bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uterine natural killer cells: their modulation by carbon monoxide and their impact on the remodeling of spiral arteries (MUC7P.768)
Authors: Zenclussen Ana , Schumacher Anne , Linzke Nadja 
Published: January 2023

Abstract
Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are linked to impaired remodeling of maternal spiral arteries (SA). We previously introduced Heme Oxygenase-1 (HO-1) as a positive modulator of pregnancy. Its main mediator, carbon monoxide, could mimic HO-1 protective effects in a mouse model of Hmox1 genetic deficiency. Here, we investigated whether HO-1 deficiency is related to gestational hypertension and if CO is able to prevent PE and IUGR through the modulation of uterine NK cells (uNK) that are necessary for initiation of SA remodeling. Hmox1+/- or Hmox1-/- implantations presented fewer uNK cell numbers and lower expression of uNK-related angiogeneic factors than Hmox1+/+ sites. Quantitative histology revealed that Hmox1+/- and Hmox1-/- implantations had shallow SA development. This was accompanied by IUGR and gestational hypertension. Application of CO at low dose during early to mid-gestation prevented IUGR in Hmox1+/- mothers, being this associated with enhanced in situ proliferation of uNKs and normalization of angiogenic parameters. Most importantly, CO improved SA remodeling and normalized blood pressure, ensuring a proper fetal growth. Thus, CO emerges as a key molecular player in pregnancy success by modulating uNKs, which results in promotion of SA remodeling, adequate fetal support/growth and prevention of gestational hypertension.
Characterization of IL-22 and IL-17 expressing cells in cervix (MUC7P.769)
Authors: Makinde Hadijat , Lurain Nell , Martinson Jeffrey , Mirmonsef Paria , Landay Alan , Spear Greg 
Published: January 2023

Abstract
IL22 and IL17 have important antimicrobial and epithelial repair functions. However their role in the female lower genital tract has not been well defined. We determined the frequency and phenotype of cells producing these cytokines at this mucosal site, because we postulated that they contribute to resistance to sexually transmitted infections. Cervical tissue was obtained from benign hysterectomies. Cells were obtained by collagenase digestion, stimulated with PMA/ionomycin/Monensin for 4 hrs and stained for flow cytometry. On average in endocervical tissue, the CD3+CD45+ cells were 71% (CD4+ ~50%) and CD3- CD45+ cells were 24%. 20% of CD45+ cells were Lin- (negative for CD3, CD14, CD16, CD19, CD20 and CD56). Unstimulated CD4+ T-cells were &lt; 0.05% IL22+, IL17+ and IL22+IL17+, while after stimulation the percentages were 1.9%, 5.5% and 1.6% respectively. Unstimulated CD3- cells in cervical tissue were 2.3% IL22+, 3% IL17+ and 4.6% of IL22+IL17+, and the percentages after stimulation were 1.6%, 6% and 1.9% positive respectively. Our data show that in cervical tissue, there are CD3+ and CD3- cells capable of making IL22 and IL17. This is important because this is the first study to show what types of cells in the genital tract are making these cytokines, and suggests that these cells could induce antimicrobial peptide production by cervical epithelial cells in response to sexually transmitted pathogens.
Uterine integrity is required to maintain human fetal immunologic naiveté (MUC7P.770)
Authors: Loewendorf-Snead Andrea , Nguyen Tina , Yesayan Maria , Kahn Daniel 
Published: January 2023

Abstract
Introduction: In healthy pregnancy, maternal and fetal compartments are physically separated by multiple cell layers and the fetal immune system displays an ‘in-experienced’ phenotype in utero. The uterus as an immunologic barrier contributing to the naïve state of the fetal immune system has not been explored thus far. Methods: A prospective cohort study of fetuses born to mothers with prior uterine scar was undertaken (UCLA IRB # 11-002962). Cord blood lymphocytes were analyzed for memory status of the T regulatory cells (CD4+FoxP3+RO/RA) and blinded from placental location prior to final analysis. Results: In this prospective cohort study, we identified placental implantation in apposition to a uterine scar as a sufficient factor for fetal in utero immune activation (CD45RO+), specifically in the regulatory T cell compartment. Our results (N=20) identify a risk difference of 90% with a relative risk of 10 (p&lt;0.05) of activation (RO+) of the FoxP3+ regulatory T cells when the placenta was implanted over the prior uterine scar. Discussion: Our study demonstrates that intrauterine formation of tolerogenic fetal responses is caused by fetal exposure to a scarred uterus. Our results highlight the role that uterine integrity plays as an immunologic barrier.
CCR10 regulates maintenance and function of resident regulatory and effector T cells in the skin (MUC7P.772)
Authors: FU Yaoyao , Xia Mingcan , Hu Shaomin , McDowell Mary , Sarkar Surojit , Kalia Vandana , Xiong Na 
Published: January 2023

