bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delineating tissue-specific alloimmunity during acute GVHD
Authors: Tkachev Victor , Furlan Scott Nicholas , Potter E. Lake , Zheng Betty H. , Hunt Daniel J. , Colonna Lucrezia , Taraseviciute Agne , Carlson Judith , Betz Kayla , Yu Alison , Hoffman Michelle , Herrin Sarah , Olvera Joe , Littlewood Chad , Blazar Bruce R. , Roederer Mario , Kean Leslie S. 
Published: January 2023

Abstract
After allogeneic hematopoietic cell transplantation (allo-HCT), donor T cells undergo priming in secondary lymphoid tissues followed by migration to different target organs, where they mediate inflammation and cause acute Graft-versus-Host Disease (aGVHD). Here, we characterized T cells infiltrating GVHD-target organs using a model of aGVHD in non-human primates in order to delineate tissue-specific patterns of the alloimmune response. We found that aGVHD profoundly shifted the T cell phenotype from the naïve state toward an effector-memory state in both the blood and secondary lymphoid organs, with an attenuated shift in non-lymphoid organs. However, in all compartments, tissue-infiltrating T cells demonstrated an aGVHD-specific activated phenotype characterized by a high rate of proliferation and elevated effector functions. In addition, transcriptomic profiles of aGVHD- and tissue-residency developed in T cells residing the colon, liver and lungs as well as in the blood. To further delineate the patterns of T cell trafficking and activation during aGVHD, we directly labeled leukocytes in vivo using fluorescent anti-CD45 antibodies. Using this approach, we detected notable changes in T cell trafficking patterns which included increased T cell trafficking to lymph nodes, lungs and kidneys after allo-HCT, with rates of T cell migration to the GI tract unchanged even during aGVHD. These data provides novel insights into the spatial organization of systemic alloimmunity during aGVHD and the organ-specific impact of this disease on T cell trafficking, activation and functional maturation.
Bendamustine Conditioning Induces Phenotypic and Functional Changes in Host Antigen-Presenting Cells Which May Confer Protection Against GvHD
Authors: Molina Megan Stanley , Stokes Jessica , Hoffman Emely , Eremija Jelena , Zeng Yi , Katsanis Emmanuel 
Published: January 2023

Abstract

Background
In an MHC-mismatched mouse bone marrow transplantation (BMT) model, we have found that substituting the pre-conditioning chemotherapeutic cyclophosphamide (CY) with an alternative alkylating agent, bendamustine (Ben), can significantly reduce graft-versus-host disease (GvHD) while maintaining engraftment. The mechanisms by which Ben achieves this effect are not understood, but evidence suggests that the early cellular interactions that occur in the first week after BMT can be responsible for GvHD severity later on.

Objective
We hypothesized that Ben may be affecting the function and/or phenotype of host antigen presenting cells (APCs) in the early post-BMT period (before complete myeloablation is achieved).

Design/Method
We applied a murine myeloablative MHC-mismatched model (C57BL/6 &gt; BALB/c) to study the effect of Ben versus CY pre-conditioning in conjunction with total body irradiation (TBI) on host APCs. Specifically, we evaluated the phenotype and activation state of splenic host CD11c+ dendritic cells (DCs) on days 1, 3, and 5 following BMT.

Results
We found a significant increase in number and proportion of CD8a+ DCs in Ben versus CY. We also found that the Ben CD8a+ DC subset express differing levels of activation markers versus CY CD8a+ DCs. Furthermore, functional assays revealed that Ben CD11c+ DCs induce less T cell proliferation than either CY or naïve CD11c+ DCs, and that Ben CD8a+ DCs are more suppressive than either CY or naïve CD8a+ DCs.

