bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response Gene to Complement -32 facilitates local recruitment of IL-17-producing cells in immune complex mediated glomerulonephritis through the CCR6/CCL20 axis
Authors: Rus Violeta , Tatomir Alexandru , Nguyen Vinh , Papadimitriou John , Drachenberg Cinthia , Sung Sun-Sang J , Fu Shu Man , Luzina Irina G , Badea Tudor Constantin , Rus Horea G 
Published: January 2023

Abstract
Response Gene to Complement (RGC)-32 is a cell cycle regulator induced by complement activation, growth factors and cytokines. RGC-32 mediates TGF-β dependent profibrotic pathways, while in immune cells promotes the differentiation of Th17 cells. In the nephrotoxic nephritis (NTN) mouse model of glomerulonephritis (GN), RGC-32 promotes organ damage through proinflammatory and profibrotic effects. To define the mechanisms underlying the role of RGC-32 in immune complex GN, we induced NTN in WT and RGC-32−/− mice. Proteinuria, blood urea nitrogen and kidney histopathology were determined to assess kidney damage. Single cell suspension of infiltrating kidneys and spleens cells were analyzed by flow cytometry and PCR for expression of IL-17A, CCR6, CCL20, CXCL1, CXCL2 and CXCL5.
Induction of NTN in RGC-32−/− mice resulted in decreased expression of IL-17A and CCR6 mRNA and decreased proportion of renal IL-17A+ CD4 T cells. The decrease in IL-17A+ CD4 cells was paralleled by decreased mRNA expression of CCL20 in both the renal tissue and infiltrating kidney cells of RGC-32−/− mice. In vitro, CD4+ T cells from spleens of RGC-32−/− mice cultured under Th17 conditions displayed decreased expression of CCL20 mRNA. These data suggest a role for RGC-32 in the positive feedback loop that enhances Th17 cell recruitment. The decrease in renal IL-17A+ cells was associated with decreased expression of IL-17 induced chemokines CXCL1, CXCL2 and CXCL5 and decreased local infiltration of neutrophils. These results suggest that RGC-32 promotes the proinflammatory pathway in immune complex mediated GN by enhancing local recruitment of IL-17A+ cells through the CCR6/CCL20 axis. RGC-32 is a potential novel therapeutic target in the treatment of LN.
IL-35 producing antigen presenting cells in type 1 diabetes
Authors: Luo Zhengkang , Blixt Martin , Carlsson Per-Ola , Espes Daniel , Sandler Stellan , Singh Kailash 
Published: January 2023

Abstract
In type 1 diabetes (T1D), the insulin producing β cells are damaged by unknown factors. Antigen presenting cells (APCs) are believed to present autoantigens to T cells, thus initiating the immune attacks to β cells. However, several types of APCs also possess regulatory functions by producing anti-inflammatory cytokines like IL-35. We found the proportions of IL-35+ cells among both CD11c+CD123− dendritic cells (DCs) and CD11c−CD123+ DCs were decreased in the peripheral blood mononuclear cells from T1D patients than healthy controls. Multiple low dose streptozotocin (MLDSTZ) mouse model of T1D was used to study the immune response of IL-35 producing APCs. Male CD-1 mice were injected with STZ for five consecutive days to induce experimental T1D. We found the proportions of IL-35 expressing MHC-II+CD11b−CD11chigh conventional DCs (cDCs) were decreased in the spleens of MLDSTZ mice than in control mice on day 21 after the first STZ injection. We next investigated which subtype of cDCs contribute to the IL-35 production, and found that it is CD8+XCR1+ cDC1s that produce IL-35 while cDC2s do not. After the five day STZ injections, male CD-1 mice further received recombinant mouse IL-35 injection or PBS daily for 8 days. We found increased proportions of IL-35+ cells among cDC1s in IL-35 treated mice than PBS treated mice. Only a minority of plasmacytoid DCs (pDCs) produce IL-35, and IL-35 treatment did not increase the proportion of IL-35+ pDCs. We further investigated macrophage polarization, finding that IL-35 treatment increased Arg1+ M2 proportions and decreased TNF-α+ M1 proportions. Our results illustrate that the decrease in IL-35 producing APCs may contribute to the development of T1D.
Iloprost-treated dendritic cells promote antigen-specific regulatory T cell differentiation in mice
Authors: Wong Tzu-Hsuan , Gau Rong-Jiun , Chen Yu-Fang , Shen Hsin-Hsin , Lin Carl Tsai-Yu , Chen Sen-Lu , Suen Jau-Ling 
Published: January 2023