Abstract
Skin, the largest organ of human body, is under frequent assaults by various environmental agents. To maintain its integrity and function, immune cells in the skin are tightly regulated to allow tolerance to harmless antigens but mount effective response to dangerous assaults, and their dysregulation might increase incidence of skin diseases. CCR10, with its ligand CCL27 uniquely expressed by keratinocytes, are the most skin-specific chemokine/receptor pair implicated in the skin T cell migration and inflammatory diseases. However, targeting CCR10 or CCL27 had little effects on these processes in animal models and the regulation and function of CCR10 in vivo remain elusive. Using CCR10 knockout/EGFP knockin mice we found that CCR10-/- mice had imbalanced numbers and dysregulated functions of skin-resident effector and regulatory T (Teff and Treg) cells associated with enhanced innate and memory skin immune responses to antigen stimulations. On the other hand, CCR10 -/- mice cleared the skin Leishmania major (L. major) infection more efficiently than wild type (WT) mice did. Adoptive transfer studies found that CCR10 is required for the migration and maintenance of skin-resident CD8+ and CD4+ cells into homeostatic skin but not during the inflammation. These findings reveal that the CCR10/CCL27 axis plays important roles in the migration, maintenance and function of skin-resident regulatory and effector T cells for the local homeostatic regulation.
Gastric epithelial cells drive retinoic acid biosynthesis in human gastric dendritic cells (MUC8P.803)
Authors: Bimczok Diane , Beliaeva Olga , Kedishvili Natalia , Smith Phillip , Smythies Lesley 
Published: January 2023

Abstract
Despite the high prevalence of chronic gastritis caused by H. pylori, the gastric mucosa as a unique immune environment has received little investigative attention. Here, we analyzed whether retinoic acid (RA), an important homeostatic factor in small intestine, also contributes to gastric immune regulation. Using HPLC, we detected both RA and the RA precursor molecule retinol in human gastric tissue, indicating that the gastric mucosa is an active site of RA biosynthesis. To determine the source of RA in gastric mucosa, we show that primary human gastric epithelial cells expressed RA biosynthesis genes Rdh10 and Aldh1a1, surprisingly at higher levels than small intestinal epithelial cells. Moreover, primary gastric epithelial cell cultures provided with retinol synthesized RA in vitro and induced the expression of the RA biosynthesis gene Aldh1a2 in co-cultured antigen-presenting cells through an RA-dependent mechanism, evidence that gastric epithelial cells confer the ability to generate RA to gastric DCs. Indeed, DCs purified from gastric mucosa had similar levels of aldehyde dehydrogenase activity and RA biosynthesis gene expression as small intestinal DCs, although gastric DCs lacked CD103. In summary, gastric epithelial cells have access to retinol, convert retinol to RA and drive RA biosynthesis in gastric DCs. Such RA biosynthesis capacity may enable gastric DCs to induce regulatory T cells and drive mucosal T cell homing during H. pylori infection.
Tregitope-mediated antigen-specific tolerance induction in autoimmune and allergic disease in vivo. (THER5P.831)
Authors: Cousens Leslie , Mingozzi Federico , Mazer Bruce , Elyaman Wassim , Khoury Samia , Martin Bill , De Groot Anne 
Published: January 2023

