeutic tool, mesenchymal stem cells (MSCs), offer promising migratory and homing capabilities; however, the preparation of homogeneous therapeutic MSCs at sufficient levels in vitro is challenging. Therefore, we developed a novel line of MSCs (HAC-MSC) with significant therapeutic effects in dextran sodium sulfate (DSS)-induced colitis mice. Construction of HAC-MSC involved a two-part strategy: 1) establishment of a non-integrating human artificial chromosome (HAC) vector carrying therapeutic genes encoding IL22 and RSPO1; and 2) transfer of the HAC to previously characterized rejuvenated MSCs (rej-MSCs) prepared using Sendai virus technology for prolonged proliferation capacity in vitro. HAC-MSC stably and efficiently produced therapeutic factors in vitro and, following intraperitoneal administration to DSS-induced colitis mice, showed continuous expression of the therapeutic factors over 5 days. Additionally, HAC-MSC-treated mice showed alleviation of the disease activity index score, reduced depth of injury, and promotion of intestinal growth compared with MSC-treated mice. Furthermore, effective treatment with HAC-MSC required only a fraction (1 %-10 %) of the number of cells needed for conventional MSC therapy. These findings highlight the outstanding potential of rej-MSCs carrying therapeutic factor-loaded HACs as a cell therapy tool with prospective applications in the treatment of UC and other diseases.

关键词： norovirus   virus-like particles   lipid nanoparticles   adjuvants   type I IFN   immune responses  

摘要： Norovirus (NoV) virus-like particles (VLPs) adjuvanted with aluminum hydroxide (Alum) are common vaccine candidates in clinical studies. Alum adjuvants usually inefficiently assist recombinant proteins to induce cellular immune responses. Thus, novel adjuvants are required to develop NoV vaccines that could induce both efficient humoral and robust cellular immune responses. Lipid nanoparticles (LNPs) are well-known mRNA delivery vehicles. Increasing evidence suggests that LNPs may have intrinsic adjuvant activity and can be used as adjuvants for recombinant protein vaccines;however, the underlying mechanism remains poorly understood. In this study, we compared the adjuvant effect of LNPs and Alum for a bivalent GI.1/GII.4 NoV VLP vaccine. Compared with Alum, LNP-adjuvanted vaccines induced earlier production of binding, blocking, and neutralizing antibodies and promoted a more balanced IgG2a/IgG1 ratio. It is crucial that LNP-adjuvanted vaccines induced stronger Th1-type cytokine-producing CD4(+) T cell and CD8(+) T cell responses than Alum. The adjuvant activity of LNPs depended on the ionizable lipid components. Mechanistically, LNPs activated innate immune responses in a type I IFN-dependent manner and were partially dependent on Toll-like receptor (TLR) 9, thus affecting the adaptive immune responses of the vaccine. This conclusion was supported by RNA-seq analysis and in vitro cell experiments and by the deeply blunted T cell responses in IFN alpha R1(-/-) mice immunized with LNP-adjuvanted vaccines. This study not only identified LNPs as a high quality adjuvant for NoV VLP vaccines, but also clarified the underlying mechanism of LNPs as a potent immunostimulatory component for improving protein subunit vaccines.

关键词： Interleukin-4   Virtual memory   CD8 T cell   Ly6a   Single-cell RNA sequencing  

摘要： Antigen-inexperienced memory-phenotype CD8+ T cells are categorized as innate memory cells in the thymus or virtual memory (VM) CD8+ T cells in peripheral tissues. The key distinction between these cell types is their differing responses to IL-4, but the minimal effect of IL-4 on VM CD8+ T cell expansion in the periphery is not well understood. To address this, we investigated the development of VM CD8+ T cells in the periphery of IL-4 knockout (KO) C57BL/6 mouse. CD8+ splenocytes were isolated from the spleen of wilt-type (WT) and IL-4 KO mice, followed by single-cell RNA sequencing and Seurat analysis on sorted CD8+ cells using the 10x Genomics platform. This study identified various CD8+ T cell subtypes, including naive, effector, IFN-stimulated, true memory (TM), and VM T cells. VM CD8+ T cells were characterized by high expression of Cd44, Cxcr3, Il2rb, Eomes, Tbx21, Ly6c2, and low expression of Itga4. In IL-4-deficient mouse, macrophages were significantly reduced, while memory T cell populations showed a slight increase compared to WT mouse. Both Itga4+ TM and Itga4- VM CD8+ T cells were more abundant in IL-4 KO mouse. Within the VM T cell group, Ly6a+ VM CD8+ T cells were reduced, while Ly6a + VM CD8+ T cells were increased relative to WT mouse. These Ly6a+ VM CD8+ cells exhibited high expression of genes linked to type I IFN signaling, such as Isg15, Ifit1, and Stat1. Our findings suggest that IFN-influenced Ly6a + VM CD8+ T cells play a role in maintaining the peripheral VM CD8+ T cell population in the absence of IL-4.