Abstract
Iloprost, a stable prostaglandin I2 (PGI2) analog, can inhibit allergic inflammation in an OVA-induced asthma model via inhibition of airway dendritic cell (DC) function. However, the underlying mechanism of PGI2 signaling-mediated immunosuppression remains unclear. This study explored whether iloprost-treated DCs can suppress inflammation by promoting antigen-specific regulatory T cell (Treg) differentiation. We established an allergic lung inflammation model using a hydrogel biomaterial delivery system and observed that iloprost significantly suppressed OVA-induced Th2 lung inflammation and increased the frequency of OVA-specific Tregs in vivo. We further observed that iloprost-treated DCs displayed tolerogenic characteristics, including low inflammatory cytokine (IL-12p70, TNF-α, IL-6, IL-23) expression levels, high anti-inflammatory cytokine (IL-10) production, and a semimature phenotype. In addition, iloprost-treated DCs increased OVA-specific CD4+Foxp3+ T cell differentiation from naïve T cells in vitro and in vivo. Blocking experiments showed that iloprost-treated DCs promoted Treg differentiation, at least in part, through PD-L1. Furthermore, iloprost treatment suppressed DC-mediated airway inflammation and increased the frequency of OVA-specific Tregs through PD-L1 in vivo. Taken together, these results show that PGI2 signaling in DCs may lead to immune tolerance, suggesting that the PGI2 analog has the potential to be applied therapeutically for tolerogenic DC immunotherapy in autoimmune diseases or allergic asthma.
Olfactory ecto-mesenchymal stem cells derived exosomes reverse the immunosuppressive capacity of myeloid-derived suppressor cells to ameliorates experimental Sjögren’s syndrome
Authors: Rui Ke , Tian Jie , Hong Yue , Lu Liwei , Wang Shengjun 
Published: January 2023

Abstract
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by progressive inflammation and tissue damage of salivary glands and lacrimal glands. Our previous studies have shown myeloid-derived suppressor cells (MDSCs) were significantly increased but exhibited gradually diminished suppressive capacity in experimental Sjögren’s syndrome (ESS), thus leading to the development of the disease. In this study, we found that exosomes derived from olfactory ecto-mesenchymal stem cells (OE-MSCs-Exo) effectively enhanced the suppressive function of MDSCs on T cell proliferation, up-regulated MDSC-mediated suppressive factors (Arginase, ROS and NO), and subsequently suppressing the development of ESS. Additionally, levels of CD40, CD80, CD86 and MHCII on MDSCs were dramatically decreased, indicating the differentiated late stage MDSCs were reversed to the original undifferentiated status by OE-MSCs-Exo. Further investigation demonstrated that the increased suppressive function of MDSCs was orchestrated by IL-6, from both exosomes secreted IL-6 as well as its own IL-6 autocrine signaling pathway. Taken together, OE-MSCs-Exo have the potential to alleviate ESS severity through inducing MDSC expansion and potentiating their immunosuppressive function, indicating OE-MSCs-Exo may represent a new therapeutic strategy for the treatment of Sjögren’s syndrome and other autoimmune diseases.
IL-37 increases liver inflammation in Con A-induced hepatitis by increasing IFN-γ secretion of infiltrated NK Cells
Authors: Lin Chia I , Tsao Cheng Chiu , Chuang Ya Hui 
Published: January 2023

