bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha-synuclein specific regulatory T cells expanded with bee venom phospholipase A2 improves the neuroprotective effects in MPTP-induced mouse model of Parkinson’s disease
Authors: Park Seon-Young , Min Daeun 
Published: January 2023

Abstract
Parkinson’s disease (PD) is a long-term degenerative autoimmune disease that mainly affects the motor system. Cell therapy using regulatory T cells (Tregs) has been shown to be effective on PD progression. To improve the efficiency of Treg therapy on PD, alpha-synuclein (a-syn) was used as a self-antigen for enrichment of a-syn specific Tregs during ex vivo expansion. In addition, to solve the problem of changing the phenotype of Tregs during expansion, bee venom phospholipase A2 (bvPLA2) was treated. The results showed that treatment of bvPLA2 remains Tregs to naïve phenotype that possessed optimal suppressive activities. And a-syn presenting changed the TCR repertoire in Tregs. As a result, these changes in Tregs by bvPLA2 and a-syn improve the neuroprotective effects on MPTP-induced mouse model of PD. Motor function deficits induced MPTP intoxication was palliated by adoptive transfer of a-syn specific and bvPLA2 treated Treg. Adoptive transfer of a-syn specific and bvPLA2 treated Treg also reduced activated microglia, especially pro-inflammatory microglia in MPTP-induced PD model. Dopaminergic neurons in substantia nigra (SN) was dramatically protected from MPTP intoxication by the Tregs that has treated with a-syn and bvPLA2. Thus, adoptive transfer of a-syn specific and bvPLA2 treated Tregs shows substantial neuroprotective effects on MPTP-induced PD mice.
B Cell Maturation Antigen deficiency increases inflammatory B-cell functions in multiple sclerosis
Authors: Kumar Gaurav , Ko Rose M. , Axtell Robert C. 
Published: January 2023

Abstract
B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, TACI-Ig treatment, which blocks BAFF and APRIL (two cytokines important for B cell development and function), paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we explored the impact BCMA deficiency has on the development and progression of the experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Here, we identified that the expression of BCMA is dysregulated in B cells from MS patients and is important in inhibiting inflammatory B cell responses in EAE. We discovered that BCMA expression is decreased on transitional B cells in MS. In mice we found that EAE induced with MOG35–55 was severe in BCMA−/− mice compared to BCMA+/+. The increased disease was associated with increased CNS inflammation, significantly reduced transitional B cells and a skewing of B-cells toward a mature/inflammatory phenotype. Bone marrow chimeric and in vitro experiments demonstrated that BCMA directly inhibits memory B cell expansion and anti-inflammatory cytokine production by B cells. Strikingly, BCMA impacts the efficacy of B cell depleting therapies, as anti-CD20 antibody treatment attenuated EAE in BCMA-deficient mice but not BCMA-sufficient mice. These data provide novel insights into B-cell dysregulation in MS.
Immunomodulatory networks in multiple sclerosis
Authors: Ntranos Achillefs , Lee Brian , Xie Hui , Rockoff Jonathan , Brandstadter Rachel , Kim-Schulze Seunghee , Lublin Fred 
Published: January 2023

Abstract

Background
Dimethylfumarate (DMF) and ocrelizumab are two effective immunomodulators for multiple sclerosis but their mechanism of action involves different immune pathways. In this study we constructed immunomodulatory networks from cytokine and immunoprofiling data to evaluate the similarities and differences between these two disease modifying therapies in multiple sclerosis (MS).

Methods
Plasma and PBMCs from 16 and 13 MS patients were collected at baseline, 3 months and 6 months after treatment with DMF and ocrelizumab respectively. Cytokine analysis from plasma was performed with Olink assays and immunophenotyping was done by Cytof. Data were integrated with weighted correlation network analysis and highly interconnected modules were identified. Associations between modules and therapy was done with linear mixed effect models.

Results
DMF treatment was associated with a significant reduction of a module responsible for chemokine signaling pathways and cytokine-cytokine receptor interactions, whereas ocrelizumab treatment led to the increase of a module of soluble factors that are involved in tryptophan metabolism and foxp3 activation. DMF also reduced both T and B cell memory populations and ocrelizumab exerted its immunomodulatory effect by mostly reducing the frequency of memory B cells.

