bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocytic myeloid-derived suppressor cells mediate the resolution of lung ischemia-reperfusion injury via MerTK-dependent efferocytosis
Authors: Leroy Victoria , Kollareth Denny Joseph Manual , Tu Zhenxiao , Atkinson Carl , Upchurch Gilbert R , Sharma Ashish K 
Published: August 2023

Abstract
Ischemia-reperfusion injury (IRI) after lung transplantation results in primary graft dysfunction leading to acute and chronic graft rejection. We investigated the role of monocytic myeloid-derived suppressor cells (M-MDSCs) to mediate inflammation-resolution of lung IRI. A murine model of lung hilar ligation was used in Balb/c (WT) and cebpβ−/− (M-MDSC deficient) mice. Lung function, inflammation and M-MDSC infiltration were assessed after 6- or 24hrs in mice undergoing sham control or IRI surgeries. CD11b+Ly6G−Ly6C+iNOS+ M-MDSC lung infiltration in WT mice was significantly increased after 24hrs of IRI compared to 6hrs of IRI (9.9×103±1.2×103 vs. 6.5×103±0.4×103; p=0.02; n=8/group), The upregulation of M-MDSC infiltration at 24hrs was accompanied by increased pulmonary compliance (5.3±0.2 vs. 2.9±0.1 μl/cm H2O; p&lt;0.0001; n=12/group), decreased neutrophil infiltration as well as decreased pro-inflammatory IL-17, TNF-α, and CXCL1 secretion compared to 6hrs of lung IRI. The resolution of lung IRI at 24hrs was blocked in cebpβ−/− mice compared to Balb/c mice as demonstrated by decreased pulmonary compliance (3.1±0.1 vs. 5.3±0.2 μl/cm H2O; p&lt;0.0001; n=7–12/group), that was accompanied by a decrease in M-MDSC lung infiltration (3.3×103±0.20×103 vs. 9.9×103±1.2×103; p=0.003; n=5–8/group). In vitro analysis using a hypoxia-reoxygenation model of lung IRI displayed an increase in efferocytosis as shown by M-MDSC-dependent uptake of apoptotic neutrophils as well as alveolar epithelial cells via a MerTK-dependent mechanism, Collectively, our results indicate that lung IRI entails dysregulated inflammation-resolution which can be mitigated by M-MDSC-mediated MerTK-dependent efferocytosis.
Assessment of donor compatibility in human solid organ transplantation and evaluation of allogeneic responses using a novel humanized mouse model
Authors: Ajith Ashwin , Musa Abu , Horuzsko Daniel David , Horuzsko Anatolij 
Published: August 2023

Abstract
The end result of solid organ transplantation is dictated by selection of a well-matched donor, leading to allograft survival. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching results in poor graft acceptance, inflammation and rejection. The current evaluations for donor-recipient HLA incompatibility does not provide adequate information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a novel method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient’s personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing and mixed lymphocyte reaction (MLR) for assessment of allogeneic response was indistinguishable between 2 related donors of the recipient. Contrastingly in recipient’s humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with increased infiltration of cytotoxic GzmB+CD8+ T cells. Moreover, the same donor induced upregulation of genes involved in the allograft rejection identified by transcriptomic analysis of graft infiltrating CD45+ cells. Humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in transplantation. This approach can be used to evaluate alloresponses in cell based therapies as well.
This study was supported by research funding from the Carlos and Marguerite Mason Trust, and by U.S. National Institutes of Health, National Cancer Institute Grant CA 172230
Engineering islet surface with a novel form of thrombomodulin protein to mitigate instant blood-mediated inflammatory reaction following intraportal transplantation
Authors: Turan Ali , Zhang Lei , Tarique Mohammad , Ulker Vahap , Arguc Feyza , Yolcu Esma , Shirwan Haval 
Published: August 2023