Abstract
Liver is an immunologically tolerogenic organ, while, autoreactive immune cells mediated autoimmune hepatitis (AIH) is observed. Suppression of the hyper-reactive immune responses may restore the tolerance of liver. IL-37, an emerging IL-1 family cytokine with anti-inflammatory effects on innate and adaptive immunity, shows benefit on many autoimmune diseases. We proposed IL-37 could inhibit immune responses and improve AIH. IL-37 expressing adeno-associated virus (AAV-IL-37) successfully dampened the activation of macrophages in vitro. We next analyzed the effect of IL-37 in Con A-induced autoimmune hepatitis mouse model. Surprisingly, the liver histopathology showed more necrotic hepatocytes and infiltrating immune cells in AAV-IL-37 treated Con A mice than in control mice. Higher levels of serum IFN-γ in IL-37-expressing Con A mice were observed. Moreover, expression of inflammation-related mRNA in the liver were also highly induced with AAV-IL-37 treatment. Among hepatic lymphoid cells, NK and NKT cells were particularly increased in IL-37 treated Con A mice. The frequency of IFN-γ-secreting NK cells was also significantly increased. Further, CCL5, a chemoattractant for NK cells, was significantly elevated in the serum of AAV-IL-37 injected Con A mice. These results suggest that IL-37 worsen liver inflammation instead of relieving the disease. Of note, there was no obvious inflammation in AAV-IL-37 treated naïve mice, suggesting the proinflammatory effect of IL-37 in Con A treated mice resulted from the inflamed liver microenvironment. In conclusion, IL-37 aggravated liver inflammation in Con A induced hepatitis through recruiting NK cells and elevating the IFN-γ secretion of NK cells.
Single-cell analysis of autoreactive B cells in patients with systemic sclerosis revealed that responses to therapy are determined by effector and regulatory B cell balance
Authors: Ebata Satoshi , Yoshizaki Ayumi , Fukasawa Takemichi , Sato Shinichi 
Published: January 2023

Abstract

Objective
Systemic sclerosis (SSc) is a connective tissue disease with poor prognosis. Although the standard treatment for skin and lung fibrosis is cyclophosphamide (CYC), there are not a few non-responders to the treatment. Recent studies showed that autoreactive B cells play a critical role in SSc. We hypothesized that these B cells determine the effectiveness of CYC treatment. We focused on cytokine profiles of single autoreactive B cells in patients with SSc.

Methods
We simulated the interaction of B cells and endothelial cells in microfluidic cell culture systems. We cultured endothelial cells in a microchannel. Then, we loaded B cells of patients with SSc. We collected single B cells which adhere to endothelial cells by trypsin treatment. We stimulated these B cells, with PMA and ionomycin, and measured the levels of produced interleukin (IL)-10 and IL-6 to detect the percentages of regulatory and effector B cells, by our original micro fluidic-ELISA system.

Results
In SSc patients, the number of B cells adhering to endothelial cells significantly increased compared with healthy controls. Most of these B cells produced anti-endothelial cells antibodies. The frequencies of IL-10-producing regulatory B cells after the CYC treatment increased in responders and decresed in non-responders. Those of IL-6-producing effector B cells after the treatment decreased in responders and increased in non-responders.