Conclusions
Our results suggest that DMF and ocrelizumab affect different immune networks to exert their effect in multiple sclerosis patients.
Recipient expression of C-type lectin receptor Mincle promotes rapid T cell homeostatic recovery following antibody mediated lymphoablation
Authors: Hasgur Suheyla , Fan Ran , Valujskikh Anna 
Published: January 2023

Abstract
Antibody-mediated lymphocyte depletion is widely used in transplantation. We recently showed that T cell recovery in mouse heart allograft recipients treated with anti-thymocyte globulin (mATG) depends on B cells activated via CD40 and is mediated by B cell-derived IL-1β and IL-6. Mincle (Clec-4e) is a FcRγ-coupled C-type lectin receptor that binds ligands released by pathogens or damaged cells and signals through the Card-9 pathway. While Mincle functions are well characterized in myeloid cells, its significance in B cells remains to be determined. Our goal was to investigate the role of Mincle in initiating B cell cytokine production in lymphopenic heart allograft recipients. The NanoString and RT-PCR analyses of B cells showed that mATG depletion resulted in B cell up-regulation of Mincle and Card-9 gene expression. Flow cytometry confirmed cell surface Mincle expression in B cells from mATG-treated recipients but not from naïve mice. Treatment with anti-CD154 mAb in addition to mATG decreased the B cell expression of Mincle, IL-1β, IL-6 and TNF-α. Moreover, B cell IL-1β and TNF-α expression were reduced in mATG treated Mincle KO allograft recipients compared to WT controls. Most importantly, Mincle KO recipients treated with mATG had severely impaired T cell recovery and significantly prolonged allograft survival compared to WT recipients. We propose that B cells activation via CD40 results in up-regulation of cell surface Mincle. Endogenous ligands released from necrotic graft cells bind to Mincle thus inducing B cells to secrete proinflammatory cytokines and facilitate CD8+ T cell proliferation. These data identify Mincle as a novel therapeutic target to improve the efficacy of lymphoablation in allograft recipients.
Tertiary lymphoid organs in renal chronic allograft rejection
Authors: Daya Khodor Abou , Zhao Daqiang , Biery Kyle , Oberbarnscheidt Martin H. 
Published: January 2023

Abstract
Chronic allograft rejection remains a major obstacle to long-term allograft survival. The immunologic role of tertiary lymphoid organs (TLO) in allograft rejection is unclear. Here, we employed a chronic renal allograft rejection model in mice and intravital 2-photon microscopy to investigate the function of TLO in transplant rejection.
CB6F1 (F1) RIP-LTα (preformed TLO) or F1 (no TLO) kidney grafts were transplanted to WT B6 recipients and survival monitored. To investigate immunologic function of TLO, we adoptively transferred B6-RIPLTα CD11c-YFP mice with 10m naïve dsRed OT-I T cells or 10m CTR-labeled NP-specific B cells + 10m CFP+ OT-II cells and immunized with NP-OVA + alum. Intravital 2P imaging of renal TLO was performed at time points 0, 3, 6, 24 or 72 hours after immunization. 4D image analysis was performed and mean speed, displacement, arrest coefficient (AC) and contact times (CT) with DC were calculated for OT-I, OT-II and NP-B cells.
F1 RIP-LTα grafts rejected significantly faster (MST= 54) than F1 grafts (MST= 225), demonstrating that TLO contribute to allograft rejection. F1 RIP-LTα grafts contained similar numbers of, but larger TLO than F1 grafts as demonstrated by histology. Mean speed and displacement of OT-I and OT-II cells significantly decreased over time after immunization while AC and mean CT significantly increased. B cell mean speed, displacement and AC increased after immunization. These data are consistent with B cell activation and productive T cell-DC interactions and mirror previously reported data in secondary lymphoid organs.
We provide first evidence that TLO provide a local structure for T and B cell activation that propagates anti-graft immune responses in the setting of chronic rejection.
Circulating exosomes from human lung transplant recipients with respiratory viral infections contain nucleic acids potential to activate innate immune signaling (cGAS/STING and RIG-1 Pathways)
Authors: Bansal Sandhya , Limaye Ajit , Omar Ashraf , Smith Michael , Bremner Ross , Mohanakumar Thalachallour 
Published: January 2023