Abstract
Intraportal infusion of islets initiates an innate immune response termed instant blood-mediated inflammatory reaction (IBMIR) that is responsible for significant islet mass peritransplant. We herein used thrombomodulin (TM) as a multifaceted innate immune regulator to mitigate IBMIR to prevent the destruction of islets in a minimal mass syngeneic intraportal transplantation model.
A novel form of TM molecule chimeric with streptavidin (SA-TM) was produced in insect cells and characterized for structure and attachment to biotinylated cell surface taking advantage of the high affinity interaction of biotin with streptavidin (SA). Islets were engineered with SA-TM and assessed for the ability to mitigate IBMIR in an in vitro blood loop assay and survival following intraportal transplantation (200 IEQ/mouse) in STZ diabetic mice (n=7). SA-engineered islets served as control (n=6). Animals were monitored for islet engraftment and subjected to various mechanistic studies.
SA-TM prevented phagocytosis of xenogeneic cells by macrophages and inhibited neutrophil NETs formation. Engineering islets with SA-TM did not impact the viability and function of islets and prevented damage in a blood loop assay. SA-TM-engineered islets showed enhanced engraftment compared to SA-engineered islets (83% vs 29%) following transplantation. Enhanced engraftment was associated with decreased frequency of intragraft myeloid cells and expression of various inflammatory mediators, such as HMGB-1, tissue factor, and IL-1β.
Engineering islets with the SA-TM protein provides a facile and clinically applicable approach to modulate innate immune responses for prevention of IBMIR with potential applications to allo/auto islet transplantation.
Funded in parts by NIH U01AI132817 and R01AI121281 grants.
CD154:CD11b blockade increases MPEC differentiation of virus-specific CD8+ T cells
Authors: Alexander Katie , Liu Danya , Ford Mandy L 
Published: August 2023

Abstract
CD154 pathway blockade has been shown to significantly improve graft survival in transplantation. Recently, CD11b was identified as an alternate receptor for CD154. CD154:CD11b interactions promote rejection by increasing the recruitment of innate and adaptive immune cells into the allograft. However, the effects of CD154:CD11b blockade on the protective immune response to infection during immunosuppression has not been elucidated. To address this, MHV68, a murine homolog of EBV, was used to assess the antigen-specific CD8+ T cell response. Naïve B6 mice were infected with MHV68 and treated on days 0, 2, 4, and 6 with a peptide inhibitor of CD154:CD11b binding (cM7). cM7 treatment resulted in an increase in tetramer+ antigen-specific CD8+ T cells 10 days post-infection that exhibited an increase in gene expression associated with activation and antigen processing. To determine if this increase was a result of enhanced proliferation, CTV-labeled OT-I T cells were stimulated in vitro in the presence or absence of CD154:CD11b blockade. Results indicated that CD154:CD11b blockade did not impact proliferation. Instead, cM7 treatment in vitro resulted in an increase in the expression of CD69, CD25, and CD44, and in vivo resulted in an increase in CD127hiKLRG1lo MPECs. In conclusion, these data demonstrate that CD154:CD11b blockade enhances the quantity and quality of virus-specific CD8+ T cells during protective immunity. We speculate that this could be due to the inhibition of terminal differentiation of antigen-specific T cells resulting in enhanced differentiation of high quality memory precursors, or could be due to an altered balance of CD154:CD40 vs CD154:CD11b binding, resulting in an increase in CD40-driven costimulation.
Supported by grants from NIH (R01 AI152516)
Oral administration of the commensal Alistipes onderdonkii prolongs allograft survival
Authors: Kwan Montserrat , Li Zhipeng , Rasic Mladen , Sepulveda Martin , McIntosh Christine , Shastry Vivaswat , Chen Luqiu , Finn Patricia , Perkins David , Alegre Maria-Luisa 
Published: August 2023