Conclusions
The effectiveness of CYC treatment to SSc patients is associated with cytokine profiles of B cells, which interact with endothelial cells. Checking the profiles of these B cells, after the first few months on from initiation of CYC therapy, may help to decide whether or not we should continue the treatment.
Enhancing ADCC by human natural killer cells to improve tumor cell killing
Authors: Snyder Kristin M , Hullsiek Robert , Mishra Hemant Kumar , Dixon Kate J , Mendez Daniel C , Li Yunfang , Rogich Allison , Wu Jianming , Walcheck Bruce 
Published: January 2023

Abstract
Natural killer (NK) cells are cytotoxic lymphocytes that can rapidly kill tumor cells with exquisite specificity by antibody-dependent cell-mediated cytotoxicity (ADCC), which is exclusively mediated by the IgG Fcγ receptor CD16A. Many clinically successful therapeutic monoclonal antibodies (mAbs) utilize ADCC as a mechanism of action. However, CD16A binds IgG with low affinity and is rapidly cleaved by a proteolytic process from the cell surface upon activation, limiting therapeutic mAb efficacy. We generated NK cells expressing engineered high affinity FcγRs. Here, we investigated CD64/16A, a recombinant receptor consisting of the extracellular region of CD64, the highest affinity IgG FcγR, and the transmembrane and intracellular regions of CD16A. We expressed CD64/16A in human NK92 cells, which lack endogenous FcγRs but mediates ADCC upon expression of CD16A, and in induced pluripotent stem cells differentiated into NK (iNK) cells. We determined that CD64/16A was functional in vitro, facilitated ADCC and the production of cytokines, did not undergo rapid downregulation in expression upon NK cell activation, and facilitated conjugation to antibody-opsonized target cells. We are currently exploring an in vivo xenograft model using NSG immunocompromised mice engrafted with a HER2+ ovarian cancer cells to further examine the ADCC potency of CD64/16A iNK cells. Our findings suggest that CD64/16A may be utilized by engineered NK cells, leading to the formation of an “off-the-shelf” cellular therapy that can be combined with therapeutic mAbs for the treatment of various tumor types.
Targeting REGNASE-1 improves efficacy of chimeric antigen receptor T cell therapy for leukemia
Authors: Zheng Wenting , Wei Jun , Jones Lindsay , Chi Hongbo , Geiger Terrence 
Published: January 2023

Abstract
Chimeric Antigen Receptor (CAR) modified T cells have been successful in treatment of acute lymphoblastic leukemia (ALL), however the efficacy of CAR T cell therapy is often limited by the poor persistence and function of adoptively transferred cells. We identified REGNASE-1 as a negative regulator of antitumor responses that modulates the persistence and effector function of adoptively transferred CD8+ T cells. [1] We developed a novel model to study the efficacy of Regnase-1-deficient CAR T cells in an immune replete environment. T cells from transgenic mice expressing a clinically relevant anti-human CD19 CAR were used to treat primary mouse ALL cells that express human CD19. We find that REGNASE-1-deficient CD8+ CAR T cells have improved in vivo persistence and exhibit markedly improved therapeutic efficacy against ALL. REGNASE-1-deficient CD8+ CAR T cells undergo antigen-dependent reprogramming to a naïve/memory-like phenotype, with simultaneous antigen-independent reduction in exhaustion marker expression. Regnase-1-deficiency also leads to enhanced memory responses of CAR T cells after primary tumor clearance. Our findings indicate that Regnase-1 modulates long term persistence and memory in CAR T cells. Depletion of Regnase-1 provides a new approach to improve the therapeutic efficacy of CAR T cell therapy.
Supported by ALSAC/St. Jude Children’s Research Hospital and The Assisi Foundation of Memphis
Fasting Mimicking Diet promotes immunotherapy-associated changes and inhibits autophagy to promote cancer free survival in Acute Lymphoblastic Leukemia models
Authors: Buono Roberta , Tucci Jonathan , Cutri Raffaello , Guidi Novella , Mangul Serghei , Pellegrini Matteo , Fruman David A , Mittelman Steven D. , Longo Valter 
Published: January 2023