Conclusion
These results suggest that pre-transplant Ben engenders phenotypic and functional changes in host CD11c+CD8a+ splenic DCs, inducing a suppressive phenotype, signifying a possible mechanism by which Ben induces protection against GvHD.
NOD2 acts as a master regulator of regeneration pathways in the thymus
Authors: Kinsella Sinéad , Cooper Kirsten , deRoos Paul , Iovino Lorenzo , Jain Reema , Dudakov Jarrod A. 
Published: January 2023

Abstract
Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence following stress, infection and cytotoxic cancer treatments. Although there is continuous thymic involution and regeneration in response to stress and infection in the healthy state, prolonged T cell deficiency is common after profound thymic damage, such as that caused by the conditioning required for hematopoietic stem cell transplant. Our previous studies have revealed two pathways important for thymic repair, centered around the production of IL-22 and BMP4 by innate lymphoid cells and endothelial cells (ECs), respectively. However, the specific mechanisms that trigger these pathways are poorly understood. Here we reveal an unexpected role for the pattern recognition receptor Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in governing multiple pathways of thymic regeneration. Mice deficient in NOD2 showed increased intrathymic levels of L-22, IL-23 and BMP4 and increased thymus cellularity after damage caused by total body irradiation (TBI). Although NOD2 is classically defined as a bacterial sensor, members of the Rho GTPase family have been implicated to promote NOD signaling, even in the absence of pattern recognition. Consistent with this, inhibition of RhoA or Rac1 can induce the production of BMP4 by ECs in vitro, and after TBI there is a significant reduction in these two Rho GTPases. These studies not only enhance our understanding of endogenous tissue regeneration, but in identifying a master regulator of multiple pathways, offers a superior therapeutic strategy to boost thymic function in patients whose immune system has been decimated due to age, infection or cancer therapies.
Immunosuppression reverse engineered from cancer: Reducing nicotinamide adenine dinucleotide (NAD) impairs effector T cell function through glycolysis
Authors: Beier Ulf H. , Quinn William J. , Jiao Jing , TeSlaa Tara , Dahiya Satinder , Wang Zhonglin , Levine Matthew H. , Hancock Wayne W. , Rabinowitz Joshua D. , Baur Joseph A. 
Published: January 2023

Abstract
Understanding the mechanisms by which cancers evade immune responses may lead to new immunosuppressive therapies. The metabolic environment surrounding solid tumors is often enriched in lactic acid and glucose depleted, which impairs effector T cells (Teff). We observed that sodium L- and D-lactate inhibit T cell proliferation in vivo and increase Foxp3+ formation independent of acidity, while sodium pyruvate achieved the opposite. Inhibiting lactate dehydrogenase (GSK 2837808A) negated the effects of L-lactate on Teff and regulatory T cells (Treg). These findings suggested a role of NAD in controlling Teff function and Foxp3 stability. NAD is a co-factor for GAPDH (glycolysis), poly (ADP-ribose) polymerase-1 and sirtuin-1 (Foxp3 stability). We impaired NAD oxidation through oligomycin, rotenone, antimycin, or blocking NAD recycling (FK866). We used mitochondrial uncoupling, β-lapachone, and α-ketobutyrate to augment NAD oxidation, or added nicotinamide riboside to restore NAD after FK866 treatment. Reducing NAD led to decreased glycolytic flux and accumulation of pre-GAPDH glycolytic metabolites, which was reversed by increasing oxidized NAD. T cell IFN-γ production and Foxp3 turnover were increased by NAD oxidation, and impaired by NAD reduction. Blocking NAD recycling also impaired Teff proliferation and IFN-γ production, which was reversed by restoring NAD. Reducing NAD in vivo with sodium D-lactate (9 μmol/g/d x 5 d) or phenformin (70 mg/kg/d x 14 d) prolonged MHC-mismatched BALB/c to C57BL/6 cardiac allograft survival. We conclude that NAD controls T cell function through glycolysis and Foxp3 stability, which may be exploited for therapeutic immunosuppression.
Tannic acid-encapsulated islets delay immune rejection following transplantation
Authors: Barra Jessie M. , Kozlovskaya Veronika , Kharlampieva Eugenia , Tse Hubert Ming 
Published: January 2023