Abstract
Exosomes are 50–200nm size vesicles released by cells into the body fluids. We reported the presence of circulating exosomes with lung self-antigens (SAgs) (Collagen-V,K-α Tubulin) and donor HLA in lung transplant recipients (LTxRs) undergoing rejection. Respiratory viral infections (RVI) is a known risk factor for development of chronic lung allograft dysfunction (CLAD) post lung transplant. We postulated immune mechanism by which RVI increases risk for CLAD is by induction of exosomes with SAgs containing viral DNA/RNA capable of activating innate immune signaling via DNA/RNA sensing. Exosomes were isolated using ultracentrifugation. Exosomal DNA and RNA were used to generate libraries using Kapa Biosystem’s kit. Illumina 2×150bp pair-end reads were checked on FastQC, aligned to human/viral genome from CHIP seeker Database. Role of exosomes inducing cell signaling in human airway epithelial cells (KCC266) and Hep2 were analyzed by incubating exosomes from LTxRs with RVI or stable. Viral nucleic acid sequences were higher in exosomes from LTxRs with RVI while comparison with human genome identified the presence of DNA sequences specific to defensins, GTPase, apoptotic cleavage, and NMDA receptor in exosomes from RVI. We observed upregulation of proteins associated with cGAS/STING and RIG1 in KCC266 and Hep2 cells (STING; 1.5, cGAS; 1.9, pIRF3; 2.5, pTBK; 3.1, MAVS; 1.7 and IFNβ; 3.8 fold respectively) incubated with exosomes from LTxRs with RVI. We conclude that LTxRs with RVI leads to induction of circulating exosomes having unique viral nucleic acid sequences capable of inducing signaling. This can lead to activation of innate immune signaling resulting in adaptive immune responses to viral and donor antigens resulting in CLAD.
The effect of SLA expression on genetically-engineered pig renal cells on the human T cell xenoresponse
Authors: Wang Zheng-Yu , Ladowski Joseph M. , Li Juan , Martens Gregory R. , Reyes Luz M. , Estrada Jose L. , Tector A. Joseph 
Published: January 2023

Abstract

Background
Xenotransplantation using genetically-engineered (GE) pig organs offers an unlimited supply of organs for patients with end-stage organ failure. Disrupting the porcine GGTA1/CMAH/β4GalNT2 genes (TKO) markedly reduces binding of human natural anti-pig antibodies in human to carbohydrate antigens expressed on the pig organ. However, more evident have demonstrated that T cell responses play a major role in xenogeneic rejection, and that immunosuppression alone is likely incapable of completely suppressing these responses. The object of this study is at an organ-specific level to evaluate human T cell-mediated response against GE pig renal microvascular endothelial cells (RMEC) with or without swine leukocyte antigen (SLA) class I or II.

Methods
Primary RMEC were isolated from the GGTA1/CMAH knockout (DKO) pigs, and immortalized using Lenti-SV40 T. The gene editing was performed to create specific TKO RMEC cell lines expressing SLA class II. Stimulation of human T cell activation or proliferation by RMEC was performed flow cytometry-based mixed lymphocyte reaction (MLR).

Results
The specific GE cells lacking carbohydrates or expressing SLA class I or II were confirmed. MLR data shows that human CD4+ T cell proliferation by CD31+ RMEC was higher than that by fibroblast-like renal cells (RC), and was significantly inhibited by immunosuppressive drugs. Furthermore, both of CD69+ and CD25+ T cells were significantly enhanced by RMEC with expression of SLA class I and II compared with SLA class I alone.

Conclusion
Porcine RMEC express SLA class I/II and known costimulatory molecules and have the ability to simulate human T cell proliferation. RMEC will be a useful reagent for the further study of xenotransplantation.
Developing a novel biologic for the treatment of high-risk B cell acute lymphoblastic leukemia
Authors: Ruiz-Jiménez Caleb , Coats Jacqueline , Meng Xianmei , Stoian Cornelia , Baez Ineavely , AlKashgari Hossam , Paz-Aldana Andy , Doublet Sarah , Choi Hannah , Williams Roland , Farzin-Gohar Shadi , Dovat Sinisa , Payne Kimberly J 
Published: January 2023