Abstract
One of the new therapeutic strategy to promote cancer free survival is to combine dietary intervention like fasting or fasting mimicking diets (FMDs) with cancer treatments. FMDs enhance the efficacy of a wide variety of therapies ranging from chemotherapy to kinase inhibitors to immunotherapy, weakening cancer cells while protecting normal cells and tissues.
In this work we show that FMD in combination with vincristine (VC), enhance the death of acute lymphoblastic leukemia (ALL) by inhibition of autophagy and induction of apoptosis by p53 modulation and activation of caspase-3. Our data indicates that a periodic FMD increases the efficacy of VC and extends the cancer free survival of an in-vivo mouse syngeneic pre-B ALL model. We identify in human and mice leukemic cells that the autophagy inhibition is the mechanism used by FMD to potentiate the cytotoxic effect of VC. Finally, in vivo treatment of FMD+VC with an autophagy inhibitor shows a synergistic effect on increasing survival in ALL mice.
Furthermore, FMD induces activation of anticancer immunity. The gene expression profile consistent with anti-cancer immune responses resulting from VC plus FMD together with accelerated cancer progression when these treatments were combined with anti-CD8 antibodies indicate a central role of the immune system in these effects. Thus, the inhibition of autophagy and enhancement of immune responses are responsible for the ability of FMD to promote cancer free survival in ALL mice.
Macrophage repolarization via leptin increases immunotherapy efficacy in obesity
Authors: Dudzinski Stephanie O , Beckermann Kathryn E. , Young Kirsten , Hongo Rachel , Giorgio Todd , Rathmell Jeffrey 
Published: January 2023

Abstract
Immune checkpoint blockade treatment is life-saving for some patients, but most do not respond. While systemic immune dysfunction occurs in obesity, early studies have surprisingly shown that obesity increases immunotherapy efficacy. Obesity promotes immune dysfunction through T cell exhaustion, which is well understood, but obesity also affects macrophage polarization, which is understudied in the setting of obesity, cancer, and immunotherapy. Male C57BL/6 mice received a 60 kcal high-fat diet for 12 weeks and received 250,000 MC38 colon cancer cells subcutaneously. Mice received 200 ug of IgG control antibody or anti-PD-1 antibody every 2 days starting on day 5. Tumors were collected 16 days post-injection and processed for flow cytometry. Samples were stained for T cells (CD4+ helper, T Regulatory, and CD8+ cells), macrophages (M1 and M2), and myeloid derived suppressor cells. Obese mice had larger tumor growth rates and tumor burden than lean mice. Tumors in obese mice had fewer CD8+ and CD4+ T cells, but the T cells expressed higher levels of CD44 and PD1. MC38 tumors in obese mice had greater immunotherapy efficacy than lean mouse tumors. Flow cytometry revealed that the anti-PD-1 treatment repolarized the macrophages to an M1-phentoype, whereas anti-PD-1 treatment in lean mice increased the T cell percentage in tumors. In experiments where lean mice received leptin treatments to emulate the elevated leptin in obesity, leptin-treated mice had smaller tumors and an increased M1-phenotype of macrophage. Our work shows that macrophage repolarization was the most significant immune cell change in our obesity and immunotherapy studies. Future work will investigate the efficacy of immunotherapy in macrophage depleted models.
Consumption of the fish oil high fat diet uncouples obesity and tumor growth through induction of reactive oxygen species in pro-tumor macrophages
Authors: Li Bing , Jin Rong , Hao Jiaqing 
Published: January 2023

Abstract
It is clear that obesity is associated with increased risk of many types of cancer. However, obesity can be induced by various high fat diets (HFDs) from different fat sources. It remains unknown whether fatty acid composition in different HFDs influences obesity-associated tumor development. Herein we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated tumor growth, consumption of the fish oil HFD uncoupled obesity from increased tumor growth and exhibited a decrease in pro-tumor macrophages. Interestingly, compared to FA components in both HFDs, n-3 FAs rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage cell death. Moreover, we found that A-FABP expression in the pro-tumor macrophages facilitated n-3 FA intracellular transportation and mitochondrial FA oxidation. A-FABP deficiency diminished n-3 FA-mediated ROS production and macrophage cell death both in vitro and in vivo. Altogether, our results demonstrate a novel mechanism by which n-3 FAs induce ROS-mediated pro-tumor macrophage cell death in an A-FABP dependent manner. This study provides mechanistic insights into dietary supplementation with fish oil for cancer prevention and puts forwards a new concept that not all HFDs leading to obesity are tumorigenic.
Increasing AMPK activity supports enhanced oxidative metabolism, proliferation, and in vitro recovery of human CD4+ T cells
Authors: Braverman Erica , Dobbs Andrea , Monlish Darlene , Brown Rebecca Audrey , Byersdorfer Craig A 
Published: January 2023