Abstract
Intestinal commensals can exert immunomodulatory effects on the host, with beneficial or detrimental consequences depending on underlying diseases. We have previously identified a specific commensal, Alistipes onderdonkii, as mediator of prolonged allograft survival and reduced alloimmunity. Here, we investigated its sufficiency and mechanism of action and found that oral administration of a beneficial A. onderdonkii strain DSM19147 but not a neutral strain, DSM108265, was sufficient to delay minor mismatched skin graft rejection in a TNF-dependent manner. Specifically, DSM19147 decreased TNF production in T cells and antigen-presenting cells, and TNF neutralization prolonged graft survival. Metagenomics and metabolomics analyses between DSM19147 versus strains that did not prolong graft survival identified unique genes and metabolites correlated with the anti-inflammatory effect of DSM19147. Candidate metabolic pathways unique to DSM19147 pointed to sialic acid and KDO2-lipid A modifications. Our findings identify A. onderdonkii DSM19147 as an anti-inflammatory probiotic that improves transplant survival.
Supported by NIAID grant 2R01AI115716 to MLA, NIAID grant 1U01AI132898 to MLD and DP, NIDDK grant TL1DK132769 to MR, NIAID grant 5T32AI007090 to MS and MK, and by the Growth, Development, and Disabilities Training Program grant (T32 HD007009) to CM.
Tregs are important to maintain CD4+ Tconv hypofunction in allograft tolerance
Authors: Cassano Alexandra , Mora-Cartin Ricardo , Wang Peter , Wang Ying , McIntosh Christine , Chong Anita S F , Alegre Maria-Luisa 
Published: August 2023

Abstract
Regulatory T cells (Tregs) are necessary for the induction of murine cardiac transplantation tolerance via costimulation blockade. In this model, peri-transplant Treg depletion prevents induction of graft-reactive Tconv hypofunction. Whether Tregs are necessary to maintain Tconv dysfunction long-term after tolerance has been achieved remains to be seen. Our preliminary data indicate that complete depletion of Tregs using diphtheria toxin (DT) in Foxp3-DTR mice at the maintenance phase of tolerance precipitated rejection of previously tolerized cardiac allografts and resulted in the de novo production of graft-specific alloantibodies – potentially implying a reinvigoration of Tconvs which then provide help to B cells. Indeed, these Tconvs showed a trend toward renewed cytokine production after Treg depletion and were transcriptionally distinct by RNAseq from Tconvs in tolerant mice. Conversely, Tconvs from tolerant mice infected with Listeria monocytogenes, which precipitates rejection, were transcriptionally similar to Tconvs from unmanipulated tolerant mice. Gene set enrichment analysis revealed that B cell-mediated immune response related pathways were enriched in differentially expressed genes between graft-specific Tconvs from tolerant and Treg-depleted mice. Tconvs from Treg-depleted mice expressed significantly higher levels of genes associated with Tfh cell differentiation compared to both tolerant and naïve graft-reactive Tconvs. This indicates a unique state of potential reinvigoration and implicates Tregs in actively maintaining dysfunction of graft-specific Tconvs, and also suggests that hypofunctional graft-reactive Tconvs may become Tfh cells when reinvigorated by Treg depletion.
Supported by the T32 Immunology Training Grant.
Identification of regulatory natural killer cells in pediatric chronic graft-versus-host disease patients
Authors: Mei Ao , Lauener Madeline P , Schultz Kirk R , Malarkannan Subramaniam 
Published: August 2023

Abstract
Chronic graft-versus-host disease (cGVHD) is the leading cause of late morbidity and mortality in pediatric patients, which is caused by dynamic interferences of multiple types of immune cells, including natural killer (NK) cells. While earlier studies have indicated the potential regulatory function of NK cells restraining pathogenic cell types, the identity of unique NK cell subsets remains unknown. We performed single-cell RNA sequencing on NK cells isolated from the PBMC of patients who developed cGVHD (3 patients) or not (4 patients). Through computational analyses, we identified distinct NK cell populations and found multiple subsets of NK cells expressing unique transcriptomes in patients who received hematopoietic stem cell transplantation (HSCT) compared to healthy individuals, with one of the NK cell subsets exclusively present in post-HSCT patients. Significantly different gene expression patterns were observed between the two groups of patients, including cytotoxicity-related genes elevated in cGVHD patients. By applying diverse statistical analyses, we were able to characterize these NK cell subsets, indicating their potential roles in the development or prevention of cGVHD. Our study defines novel subsets of protective NK cells during cGVHD. These findings are of high translational relevance and can contribute to the treatment of cGVHD patients.
Immune-Modifying Microparticles for Treatment of Acute Graft-Versus-Host-Disease
Authors: Beddow Sara A , Lust Hannah , Galvin John , Miller Stephen D 
Published: August 2023

Abstract

Background
Acute Graft versus host disease (aGVHD) is one of the most common complication of allogeneic hematopoietic stem cell transplant. We have previously shown that infused immune-modifying particles (IMPs) can reduce clinical symptoms and improve survival in inflammatory conditions. IMPs are taken up by inflammatory monocytes (θIM) via the macrophage receptor with collagenous structure (MARCO) and then undergo splenic sequestration. Given these findings, IMPs may be an effective method of reducing inflammation in aGVHD.