Abstract
The subtype of B cell acute lymphoblastic leukemia (B-ALL) at highest risk for relapse overexpresses surface CRLF2 (CRLF2 B-ALL) and disproportionately affects Hispanic children and adults. CRLF2 partners with the IL-7Ra to form a receptor complex activated by the cytokine, Thymic Stromal Lymphopoietin (TSLP). TSLP activates the JAK/STAT and PI3/AKT/mTOR pathways which are known to promote cell survival and proliferation. Our in vitro studies of CRLF2 B-ALL cells showed that supra-physiological levels of TSLP (1 ng/ml) induced a complete shutdown of TSLP receptor signaling, following the initial activation event. This effect was dose dependent and did not occur at physiological levels (20 pg/ml) of TSLP. This signal shutdown was correlated with the loss of surface IL-7Ra. Using a novel patient-derived xenograft (PDX) model that expresses human TSLP (hTSLP, mouse TSLP does not activate the human TSLP receptor) created in our lab, we showed that high dose hTSLP virtually eliminated human CRLF2 B-ALL cells in vivo. The goal of work presented here was to test whether treatment of CRLF2 B-ALL PDX with high doses of recombinant hTSLP (rhTSLP) could re-capitulate anti-tumor effects of hTSLP observed in our engineered mice and to evaluate its effects on prolonged survival. After 24 days of treatment, rhTSLP reduced the leukemia cell burden by 90% in treated PDX as compared to control PDX that received physiological levels of rhTSLP. Similarly, survival was prolonged in PDX mice receiving high-dose rhTSLP as compared to controls: all 11 control mice died before any of the 11 treated mice died. Taken together, these data suggest that TSLP has promise as a biologic for the treatment of CRLF2 B-ALL.
Overexpression of LLT1 (CLEC2D) in childhood Acute Lymphoblastic Leukemia (ALL)
Authors: Mathew Stephen O , Powers Sheila , Daniel Steffi , Jose Roslin , Aryal Subhash , Bowman W. Paul , Mathew Porunelloor 
Published: January 2023

Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in the developed world with peak incidence between the ages of 2 and 5 years. Despite current treatment protocols achieving significant improvement in survival of ALL patients, serious acute and late complications are frequent and resistance to chemotherapy often develops. Although NK cells have long been known to mediate antigen independent tumor killing, the therapeutic potential of NK cell-based immunotherapy has yet to be realized. NK cells have the capacity to kill virus-infected or tumor-transformed cells and they express several surface molecules that regulate NK cell function both positively and negatively. We have previously identified 2B4 (CD244), CS1 (CRACC) and LLT1 (CLEC2D) to play a major role in NK cell activation. In this study, we evaluated the cell surface and mRNA expression of NK cell receptors in 42 ALL subjects and 20 healthy subjects both male and female in the age range of 2 – 20 yrs from different racial/ethnic groups. The peripheral blood samples were collected and analyzed by flow cytometry and real-time PCR for expression. A significant increase in the expression of LLT1 in the T and NK cell populations was observed in ALL subjects as compared to healthy subjects. NK cells from 3 ALL subjects also showed impaired cytotoxic function as they demonstrated lower killing of K562 cells compared to a healthy subject. These results indicate that LLT1 may play a role in NK-mediated surveillance of childhood ALL.
Circulating Low Density Neutrophils In Advanced Lung Cancer Patients Exhibit Unique Immune Signatures and affect prognosis
Authors: Krieg Carsten , Shaul Merav , Guglietta Silvia , Weber Lukas , Robinson Mark , Fridlender Zvi 
Published: January 2023