Abstract
Islet transplantation can restore β-cell function in patients with Type 1 diabetes (T1D), however, limited islet availability, toxicity of immunosuppressants, and poor graft survival are major hurdles for clinical application. We hypothesize that islet encapsulation with a nanothin multilayer coating consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), will provide an immunoprotective barrier and maintain β-cell function after transplantation. (PVPON/TA)-encapsulated syngeneic NOD.Rag islets restored euglycemia after transplantation under the kidney capsule of streptozotocin-treated diabetic NOD mice by more than 30 days in comparison to non-encapsulated islets. Allogeneic encapsulated B6 islets also restored euglycemia in diabetic NOD recipients and delayed rejection by 7.5 days in contrast to non-encapsulated islets. Gene expression of allogeneic B6 islets at 5 days post-transplant displayed an increase in Ins2 (6-fold), Gcg (6-fold), Pdx1 (5-fold), Ccl22 (3-fold), and Arg1 (2.5-fold) mRNA accumulation with (PVPON/TA)-encapsulated islet grafts, suggesting a potential shift toward an alternatively-activated M2 macrophage phenotype. To address limited islet availability, the use of (PVPON/TA)-encapsulated differentiated neonatal porcine islets restored euglycemia and maintained β-cell function for more than 200 days after transplantation into diabetic NOD. scid mice, displaying a potential intervention to delay xenotransplant rejection. Our results support the hypothesis that (PVPON/TA) coatings are immunoprotective and may promote islet graft acceptance following transplantation.
Obesity results in marked increases in gut permeability, inflammatory cytokines, and acute gut graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
Authors: Khuat Lam T. , Pai Chien-Chun Steven , Le Catherine T. , Dunai Cordelia , Chen Mingyi , Raybould Helen E. , Abedi Mehrdad , Murphy William J. 
Published: January 2023

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most applicable curative option for treating hematologic diseases. In this study, we assessed the impact of obesity on recipient graft-versus-host disease (GVHD) outcome post allogeneic HSCT using a minor histocompatibility antigens (miHA)-mismatched mouse model. Control or diet-induced obese (DIO) BALB/c mice received HSCT from H2-identical B10.D2 mice which is known for resulting in chronic skin GVHD. Strikingly, DIO mice rapidly succumbed to gut GVHD while control mice survived and developed sclerodermatous GVHD much later post-HSCT. The DIO recipient mice had higher expression of pro-inflammatory cytokines (IL-6 and TNF-α) in the gut and serum, as well as higher serum ST2. There were increased numbers of donor CD4+ T cells in the mesenteric lymph nodes of DIO mice compared to control mice. Untreated DIO mice also displayed increased gut permeability and lipopolysaccharide translocation, as well as having less-diverse microbiota which potentially contributed to the severe GVHD post-HSCT. Importantly, administration of anti-IL-6R monoclonal antibody and Enbrel significantly protected DIO mice from lethal gut GVHD, correlating with lower pro-inflammatory cytokine concentrations (IL-6 and TNF-α) and ST2 in the serum. In an initial evaluation, treating DIO mice with broad-spectrum antibiotics 2 weeks before HSCT also ameliorated GVHD. Taken together, these results indicate that obesity exacerbates GVHD, manifested primarily as gut pathology, and therapeutic intervention by blockade of pro-inflammatory cytokine signaling ameliorates GVHD post-HSCT.
Allograft transplantation provokes miRNA 297–669 cluster that reduces T regulatory cell generation through targeting TGF-β2
Authors: Becker William J. , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
T regulatory cells (Tregs) are anti-inflammatory cells capable of quelling the harshest immune responses. Accordingly, Treg therapy is rapidly becoming a viable treatment option for patients stricken with autoimmune diseases or those in need of an organ transplant. In a model of allotransplantation, via microarray, our work identified miRNA cluster 297–669 is induced in CD4+ cells in the lymph nodes draining the allograft in C57BL/6 mice given a C3H skin transplant. One member of this cluster, miR 466a-3p, is induced in a co-culture of lymph node cells stimulated with alloantigen in vitro. We have shown that this miRNA specifically targets transforming growth factor beta 2 (TGF-β2). The reduction in TGF-β2 levels in draining lymph node CD4+ T cells caused a resultant decrease in the generation of FoxP3+ Tregs, both within the graft and in the draining lymph node. Furthermore, blocking the effect of this miRNA using a specific locked nucleic acid (LNA) reversed this effect. Generation of Tregs using transforming growth factor beta1 (TGF-β1), interleukin-2 and CD3/CD28 is the most common method of induction. Here we show that replacing TGF-β1 with TGF-β2 has no detrimental effect on Treg induction. Indeed, Tregs induced with TGF-β2 have equal in vivo suppressive capability as TGF-β1 Tregs in a skin graft model when adoptively transferred. Moreover, these TGF-β2 Tregs have increased inducible T-cell costimulatory (ICOS) expression. The ability of TGF-β2 to induce Tregs was reversed when a TGF-β2 neutralizing antibody was used, while this antibody had no effect on TGF-β1 induced Tregs. The work herein describes, for the first time, a novel isoform of TGF-β that may be involved in the generation of Tregs with implications in all areas of immunology.
Tolerogenic synthetic nanoparticles for the prevention of murine acute graft-versus-host disease
Authors: Ferrari Daniel , LaMothe Robert , Kolte Pallavi , Griset Aaron , O’Neil Conlin , Leland Thomas , Fu Fen-ni , Viseux Nelly , Johnston Lloyd , Kishimoto Takashi K. , Maldonado Roberto 
Published: January 2023

