bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of donor memory-like NK cell infusion in allogeneic hematopoietic stem cell transplantation
Authors: Liu Haiyan , Hu Bo , Song Yuan 
Published: January 2023

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with chemotherapy-resistant hematologic malignancies and some solid tumors. However, relapse after allo-HSCT is common in those with high-risk disease and typically portends a poor prognosis. Previous studies showed that donor NK cell infusion could prevent disease recurrence possibly through killing residual leukemia cells. However, NK cell-based immunotherapy is hampered by their transient effector function. Recently, IL-12/15/18-preactivated memory-like NK cells were shown to persist with sustained effector function, we investigated whether memory-like donor NK cells could improve donor NK cell’s GVL effect in murine allo-HSCT. NK cells preactivated with IL-12/18 or IL-12/15/18 produce high levels of IFN-γ upon restimulation by IL-12/15 after 4d of in vitro culture. The infusion of IL-12/15/18 or IL-12/18-preactivated NK cells significantly promoted the GVL effects compared to donor HSCs infusion alone. After adoptive transfer, IL-12/18 and IL-12/15/18 preactivated NK cells were found in higher numbers in spleen, liver and lung compared with the control NK cells. The proliferation of the transferred NK cells was greatly promoted by IL-12/18 and IL-12/15/18 preactivation. Despite of the strong GVL effect of the IL-12/15/18-preactivated NK cells, they aggravated acute GVHD whereas IL-12/18-preactivated NK cell infusion significantly prolonged the GVHD-related survival compared with the HSCs alone or control NK cells. Therefore, IL-12/18-preactivated memory-like donor NK cell infusion may be a more effective and safer strategy for preventing or treating relapse after allo-HSCT.
The effects of mesenchymal stem cells in a murine sclerodermatous model of graft-versus-host disease
Authors: Lim Ji-Young , Ryu Da-Bin , Lee Sung-Eun , Oh Il-Hoan , Min Chang-Ki 
Published: January 2023

Abstract
Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (scl GVHD) model that is characterized by skin and lung fibrosis. We used B10.D2 → BALB/c model of scl GVHD, which differ at minor histocompatibility loci, to address the therapeutic effect of mesenchymal stem cells (MSCs) on the development of CGVHD. MSCs were intravenously treated on days 3, 5 and 7 post-transplantation. The clinical severity of cutaneous scl GVHD was significantly attenuated after the treatment of MSCs. Pathologically, animals treated with MSCs showed less fibrosis and inflammatory cell infiltrations in skin and ear but not in visceral organs including lung and liver. Accordingly, the mRNA expression of collagen type 1 α1, 1 α2 and 3 α1 as well as collagen production were significantly reduced after the MSC treatment only in skin compared to the allogeneic scl GVHD controls. MSCs down-regulated mRNA of proinflammatory cytokines mainly in skin tissues and among them TGF-β expression was consistently reduced 28 days after HSCT. The effects of MSCs on molecular markers implicated in persistent TGF-β signaling and fibrosis, such as phosphatase and tensin homolog (PTEN), p-Smad2/3 and matrix metaloprotease-1 (MMP-1) were observed at the skin tissues. MSCs inhibited infiltration of immune cells into skin through down-regulating CCR4, CCR8 and CCR10 on donor CD4 T cells and CCR1 on CD11b monocytes. Moreover, MSCs diminished the expression of mRNA for chemokines such as CCL1, CCL8, CCL17, CCL22 and CCL3, in skin. In conclusion, treatment of MSCs early after transplant attenuated cutaneous scl GVHD by selectively blocking of immune cell migration and down-regulating the chemokines and chemokine receptors.
Learning from cancer: Using D-lactate for therapeutic immunosuppression
Authors: Beier Ulf H , Jiao Jing , Xiao Haiyan , Angelin Alessia , Wallace Douglas C , Levine Matthew , Hancock Wayne W 
Published: January 2023