关键词： Neutrophil   Cytokine   Monoclonal antibody   Monocyte  

摘要： Background Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1 alpha and IL-1 beta bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways. The IL1RAP blocking antibody nadunolimab is currently in clinical development, but the precise consequences of inhibiting IL-1 signaling in PDAC remains *** To evaluate the biological relevance of blocking IL1RAP using nadunolimab in a PDAC animal model, human PDAC cells and cancer-associated fibroblasts (CAFs) were co-transplanted into mice. To study the underlying mechanisms of IL1RAP blockade ex vivo, co-cultured PDAC cells and CAFs were treated with nadunolimab prior to RNA sequencing. Migration assays were performed to assess how nadunolimab affects interactions between CAFs and myeloid immune cells. Finally, to establish a clinical correlation between IL1RAP expression and nadunolimab treatment effects, we analyzed tumor biopsies from a clinical phase I/II study in which nadunolimab was administered to *** In the xenograft mouse model, nadunolimab exhibited antitumor effects only when human CAFs were co-transplanted with PDAC cells. IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes. The secretion of this chemokine and the migration of myeloid cells were inhibited by nadunolimab. Media conditioned by IL-1-stimulated CAFs sustained a neutrophil population with a tissue invasion phenotype, an effect that was reversed by nadunolimab. In a cohort of metastatic late-stage PDAC patients receiving nadunolimab as monotherapy, high IL1RAP expression in tumors was associated with extended progression-

关键词： NK cell   MHC-Class I   Metastasis   Anti-tumor effector function   IFN-gamma   DNAM-1  

摘要： Natural killer (NK) cells are important innate immune effector cells for controlling tumor growth and metastasis. Differentiated mature NK cells preferentially reside in the peripheral tissues and express higher levels of selfmajor histocompatibility complex class I (MHC-I)-recognizing inhibitory receptors. MHC-I recognition by NK cells are known to be important for their development and maturation processes, however, the role of homeostatic MHC-I recognition in maintaining effector functions of mature NK cells in the peripheral tissues needs to be elucidated. In this study, we utilized a pan anti-MHC-I blocking monoclonal antibody (anti-MHC-I) to examine the role of homeostatic MHC-I recognition in the response of pulmonary mature NK cells in an experimental lung metastasis model of B16F10 melanoma. Anti-MHC-I treatment showed significant inhibition of the lung metastasis of B16F10 melanoma in NK cell- and IFN-gamma-dependent mechanisms. The blockade of homeostatic MHC-I recognition increased mature lung NK cell responsiveness, such as direct cytotoxicity and IFN-gamma production, rather than the number of lung NK cells. Mechanistically, the gene expression of activating receptors including DNAX accessory molecule-1 (DNAM-1) was upregulated in NK cells treated with anti-MHC-I, and further the enhanced NK cell cytotoxicity against B16F10 cells was DNAM-1-dependent. Collectively, homeostatic self-MHC-I recognition regulates anti-metastatic function of mature lung NK cells by restraining the expression of activating receptors.

关键词： neoantigen presentation   binding affinity   immunotherapy   biomarker   machine learning  

摘要： Human leukocyte antigen class I (HLA-I) and class II (HLA-II) proteins play an essential role in epitope binding and presentation to initiate an immune response. Accurate prediction of peptide-HLA (pHLA) binding and presentation is critical for developing effective immunotherapies. However, current tools can predict antigens exclusively for pHLA-I or pHLA-II, but not both;have constraints on peptide length;and commonly show unsatisfactory predictive accuracy. Here, we developed a convolution and attention-based model, CapHLA, trained with eluted ligand and binding affinity mass spectrometry data, to predict peptide presentation probability (PB) and binding affinities (BA) for HLA-I and HLA-II. In comparison with 11 other methods, CapHLA consistently showed improved performance in predicting pHLA BA and PB, particularly in HLA-II and non-classical peptide length datasets. Using CapHLA PB and BA predictions in combination with antigen expression level (EP) from transcriptomic data, we developed a neoantigen quality model for predicting immunotherapy response. In analyses of clinical response among 276 cancer patients given immunotherapy and overall survival in 7228 cancer patients, our neoantigen quality model outperformed other genetics-based models in predicting response to checkpoint inhibitors and patient prognosis. This study provides a versatile neoantigen screening tool, illustrating the prognostic value of neoantigen quality.