Abstract
Tregitopes are a novel class of therapeutic compounds that harness the activity of regulatory T cells (Tregs) and represent a promising new approach for the treatment of autoimmune and inflammatory diseases. Tregitopes are Treg epitopes found in IgG that provide beneficial immunomodulatory effects, paralleling those attributed to intravenous immunoglobulin (IVIG), in vitro and in vivo. When APCs present Tregitopes to Tregs, APC expression of MHC II, CD80, and CD86 are decreased; expression of the tolerance-associated marker ILT3 is increased. These results are consistent with reported effects of IVIG (Bayry et al. Blood, 2003, 101:758) and the IgG-derived peptide hCDR1 (Sela et al. Immunology, 2009, 128:395). Tregitopes also cause CD4+CD25+FoxP3+ Treg to expand and produce IL-10 in vitro. Evaluation of Tregitope effects in mouse models of MS (EAE), OVA-induced allergic airway disease, and AAV-mediated gene transfer show that effector T cells are modified in the presence of Tregitopes. In OVA-induced allergic airway disease, we observed significant and reproducible expansion of Tregs in conjunction with decreased airway reactivity comparable to, if not greater than, IVIG. We have additional unpublished evidence demonstrating the antigen specificity of tolerance induction using Tregitopes in conjunction with target antigens. Formulated with or without the target antigen, Tregitopes represent a promising new treatment for human immune-mediated disease.
Tussilagone inhibits dendritic cell functions via up-regulating heme oxygenase-1 expression (THER5P.833)
Authors: Park Yunsoo , Ryu Hwa Sun , Kim Ji Sung , Kim Ju Young , Kim Yong Guk , Pyo Min Ji , Park Mi Jeong , Lee Hong Kyung , Hwang Bang Yeon , Kim Youngsoo , Han Sang-Bae 
Published: January 2023

Abstract
Sesquiterpenoid tussilagone (TUS) has a variety of pharmacological activities. In this study, the effects of TUS on dendritic cell (DC) functions and the underlying mechanisms were investigated. TUS inhibited lipopolysaccharide (LPS)-induced activation of DCs, which was proved by the decreases of surface molecule expression, cytokine production, antigen uptake, migration, and allogenic T cell activation. TUS inhibited LPS-induced activation of NF-kB, MAPKs, and IRF-3 signalings. However, TUS did not directly inhibit kinase activities of IRAK4, IRAK1, TAK1 and IKK, suggesting that signaling molecules downstream from toll-like receptor (TLR) 4 might not be the direct targets of TUS. Instead, TUS activated heme oxygenase-1 (HO-1), which was a rate-limiting enzyme involved in heme degradation to immunosuppressive products, such as carbon monoxide and biliverdin. HO-1 antagonist reversed the inhibitory activity of TUS in DCs. Taken together, this study suggests that TUS might be an inducer of HO-1, which indirectly inhibits TLR signalings and functional activation of LPS-treated DCs
Assessment of B cell depletion in combination with IL-2/anti-IL-2 mAb complexes in experimental arthritis (THER5P.824)
Authors: Olalekan Susan , Cao Yanxia , Finnegan Alison 
Published: January 2023

Abstract
Autoimmunity is often associated with a deficiency in functional CD4+CD25+Foxp3+ T regulatory cells (Tregs). In our mouse model of rheumatoid arthritis (RA), proteoglycan induced arthritis (PGIA); we have shown that B cell depletion using a monoclonal antibody against CD20 suppresses disease along with an increase in functional Tregs. In an effort to enhance these Tregs we combined anti-mCD20 with administration of IL-2/anti-IL-2 mAb complexes and investigated the effects of the combination on PGIA. We show in G1 primed mice that IL-2/anti-IL-2 mAb complexes increase the percentage and numbers of Tregs higher than anti-mCD20 or control ab. To determine the effects of the complex on arthritis, we induced PGIA in BALB/c mice. Mice treated with the complex displayed an accelerated severe disease as compared to B cell depleted or control ab treated mice. This was due to an early increase in antigen specific CD4+T cells. Mice that received anti-mCD20 together with IL-2/anti-IL-2 mAb however displayed a less severe disease as compared to the group that only received the complex. Anti-mCD20 treated mice displayed the least arthritic severity. To determine the suppressive capacity of Tregs from the different treatment groups we setup Treg suppression assays. Tregs isolated from B cell depleted mice displayed the highest suppressive capacity. Our findings demonstrate that B cell depletion generates better Tregs and ameliorates PGIA better than IL-2/anti-IL-2 mAb complexes.
Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice (THER6P.858)
Authors: Regna Nicole , Chafin Cristen , Hammond Sarah , Caudell David , Reilly Christopher 
Published: January 2023