Abstract
Accumulation of lactic acid in the tumor microenvironment contributes to local immunosuppressive conditions that weaken anti-tumor immunity. In mammals including humans, lactate is present almost entirely as the L-lactate optical isomer. We hypothesized that D-lactate could have similar immune modulatory effects that maybe exploited for therapeutic immunosuppression. 5–40 mM of added sodium D- and L-lactate caused marked impairment of murine, and human, CD4 and CD8 T cell proliferation in vitro, with stronger effects of D-lactate than L-lactate. Neither D- nor L-lactate affected cell viability or apoptosis. Adding 20 mM D-lactate to CD4+ Foxp3− T cells under polarizing conditions increased Foxp3+ induced regulatory T cell (iTreg) formation by 46.2 ±31.5% (P&lt;0.03, n=4). L-lactate also augmented Treg induction but to a lesser degree. Next, we adoptively transferred 1×106 conventional T cells, with or without 1.25×105 Tregs, into Rag1−/− mice, treated each group with 90 mmol/kg/d D-lactate or NaCl for 5 days. After 7 days, T cell proliferation was reduced by 62.1% using D-lactate treatment (P&lt;0.03, n=8). While Treg suppressive function was unaffected, de-novo Foxp3+ Treg formation was increased in D-lactate (14.9 ±3.4%) vs. NaCl (10.6 ±2.3%) treated animals (P&lt;0.01, n=8). Adding D-lactate to proliferating T cells increased oxygen consumption rates compared to NaCl controls, by 56.1 ±35.1% (p&lt;0.05, n=4). In contrast, methyl-esters of L- and D-lactate resistant to either lactate dehydrogenase isoform did not reduce T cell homeostatic proliferation. Our data show that D-lactate has in vivo immunosuppressive effects and can induce de-novo iTregs. The process of lactate oxidation is likely required for its immune modulatory effects.
Induction of donor-specific immune tolerance using bioengineered thymus organoid
Authors: Pradhan Isha , Tajima Asako , Bertera Suzzane , Rudert William , Trucco Massimo , Fan Yong 
Published: January 2023

Abstract
Extended use of immunosuppression is a major setback in organ transplantation. Hence, establishment of donor specific immune unresponsiveness, without the need of immunosuppression, is critical and remains a major challenge. Immunological tolerance is known to occur through two main mechanisms: central (thymus) and peripheral. Our lab has recently reported that bioengineered thymus organoids, made of de-cellularized thymus scaffolds populated with thymic epithelial cells (TECs), can successfully support T-cell generation in athymic nude mice. Here, we aim to test the hypothesis that transplantation of bioengineered thymus, incorporated with donor TECs, can induce central tolerance to donor antigens. Thymus scaffold were reconstructed with either TECs harvested from F1 offspring of B6 (H-2b) and NOD (H-2b/g7) or TECs from both B6 and CBA/J (H-2k) mixed in 1:1 ratio. These reconstructed thymus organoids are transplanted to the B6. Nude recipient, that are subsequently challenged with syngeneic, allogeneic and third party skin graft. Results from recipients with transplanted bioengineered thymus consisting F1 TECs demonstrated successful engraftment of skin transplants from both syngeneic (B6) and allogeneic (B6.H-2b/g7) whereas, clear rejection of the third party (CBA/J). Similarly, we observed prolonged survival of allograft skin (CBA/J) than third party (Balb/C) in recipient mice with reconstructed thymus organoids containing TECS from both donor (B6) and recipient (Balb/c). Furthermore, immune unresponsiveness to allograft was shown in MLR assay. Overall, our findings suggest reconstructed thymus-containing donor TECs could potentially have clinical application to induce-donor specific immune tolerance.
Monitoring the Cytomegalovirus-specific cellular immunity in lung transplant recipients: A comparative analysis of two assay systems
Authors: Boeckl Katharina , Striebinger Hannah , Kneidinger Nikolaus , Barabas Sascha , Neurohr Claus , Nitschko Hans , Jäger Gundula 
Published: January 2023

Abstract

Objective
Monitoring the cellular immunity for Cytomegalovirus (CMV) in organ transplant recipients is a promising tool to support prevention strategies for posttransplant CMV infection or reactivation. Commercially available in vitro test systems differ substantially in their capacity to stimulate subpopulations of T-lymphocytes. We compared two assays for CMV immune monitoring in respect of their clinical practicability and significance.

Methods
Blood samples of 30 lung transplant recipients (LuTRs) were examined before transplantation and over a period of six months afterwards with T-Track® CMV (Lophius Biosciences GmbH, Regensburg) and QuantiFERON®-CMV (Cellestis GmbH, Darmstadt). The T-Track® CMV is based on ELISpot-technology, allowing quantification of interferon-gamma (IFNγ) secreting CD4+ and CD8+ T-cells after specific stimulation. Contrarily, the QuantiFERON®-CMV assay is restricted to detection of IFNγ secreted by CD8+ T-lymphocytes with ELISA. The data are evaluated in the context of transplant outcome and determination of viral load in plasma by qPCR.