Abstract

Background
In adoptive immunotherapy, treatment success correlates with the in vivo expansion and subsequent persistence of transferred cells. In T cells, survival and memory formation are both enhanced when cells exhibit higher levels of oxidative metabolism. AMP-activated protein kinase (AMPK) is a master regulator of metabolism, promoting oxidative phosphorylation when nutrients are scarce. We hypothesized that enhanced AMPK signaling would improve T cell therapeutic potential by increasing their oxidative potential and prolonging their persistence.

Results
Jurkat and primary human T cells were transduced with a lentiviral construct encoding either AMPKγ2 or an empty vector. All AMPKγ2 transduced cells showed increased activation of the AMPK pathway, with AMPK-transduced Jurkat T cells exhibiting increased baseline and maximal oxygen consumption as measured on a Seahorse Metabolic Analyzer. Furthermore, they were able to maintain this enhanced oxidative metabolism despite prolonged nutrient starvation. In addition, AMPK-transduced primary human T cells increased their mitochondrial density and improved their in vitro proliferation, with significantly increased recovery of CD4+ T cells.

Discussion
Increasing AMPK activity by over-expressing AMPKγ2 increases the in vitro oxidative potential, proliferation, and recovery of human T cells, particularly CD4+ T cells. These changes are all attractive features for subsequent adoptive immunotherapy. Further work will evaluate the mechanism underlying the phenotype and metabolome of AMPK-transduced cells and will assess their metabolic activity and persistence in vivo.
Role of heat shock factor 1 (HSF1) on activation-induced metabolic reprogramming of T cells
Authors: Pandya Bhaumik D , Moskophidis Demetrius , Mivechi Nahid F 
Published: January 2023

Abstract
Heat Shock Factor 1 (HSF1) is transcriptionally activated in response to a variety of environmental stressors. Data from our laboratory indicates that genetic inactivation of HSF1 significantly delays tumorigenesis in various tumor models. Increasing evidence supports the paradigm that modulating the metabolic bioenergetics of T cells i.e., inhibiting glycolytic flux or enforcing fatty acid oxidation, enhances the formation of more efficient anti tumor CD8+ T-cells. Since, HSF1 is involved in cellular metabolism, in this study, we explored the strategies to manipulate (or reprogram) the metabolic pathways used by the immune system to improve anti-tumor immunity. We observed that deletion of HSF1 profoundly affects the metabolic reprogramming of naive CD8+ T cells upon anti-CD3/CD28 stimulation in vitro. Furthermore, HSF1-deficient T cells show reduced oxygen consumption rate and extracellular acidification rate upon activation. These effects correspond to delayed T-cell receptor signaling and slower activation of naive T cells preventing them from moving towards early exhaustion stage resulting in improved longevity. In addition, we detected delayed initiation of colon cancer MC38 tumors that was implanted into a T-cell specific HSF1 deficient mice compared to wild-type mice. Finally, we confirmed that the delay in tumorigenesis is mediated through CD8 response since treatment of above tumor bearing mice with anti-CD8 antibody reversed the suppressive effects of HSF1 deficient CD8 T cells on tumor growth. Taken together, HSF1 can be a potential therapeutic target to overcome the limitations with existing cancer therapies and further studies will be directed towards exploring impact of HSF1 on checkpoint blockade.