Abstract
Histone deacetylase inhibitors are important modifiers of gene and protein expression. In our studies, we sought to determine if a specific HDAC6 inhibitor (ACY-738) was able to decrease disease in NZB/W lupus-prone mice through regulation of B and T cell differentiation. From 22 - 38 weeks-of-age, NZB/W mice were injected intraperitoneally with 20 mg/kg of ACY-738, 5 mg/kg of ACY-738, or DMSO (vehicle control). Body weight and proteinuria were measured every 2 weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4 weeks. Kidney disease was determined using sera and urinary markers of SLE, immune complex deposition, and renal pathology. Flow cytometric analysis was used to assess thymic and splenic T cell profiles as well as bone marrow, splenic, and peripheral B cell differentiation patterns. Our results showed that HDAC6 inhibition was able to decrease many hallmarks of SLE disease including splenomegaly, immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production. ACY-738 treatment decreased the number of double-negative thymic T cells and increased the percentage of splenic Treg cells. Inhibition of HDAC6 altered BM B cell differentiation by increasing the percentage of cells in the early-stage developmental fractions of both pro-and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation.
A novel concept for tolerization of diabetogenic CD4+ T cells by intranasal treatment with CTA1R7K-peptide-DD (THER6P.859)
Authors: Cardell Susanna , Langenes Veronica , Fahlén-Yrlid Linda , Löfbom Linda , Lycke Nils 
Published: January 2023

Abstract
Type 1 diabetes results from CD4+ T cell dependent immune destruction of insulin producing β-cells in the pancreas islets. Tolerization of diabetogenic CD4+ T cells would therefore be an important advancement in the development T1D treatments. We previously described that a mutated (R7K), enzyme killed, cholera toxin A1 subunit based adjuvant CTA1R7K-DD induced specific tolerance rather than enhancement of immunity, and moreover, ameliorated murine collagen induced arthritis. Here, we investigate tolerization of diabetogenic T cells of the non-obese diabetic NOD mouse, exploring diabetogenic TCR transgenic BDC2.5 CD4+ T cells. Treatment of BDC2.5 NOD mice intranasally with CTA1R7K-PS3-DD fusion protein (PS3 = BDC2.5 TCR mimotope peptide) reduced proliferation and IFN-gamma production to PS3 peptide restimulation. Transferred CD4+ BDC2.5 T cells induced diabetes in 80-100% of recipient NOD.scid mice. In contrast, if either donor BDC2.5 NOD mice, or recipient NOD.scid mice, had been treated with CTA1R7K-PS3-DD the majority of mice remained healthy. The i n treatment resulted in systemic increase in FoxP3+ CD4+ BDC2.5 T cells, most enhanced in draining mediastinal lymph nodes. However, transfer of FoxP3 negative CD4+ BDC2.5 T cells from CTA1R7K-PS3-DD treated mice still demonstrated reduced diabetes induction compared to cells from control treated mice, suggesting that tolerance in the recipient mice is not depending on the action of FoxP3 Treg cells.
Targeting the JAK/STAT pathway in the treatment of Parkinson’s disease (THER6P.847)
Authors: Qin Hongwei , Buckley Jessica , Liu Yudong , Holdbrooks Andrew , Benveniste Etty (Tika) 
Published: January 2023

Abstract
Parkinson’s Disease (PD) is an age-related, chronic neurodegenerative disorder. At present, there are no therapies to prevent PD progression. Activated microglia and subsequent neuroinflammation associate with the pathogenesis and progression of PD. Accumulation of α-synuclein (α-syn) in the brain is a core feature of PD and leads to microglial activation, inflammatory cytokines/chemokines production and neurodegeneration. Given the importance of the JAK/STAT pathway in activating microglia and inducing cytokine/chemokine expression, we investigated the therapeutic potential of inhibiting the JAK/STAT pathway using the JAK1/2 inhibitor, AZD1480. We utilized an in vivo rat model of PD induced by viral overexpression of α-syn. We find that AZD1480 treatment inhibits α-syn-induced neuroinflammation by inhibiting microglia activation and CD3+ T-cell infiltration, and neurodegeneration by preventing the degeneration of dopaminergic neurons in vivo. In vitro, AZD1480 inhibits α-syn- and IFN-γ-induced MHC Class II, CD40, iNOS, TNF-α and IL-6 expression in microglia and macrophages by reducing STAT1 and STAT3 activation. These results indicate that inhibiting the JAK/STAT pathway can prevent neuroinflammation and neurodegeneration by suppressing activation of innate and adaptive immune responses to α-syn and inflammatory cytokines in this PD model. Furthermore, this suggests the feasibility of targeting the JAK/STAT pathway as neuroprotective therapy for neurodegenerative diseases.
Dysregulated cytokine production by leukocytes, mediated by SOCS1 deficiency, is correlated to skin pathology: implications for therapeutic targeting. (THER6P.851)
Authors: Lam Brandon , Wilson Tenisha , Bedoya Simone , Armbruster Cristina , Johnson Howard , Larkin Joseph 
Published: January 2023