Results and Conclusion
Both approaches provide similar results while exhibiting certain advantages and limitations. Early during immune suppressive therapy, QuantiFERON®-CMV generates often indeterminate results as depletion of T-cells is not taken into account. Although a comparatively large volume of blood is required, T-Track® CMV circumvents this drawback. In addition, T-Track® CMV reaches a higher sensitivity prior to LuTx and after onset of immunosuppression.
Donor γδT cells promote graft-versus-leukemia effect and ameliorate acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation
Authors: Yuan Song , Bo Hu , Ying Zhu , Haiyan Liu 
Published: January 2023

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most effective way of treating leukemia and other malignant diseases. However, disease recurrence and GVHD are still the major causes of death after allo-HSCT. Previous studies showed that immune cells involved in graft versus leukemia (GVL) effect traditionally include CD8+ T, CD4+ T and NK cells. Unfortunately, some of these T-cell subsets also cause graft-versus-host disease (GVHD). The role of donor γδ T cells after transplantation is less well defined. γδ T cells display unique features in terms of MHC-unrestricted recognition of lymphoid malignancies, which makes them promising candidates as anti-leukemia effectors. We detected direct anti-leukemia cytotoxicity of γδ T cells in vitro and the cytotoxicity of Vγ1 was stronger than the Vγ4 subset. To evaluate the role of donor γδT cells in aGVHD and GVL, we established the murine allo-HSCT GVL/GVHD model. Our results showed that TCRδ−/− donor bone marrow cells caused enhanced disease progression and aggravated aGVHD compared with wildtype donors. Furthermore, flow cytometry analysis demonstrated γδ T cells mediated anti-leukemia effects through promoting IFN-γ production by CD8+ T cells while suppressed aGVHD by inhibiting the activation of CD4+ T cells in liver, lung and IEL. The experiment of adoptive transfer of in vitro expanded γδT/Vγ1/Vγ4 cells indicated that the subset of donor γδT cells to alleviate murine aGVHD and enhance GVL effect might be Vγ4 γδT cells. The GVL effect of γδ T cells in vivo could be mediated by both direct cytotoxicity and regulation of CD8+ T cell function. These findings suggest donor γδT cells infusion as a novel strategy to improve patients’ overall survival after allo-HSCT.
Natural Killer (NK) Cells’ Response to Epstein - Barr virus Infections and its Influence on the Risk of Developing Post-transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Cell Transplantation: Effect of Donor Killer Ig-like Receptor Genes and Motifs Copy Numbers
Authors: Faridi Rehan M , Kemp Taylor J , Dharmani-Khan Poonam , Lewis Victor A , Berka Noureddine , Storek Jan , Khan Faisal M 
Published: January 2023

Abstract

BACKGROUND
Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of the major complications after T-cell depleted HCT. Recovering within weeks after HCT, natural killer (NK) cells are deemed important in the immunopathogenesis of EBV complications. Their role however remains elusive. NK cell responses are regulated by a series of activating and inhibitory cell surface receptors, central to which are the Killer Ig-like Receptors (KIR). Here we hypothesized and tested whether diverse NK cell receptor repertoires can titrate NK cell functional responses to EBV and can potentially modify the risk of developing PTLD.

METHODS
KIR genotypes, centromeric and telomeric motifs and their variants were determined for 356 allo-HCT donors through next generation sequencing of KIR locus. PBMNCs from KIR typed healthy volunteers were co-cultured with EBV-transformed cells and degranulation and IFNγ producing NK cells were enumerated using multi-parameter flow cytometry. Effect of donor KIR profile on PTLD was tested using competing risks regression statistics. Segregation of NK cell response to EBV across various KIR repertoires was tested by Mann-Whitney U statistics

RESULTS
At least one copy of Donor tA01 motifs was required for a strong protection against PTLD (p=0.0001, SHR=0.17). The number of EBV induced NK cells increased with increasing tA01 motifs. There was no influence of recipients’ KIR repertoire on the risk of developing PTLD.