Methods
We tested the efficacy of IMP in an established aGVHD murine model. We also explored the changes in immune cell subsets and serum cytokines. To assess impact of IMP on graft-versus-tumor (GVT), we infused host mice with A20 lymphoma cells.

Results
We demonstrated that treatment with IMPs effectively rescues mice in a lethal aGVHD model. Treatment with IMPs also significantly improved clinical and target organ histopathological scores. IMP treatment resulted in increased splenic and intestinal CD4+CD25+Foxp3+ Tregs. IMP treated mice had lower numbers of colonic CD11b+Ly6chi θIM and a lower peak of serum inflammatory cytokines. Maintenance of GVT effect was demonstrated by comparable survival rates in host mice with co-infusion of A20 lymphoma cells.

Conclusion
Systemic IMP was effective at rescuing mice in this lethal aGVHD model. This demonstrates that targeting θIMs with IMPs could be an effective strategy to treat aGVHD. Further investigation of the mechanisms by which IMPs ameliorate aGVHD is warranted, as is investigation of the use of IMPs to treat aGVHD in the clinical setting.

Supported by Nanoparticle Tolerance Research Fund
Immune profile changes induced by extracorporeal photopheresis as prophylactic therapy in lung transplanted cystic fibrosis patients
Authors: Fenizia Claudio , Righi Ilaria , Vanetti Claudia , Biasin Mara , Rosso Lorenzo , Torretta Lorella , Mocellin Maria Cristina , Morlacchi Letizia , Rossetti Valeria , Diotti Cristina , Nosotti Mario , Clerici Mario , Trabattoni Daria 
Published: August 2023

Abstract
Chronic rejection (CR) is the leading cause of late morbidity and mortality upon lung transplantation (LuTx). Extracorporeal photopheresis (ECP) has emerged as a promising immunomodulatory prophylactic induction treatment against rejection. We performed and in-depth investigation of the immunological effects of ECP in LuTx recipients with a diagnosis of cystic fibrosis (CF).
A pilot clinical trial enrolled 20 CF LuTx patients who were randomly allocated in 2 arms: standard immunosuppressive therapy alone vs. standard immunosuppressive therapy plus ECP for 3 months, beginning within 72h from LuTx. Functional activation of T and NK subpopulations as well as mRNA expression and cytokine secretion profiling were evaluated in peripheral blood and in bronchoalveolar lavage (BAL) up to 12 months after LuTx. Clinical parameters, including respiratory volumes (e.g. FEV1), rejection episodes and infections, were analyzed as well.
ECP was well tolerated with no complications nor opportunistic infections. Rejection rate was comparable in the two groups Notably, a significantly better FEV1 was observed in the ECP group overtime. Treg lymphocytes and IL10-producing NKs were significantly increased, while Th17 cells were significantly reduced in the ECP group compared to the control. Cytokine profile showed that ECP reduced pro-inflammatory cytokines (e.g. IL1b, IL6) production, increasing that of anti-inflammatory cytokines (e.g. IL10, IL1RA) both in plasma and BAL
ECP is associated with immune modulation resulting in improved patients’ respiratory performance. More extensive studies and longer follow-up are needed to verify if ECP-induced immune modulation will have a beneficial effect of organ rejection as well.
Supported by grants from the Cystic Fibrosis Foundation
Dietary fat source induces gut microbiota alterations and impacts chronic murine graft- versus-host disease severity
Authors: Millick Danielle , Strair Roger , Sant’Angelo Derek 
Published: August 2023