Abstract
We have shown that treatment with biodegradable tolerogenic nanoparticles carrying rapamycin (synthetic vaccine particles, SVP) and antigen (inside the particles or admixed) induces durable, antigen-specific immune tolerance even in the presence of potent Toll-like receptor agonists. Treatment with SVP and antigen results in durable B cell tolerance, the differentiation of T and B regulatory cells, the inhibition of T and B cell activation, inhibition of hypersensitivity reactions, and the treatment of relapsing experimental autoimmune encephalomyelitis and celiac disease.
Here we describe the use of SVP to promote graft tolerance and prevent acute Graft-versus-host disease (GvHD). GvHD occurs when donor T cells contained in bone marrow transplants become activated against host cells and subsequently destroy them. Current mitigation strategies involve chronic immune suppression regimens. However, prolonged immunosuppression has many side effects, including susceptibility to opportunistic infections. A favorable strategy would be to tolerize the graft to the host. To evaluate SVP we utilized two mouse models of acute GvHD: (1) B6-to-F1 and (2) B6-to-Balb/c. A single SVP administration provided at the time of the graft improved disease score, blunted inflammatory cytokines and controlled the activation of donor cells. Importantly, this resulted in a significant increase in survival compared to mock treated animals.
SVP therapy represents a novel approach for the induction of immunological tolerance and the prevention of acute GvHD.
Targeting Chemokine Receptors to Modulate MDSCs for Cancer Therapy
Authors: Mittal Payal , Leach Craig , Clemente Jose , Sender Mathew , Hancock Wayne W. , Turunen Brandon 
Published: January 2023

Abstract
Host anti-tumor responses, including the actions of cytotoxic T cells, play a key role in targeting tumors, but can be hindered by multiple mechanisms active within the tumor microenvironment. One such mechanism involves the recruitment and expansion of immunosuppressive cells such as myeloid derived suppressor cells (MDSCs) in the tumor microenvironment. We have utilized two transplantable lung tumor cell lines (TC1 and LLC) to address the role of certain chemokine receptors in MDSC associated tumor progression. In addition, we used a thioglycolate-induced peritonitis model of inflammation to validate the ability of chemokine receptor antagonists to inhibit trafficking of MDSCs to the site of inflammation. Finally, we tested the compounds for their ability to impair chemokine signaling within established tumors and promote antitumor immunity. In summary, genetic and pharmacologic data indicate that targeting chemokine receptors to modulate MDSCs may be an important new component of immuno-oncology based therapies.
Disruption of Mammalian Target of Rapamycin Complex 1 in Myeloid cells Promotes Lung Cancer Metastasis
Authors: Ding Chuanlin , Yan Jun 
Published: January 2023