Abstract
The role of innate immunity, in especially neutrophils, in supporting anti-tumor immunity in lung cancer is understudied. Neutrophil "flavors", such as low-density neutrophils (LDN) and high-density neutrophils (HDNs), have been described in cancer patients and associated with tumor-supportive properties. Nevertheless, HDN and LDN phenotypic properties and their cancer-driven modulations are still largely unknown. Here, we aimed to evaluate the clinical relevance and significance of circulating LDN in lung cancer patients, and by using data-driven artificial intelligence supported analysis tools evaluated phenotypic states of circulating neutrophils subsets during lung cancer progression. COPD patients and healthy volunteers served as controls. Using mass cytometry (CyTOF), we aimed to identify major sub-populations within circulating LDN and HDN subsets and determine a possible change in phenotype due to cancer. LDN were highly enriched in advanced lung cancer patients (12.9±2.4%), but not in early stage patients (1.2±0.2%), healthy individuals (1.3±1.1%), or stable COPD patients (2.2±0.6%). Elevated LDN (&gt;10% of LDF) showed a remarkable correlation with poorer prognosis in advanced patients. Our CyTOF analysis revealed the presence of three main neutrophil subsets with a great variability in the presence of CD10+ vs. CD10− LDNs between patients. We further demonstrated that both HDN and LDN retain a degree of inherent spontaneous plasticity. Deep characterization of cancer-related circulating neutrophils, as well as their modulation along tumor progression, will assist in suggesting new biomarkers and novel targets to improve response to current conventional therapies and immunotherapies.
Dynamic regulation of TRIM37 expression in macrophages facilitates pancreatic cancer development
Authors: Chen Hui-Chen , Chang Hung-Chih , Chang Yi-Hao , Wu Chia-Wei , Wu Guo-Wei 
Published: January 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer as the overall five-year survival rate was less than 5%. More than 90% of PDAC patients harbor Kras mutation, but only mutant Kras is insufficient to give rise to PDAC. Inflammation is essential to cooperate with mutant Kras for the initiation of pancreatic precancerous lesion, and attracted M1-polarized macrophages-induced inflammation are known to contribute to the process. Among TRIM family proteins, TRIM37 is the only protein containing MATH domain that endows it being able to interact with proteins containing TRAF domain, indicating its possible role in regulating pattern recognition receptor-, TNFR- and cytokine-mediated signaling pathways. We have observed that, when TRIM37 was knocked-down, macrophage cytokines production, such as IL-1β, IFN-β, IL-12, TNF-a, IL-6 and CCL-2 in response to LPS was reduced, and the regulation was both epigenetically and non-epigenetically. Interestingly, pro-inflammatory cytokines also upregulated TRIM37 expression in macrophages. Thus our data implicated that upregulated TRIM37 that positively regulate macrophage cytokine production might contribute to the initiation of PDAC. However, when macrophages were co-cultured with pancreatic cancer cells, the expression level of TRIM37 in macrophages were downregulated, this led to the loss of its ability in maintaining macrophages in a stable M1 phenotype, and instead, skewing the macrophages into a M2 phenotype, which promotes cancer progression. In conclusion, our data demonstrate that during pancreatic cancer development, the expression of TRIM37 in macrophages are differential regulated to favor cancer development and progression.
STAT3 induces the expression of fatty acid transport proteins (FATP2 and FATP4) to promote myeloid-derived suppressor cells function in tumor
Authors: Adeshakin Adeleye Oluwatosin , Yan Dehong , Zhang Mengqi , Afolabi Lukman Olalekan , Adeshakin Funmilayo Oladunni , Wan Xiaochun 
Published: January 2023

Abstract
Myeloid-derived suppressor cells are critical to regulation of immune responses; their accumulation in cancer patients inhibit antitumor immunity and suppress T-cells activity thereby promoting cancer progression and metastases. Metabolic reprogramming has been identified as a crucial factor in modulating MDSCs function; however, how lipid metabolism promotes MDSCs activity during tumor remains unknown. Here we report the upregulation of fatty acid transport proteins (FATP2 and FATP4) enhanced the exogenous uptake of fatty acids resulting in hyperlipidemic MDSCs during tumor. Accumulation of unsaturated fatty acids in GM-CSF-induced MDSCs in-vitro released IL-6, ARG1 and iNOS thereby inhibiting T-cells function. Increased fatty acid uptake in MDSCs induces the expression of FATP2 and FATP4 via activation of STAT3. Interestingly, therapeutic blockade of STAT3 decreased lipid accumulation and repressed FATP2 and FATP4 expression in MDSCs. Also, FATP2 specific inhibitor (Lipofermata) abrogated tumor progression in immunocompetent B16F10-tumor bearing mice in MDSCs dependent manner. Therefore, our data suggests therapeutic manipulation of lipid metabolic signaling pathways in MDSCs could be a promising approach to effective cancer immunotherapy.
CD226hiCD8+ T cells are a prerequisite for anti-TIGIT immunotherapy
Authors: PARK YOON , Jin Hyung-seung 
Published: January 2023

Abstract
Multiple clinical trials are evaluating the efficacy of anti-TIGIT antibodies for use as single-agent therapy or in combination with PD-1/PD-L1 blockade. However, TIGIT’s mechanism of action and whether a TIGIT blockade will synergize with current immunotherapies is not fully understood. Here we show that CD226loCD8+ T cells are accumulated at the tumor site and have an exhausted phenotype with an impaired functionality. In contrast, CD226hiCD8+ tumor-infiltrating T cells possess a higher self-renewal capacity and potent responsiveness. Anti-TIGIT antibody treatment selectively affects CD226hiCD8+ T cells by promoting CD226 phosphorylation at tyrosine 322. CD226 agonist antibody-mediated activation of CD226 augments the effect of TIGIT blockade on CD8+ T cell responses. Finally, mFOLFIRINOX treatment, which increases CD226hiCD8+ T cells in patients with pancreatic ductal adenocarcinoma, potentiates the effects of TIGIT or PD-1 blockade. Our results implicate CD226 as a predictive biomarker for cancer immunotherapy and suggest that increasing CD226hiCD8+ T cells may improve anti-TIGIT therapy.