Abstract
It has been observed that a constriction of the gut microbiome occurs with high fat diet, and likewise decreased microbiome diversity is directly correlated with more severe graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation. Taken together it is plausible that not only fat content, but source of dietary fat could influence gut microbiota and GvHD outcome. We sought to address this question and developed experimental rodent diets that have the same fat content (25% kcal fat, a moderate increase in fat content from normal chow) which differ only by fat source: animal- versus plant-derived fat and found that these diets drive alterations in gut microbiota diversity. Both diets yielded similar outcomes in an acute model of GvHD, however we found that mice fed the animal-derived fat diet exhibited worse survival and outcomes in a model of chronic GvHD, than mice fed the plant-derived fat diet. These findings correlated with increased inflammation and alterations in intestinal immune cell populations following chronic GvHD induction. Collectively, our data show that diets that are equal in macronutrient content but different in fat source can promote different gut microbiomes and in turn alter intestinal homeostasis and chronic GvHD outcome.
Century for the Cure - Philanthropic Fund
Examining the Relationship Between Gamma Delta T Cells and Sensory Peripheral Nerves in the Skin
Authors: Almaguer Berenice , Tulloch Patricia , La Prairie Chloe , Jameson Julie M 
Published: August 2023

Abstract
Wound repair involves a complex system of immune cells and mechanisms to induce proper healing of a laceration. The transmission of pain signals and immune functions occur simultaneously, suggesting a collaboration between immune and nervous systems. Gamma delta (γδ) T cells are present in the epidermis and dermis where they participate in wound repair by producing growth factors, cytokines, and chemokines. Dermal γδ T cells are adjacent to nerves in the skin. We set out to determine whether sensory peripheral nerve endings and γδ T cells exhibit crosstalk during wound repair. Using immunofluorescent microscopy we found that peripheral neurons and γδ T cells are in close proximity in both the epidermis and the dermis suggesting a transmission of signals. To determine whether γδ T cell dysfunction impacts neurons, we examined non-wounded and wounded skin derived from lean versus diet-induced obese (DIO) mice. There was less interaction between γδ T cells and sensory peripheral nerves in both nonwounded and wounded DIO mouse skin. To determine whether the lack of γδ T cells impacts peripheral nerve repair and wound healing responses, we compared wildtype and T-cell receptor knockout (TCRd−/−) mice. TCRd−/− mice did not exhibit any differences in the number of sensory peripheral nerves in nonwounded skin. However, there were fewer sensory peripheral nerves surrounding the wound edge in mice lacking γδ T cells. Together this data indicates that γδ T cells regulate how sensory peripheral nerves innervate a wound, but are not required for neuronal development. Understanding the mechanism that regulate the interdependent relationship between γδ T cells and sensory peripheral nerves could further our understanding of how to improve wound repair.
IL-35 Restricts Serine Metabolism to Suppress Effector T Cell Function in Atopic Dermatitis
Authors: Choi Jin Kyeong 
Published: August 2023

Abstract
IL-35 is an immunosuppressive cytokine and a critical regulator of immunity in autoimmune diseases. However, whether IL-35 controls metabolism to inhibit T cell development in atopic dermatitis (AD) remains unclear. In this study, we demonstrated that IL-35 ameliorates AD by inhibiting the serine metabolic enzyme, phosphoserine aminotransferase 1 (PSAT1), in mice and humans. When the major metabolic pathway was assessed, IL-35 was found to inhibit increased serine metabolism in activated T cells. Measure of the ear thickness, histological examination showed that treatment of the mice with IL-35 inhibited AD inflammation by suppressing expansion of Th1, Th2, Th17 cells while inducing expansion of Foxp3-expressing Tregs. IL-35 also regulated alterations in glycolytic metabolism in mice and patients with AD. Importantly, the IL-35-mediated suppression of Th2 cells and amelioration of AD correlated with the inhibition of serine metabolic pathways, such as PSAT1, in the skin. Herein, IL-35 was found to inhibit effector T cells in AD by directly regulating the serine metabolic enzyme, PSAT1. Therefore, therapies that target serine-dependent metabolic pathways via IL-35 could serve as effective therapeutic strategies for AD.