CONCLUSIONS
KIR-regulated NK cells have a profound effect on the risk of PTLD. KIR gene profile based identification of HCT recipients at high risk of PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy.
Deletion of a Class IIb Histone/protein Deacetylase (HDAC), HDAC10, Enhances FoxP3+ T-regulatory (Treg) Cell Suppressive Function, Gene Expression and Metabolism, and Promotes Allograft Survival
Authors: Dahiya Satinder , Wang Liqing , Beier Ulf H , Angelin Alessia , Han Rongxiang , Wallace Douglas C , Hancock Wayne W 
Published: January 2023

Abstract
Treg cells control immune responses that cause unwarranted inflammation and promote allograft rejection, leading to interest in their therapeutic applications. Targeting HDACs to modulate the function of Tregs has practical advantages over injecting ex-vivo-expanded Tregs that may not survive long post-injection. Several of the 11 classical HDAC enzymes are necessary for optimal Treg function while others are dispensable. We evaluated the function of HDAC10 in murine Tregs. We showed that HDAC10 bound to Foxp3 in co-immunoprecipitation assays, and that germ-line knockout of this hitherto enigmatic HDAC had no effect on the health of targeted mice. We found that HDAC10 deletion: (i) enhanced Treg suppressive function both in vitro (Treg suppression assays) and in vivo (homeostatic proliferation assays), compared to wild-type (WT) Tregs; (ii) increased Treg expression of genes including Foxp3, Granzyme-B, IL-10 and others (microarray, qPCR); (iii) increased acetylation of NFkB/p65 at lysine 310 and thereby prolonged the nuclear retention of p65 and increased transcription from p65-dependent promoters; and (iv) increased oxidative phosphorylation in Tregs compared to WT Tregs (assays of mitochondrial function on the Seahorse platform). Lastly, heterotopic cardiac allograft studies (BALB/c-&gt;C57BL/6) showed that compared to WT recipients, HDAC10−/− allograft recipients had markedly prolonged allograft survival (p&lt;0.01). While additional studies of the in vivo effects of HDAC10 deletion in transplant and autoimmune models, including colitis, are underway our data show promise for the therapeutic targeting of HDAC10 as a novel approach for transplant rejection and other immunologically mediated disorders.
The role of PI3K in modulating NKT cell responses to Mantle Cell Lymphoma
Authors: Shissler Susannah Claire , Webb Tonya J 
Published: January 2023

Abstract
Natural Killer T (NKT) cells are important in the initiation and regulation of immune responses to cancers. The observation that mantle cell lymphoma (MCL) patients have a significant reduction in both NKT cell number and function suggests that the antitumor effects mediated by these cells may be compromised. MCL is characterized by the chromosomal translocation and nuclear overexpression of Cyclin D1. Secondary chromosomal abnormalities and dysregulation of cell cycle machinery also contribute to MCL pathogenesis, such as aberrant or constitutive activation of phosphatidylinositol 3 kinase (PI3K). We hypothesize that constitutive activation of PI3K in MCL alters the repertoire of lipids in these cells, ultimately resulting in decreased CD1d-mediated NKT responses to MCL. In this study, we used small molecule pharmacologic inhibitors of PI3K (PI3Ki) to investigate the role of PI3K signaling on MCL survival and immunogenicity both in vitro and in vivo. Treatment with PI3Ki induced apoptosis in human MCL cell lines and enhanced their immunogenicity. In addition, we have found that treatment of peripheral blood mononuclear cells with isoform-specific PI3Ki does not suppress T cell activation; whereas, treatment with a pan PI3Ki, BEZ-235, completely abrogates NKT/T cell responses. These studies suggest inhibitors targeting individual isoforms may have higher therapeutic efficacy. Collectively, this work will advance our understanding of differences in the modes of PI3K signaling in MCL survival and in antigen processing and presentation.
Splenic B cells contribute to intraocular tumor progression
Authors: Whitehill Brooke M , Andersen Jessica , Kopy Stephen , McKenna Kyle C 
Published: January 2023