Abstract
The mTOR inhibitors are used in clinics for treating multiple cancers. However, this assertion does not fully address the effects on the tumor microenvironment (TME) which plays critical roles in cancer development and metastasis. Moreover, a controversy exists in the literature regarding the roles of mTOR in regulating myeloid cell activation in response to different environmental factors. In this study, conditional Raptor KO mice were generated to disrupt mTORC1 signaling in myeloid cells and LLC tumor cells were implanted either s.c. or i.v. in syngeneic mice. Although depletion of mTORC1 signaling promoted M2 macrophages and TAM toward an M1-like phenotype with decreased immunosuppressive activity, tumor progression in the s.c. model didn’t show difference between Raptor KO and control mice. Flow cytometric analysis demonstrated decreased Th1 T cell response in the TME of Raptor KO mice. The depletion of mTORC1 signaling decreased TAM trafficking and increased Ly6C+accumulation in LLC TME, which was correlated with lower levels of CD115 expression on Raptor-deficient macrophages. Cytokine profile analysis revealed that TNF-a secretion by myeloid cells was significantly decreased in Raptor-deficient TME. Further, disruption of mTORC1 in myeloid cells promoted lung cancer metastasis, which was associated with decreased Th1 and NK cell response. Accordingly, more CD11b+F4/80high macrophages were accumulated in the lungs of Raptor KO mice in LLC metastasis model. Taken together, our results demonstrate that mTORC1signaling in myeloid cells may have multiple roles in regulating anti-tumor immunity dependent on tumor environment, specifically with pro- metastatic effects in mTORC1-deficient lung myeloid cells.
Antibody-dependent cellular phagocytosis is responsible for efficacy of anti-CD20 monoclonal antibody therapy in chronic lymphocytic leukemia
Authors: Chu Charles C. , VanDerMeid Karl R. , Elliott Michael Rusty , Baran Andrea M. , Barr Paul M. , Zent Clive S. 
Published: January 2023

Abstract
Anti-CD20 (αCD20) monoclonal antibodies (mAbs) are important drugs in the management of B cell malignancies, such as chronic lymphocytic leukemia (CLL), and autoimmune diseases, such as systemic lupus erythematosus. However, the mechanisms of αCD20 mAb-induced cytotoxicity of B-cells are not fully understood. The major reported mechanisms are those highly effective at activating innate immune cytotoxic mechanisms, particularly antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC). To determine the role of these mechanisms, we tested αCD20 mAb-mediated cellular cytotoxicity of primary CLL cells by autologous or allogeneic (healthy donor) effector cells (human monocyte-derived macrophages for ADCP, or natural killer cells for ADCC) using flow cytometry or time-lapse video microscopy with fluorescent dye-labeled cells. We found that ADCP is the primary mechanism of cellular cytotoxicity by αCD20 mAb and that ADCC does not reliably predict the ADCP induced by that mAb. Furthermore, we compared ADCP using different αCD20 mAbs and found increased phagocytosis by those mAbs with higher affinity for CD20 or FcγR and by those mAbs with higher activation of complement. Finally, the effect on ADCP of inhibitors of BTK and PI3Kδ, molecules that are targeted by current CLL therapy and also found in the FcγR signaling pathway, were tested. We found that the most specific inhibitors of BTK and PI3Kδ had the least effect on ADCP. These data provide meaningful data to design more effective mAb and inhibitor regimens to best use these targeted agents to improve CLL patient outcome.
Unbiased testing of several hundred tumor-specific single nucleotide variants of a tumor for protective immunogenicity and CD8+ response reveals surprises.
Authors: Brennick Cory A. , George Mariam M. , Hagymasi Adam T. , Shcheglova Tatiana V. , Seesi Sahar Al , Mandoiu Ion I. , Srivastava Pramod K. 
Published: January 2023

Abstract
Somatic mutations in cancer cells can give rise to new MHC epitopes referred to as neoepitopes. Neoepitopes have been clearly demonstrated to elicit an antigen specific T cell response, which are capable of mediating targeted killing of cancer cells. Despite recent advancements, exactly what criteria make a good neoepitope for personalized therapy is currently unknown. Here, using a syngeneic tumor of C57BL/6 mice, named FABF, we present results of an exhaustive and exhausting study where we have tested hundreds of long peptides each containing a single nucleotide variant (SNV) (with the mutation in the center of the peptide) for their ability to elicit tumor rejection and independently, CD8+ T cell response. We observe that (i) about 2% of all SNVs lead to generation of peptides that can mediate tumor rejection to any significant degree; (ii) each peptide alone elicits a modest protection, and a combination elicits stronger protective immunity, (iii) all the neoepitopes that elicit tumor rejection have poor binding affinity for MHC I, and have positive values for Differential Agretopic Index (1). (iv) Even though the protective responses are CD8-mediated, there is no correlation between a neoepitope’s ability to elicit a CD8 response and tumor rejection. Some of these observations are inconsistent with some aspects of the current consensus about the defining characteristics of good neoepitopes.