Abstract
Primary intraocular melanomas heavily infiltrated by CD8+ T cells and macrophages are generally larger, more heavily vascularized tumors with a genetic profile indicating greater risk of metastasis to the liver. To better understand how the tumoricidal activity of these immune cell populations is inhibited within the eye, a site of immune privilege, we developed a mouse model of intraocular tumor development in which immunogenic E.G7-OVA tumor cells transplanted in the anterior chamber form progressively growing intraocular tumors in C57Bl/6 mice despite infiltration by tumor-specific CD8+ T Cells and macrophages. Recently, we demonstrated that splenectomy prior to tumor challenge restored tumoricidal activity of CD8+ T cells and macrophages and promoted complete elimination of established intraocular tumors. Herein, we show that E.G7-OVA tumors transplanted in the eye of B cell deficient μMT mice are rejected by CD8+ T cells. The rejection of intraocular tumors in μMT mice was not due to abnormal splenic architecture but rather stemmed from the absence of tumor-specific B cells as mice transgenic for an immunoglobulin molecule to an irrelevant antigen (hen egg lysozyme) also rejected intraocular E.G7-OVA tumors. These data suggest that intraocular tumor development induces the generation of tumor-specific regulatory B cells (Breg) in the spleen. How these Breg contribute to intraocular tumor growth is not completely understood. However, intraocular E.G7-OVA tumors grew progressively in mice deficient in activation-induced cytidine deaminase that cannot undergo isotype class switching suggesting that secreted tumor specific IgG does not contribute to inhibiting tumoricidal activity within the eye.
Modeling altered germinal center responses due to oncogenic activating mutations in CARMA1
Authors: Dutra Michelle N , Seymour Brenda , Sommer Karen , James Richard , Rawlings David 
Published: January 2023

Abstract
BCR engagement drives phosphorylation of the multi-adapter, CARMA1, and assembly of signaling complexes required for NF-κB activation. B cell lymphomas are frequently associated with constitutive NF-κB activation that sustains their survival. At least 10% of germinal center (GC) derived, activated B-cell like diffuse large B-cell lymphomas (ABC-DLBCLs) exhibit gain-of-function mutations in CARMA1. In the current study, we directly assess the impact activated CARMA1 (aCARMA1) on GC biology. We developed a novel mouse model that permits inducible expression of aCARMA1. Following T-dependent immunization, mice with B cell intrinsic aCARMA1 exhibit an expanded plasma cell compartment and reduced GC B cell numbers. A similar phenotype was present with GC restricted aCARMA1 expression, leading to increased total and antigen-specific IgG. ABC-DLBCL tumors frequently exhibit somatic mutations predicted to block terminal B cell differentiation. To better define how aCARMA1 impacts GC biology and cooperates with these lesions, we crossed KI mice to Blimp1F/F mice. aCARMA1 expression, in the absence of Blimp1, lead to increased GC B cell numbers compared to controls. Current studies are focused on detailed analysis of this altered response. Our results demonstrate that aCARMA1 is sufficient to alter the GC response and B cell fate, favoring plasma cell development. Further, in the setting of inability to exit the GC, aCARMA1 may be sufficient to directly promote lymphomagenesis.
B-1 cells secrete antibodies with anti-tumor properties
Authors: Rodriguez-Zhurbenko Nely , Rabadek Maura , Quach Tam D , Hopkins Thomas J , Rothstein Thomas L , Hernandez Ana Maria 
Published: January 2023

Abstract
It is well known that B-1 cells are the main B cell subset responsible for the production of natural antibodies. Several studies suggest that natural IgM antibodies play an important role in immunosurveillance against transformed cells in humans, preferentially binding glycolipids and carbohydrate structures. NeuGcGM3 ganglioside is a sialic acid containing glycosphingolipid that has been considered an attractive target for cancer immunotherapy since is not naturally expressed in healthy human tissues but is overexpressed in several tumors. We previously described the existence of cytotoxic anti-tumor antibodies against NeuGcGM3 ganglioside in healthy young subjects. However, whether this anti-tumor antibody response has a “natural origin” is unknown. With the present work we aimed to elucidate whether B-1 cells have the potential to secrete anti-NeuGcGM3 antibodies. First we generated four mouse monoclonal antibodies from Balb/c mouse peritoneal B cells. All hibridomas secreted IgM which bound NeuGcGM3 but no other gangliosides and recognized and killed NeuGcGM3 positive tumor cells. All the anti-NeuGcGM3 IgM-producing hybridomas were CD5+ B-1 cells. Then naïve, memory, plasma and B-1 cells were purified from healthy human donors PBMC and stimulated in vitro to produce immunoglobulins. All the B-1 cell supernatants reacted with NeuGcGM3 and most of them also recognized tumor cells expressing this ganglioside. Only 40% of memory samples, and none from naïve or plasma cells, recognized this antigen. These data suggest a protective role for B-1 cells against malignant cells through the production of natural antibodies reactive to tumor associated antigens such as NeuGcGM3 ganglioside.