Abstract
Dysregulated leukocyte activation and cytokine signaling are known to contribute to autoimmunity. Notably, although Suppressor of Cytokine Signaling-1(SOCS1) is important in the regulation of both leukocyte activation and cytokine signaling, how deficiencies in SOCS1 relate to autoimmunity is not well understood. Therefore we analyzed leukocytes from mice bearing heterozygous expression of SOCS1 (SOCS1+/-) for dysregulated immune function. LPS stimulated SOCS1+/- leukocytes exhibited enhanced production of IL6, and IL12. Notably we observed that SOCS1+/-IFNγ-/- mice, but not IFNγ-/-, SOCS1+/-, or wild-type mice exhibited significant skin pathology on the back and ears. The observed skin pathology in SOCS1-/-IFNγ-/- mice was correlated to leukocyte accumulation within draining lymph nodes and spleen. In vitro, SOCS1+/-IFNγ-/- leukocytes activated with αCD3/αCD28 were hyper-proliferative and produced higher levels of IL17 when compared SOCS1+/+ littermates. Finally, a peptide capable of partially mimicking SOCS1 (SOCS1-KIR) was sufficient to reduce excessive proliferation, and aberrant IL12 and IL6 production of SOCS1+/- leukocytes in vitro. Together these results implicate an important role of SOCS1 in the regulation of immune responses. Moreover these results suggest that targeting SOCS1 deficiency, by a mimetic of SOCS1, may have implications in the regulation of skin pathologies mediated by immune dysregulation.
Immunomodulatory effect of pentoxifylline and stored blood on neutrophil functions (TRAN3P.862)
Authors: Abdelrahman Zakia , Abou-Shamaa Lobna , Sadek Nadia , El hadidy Abeer , Kabary Bassam 
Published: January 2023

Abstract
Background: Allogeneic blood transfusions expose a patient to many soluble and cell-bound antigens, expressed on viable and decaying cells. Blood transfusion is a risk factor for many inflammatory processes. Its supernatant fraction has been proven to activate neutrophils Objective: To evaluate the immunomodulatory effects of stored blood supernatant and pentoxifylline on neutrophil functions Methods: Neutrophils(N) of recipient blood samples were incubated with supernatant stored blood (35 days blood bags) (N+S)or fMLP(N+F) or(N+S+F).Neutrophils incubated with PTX (N+P),(N+S+P), (N+F+P) and (N+S+F+P) .Also neutrophil functions studied by CD11b expression, phagocytosis, respiratory burst and apoptosis Results: Neutrophil expression of CD11b ,phagocytic activity, neutrophil intracellular superoxide anion production and neutrophil apoptosis in presence of (N+F), (N+S) and (N+F+S) were significantly increased in comparing to baseline. Combined incubation with (N+ F + S) induced significant increase in neutrophil functions than (N+F) or (N+S). PTX significantly attenuated neutrophil functions induced by (N+F), (N+S), ( N+S+F) Conclusion: Stored blood supernatant has an immunomodulatory effects on neutrophil function(priming them) through CD11b expression, phagocytosis, respiratory burst and apoptosis. PTX downregulates these neutrophil functions. PTX may have therapeutic potential in inflammatory injury due to blood transfusion.
Analysis of islet transplant infiltrate T cells informs design of therapeutic strategies which promote long-term euglycemia (TRAN3P.871)
Authors: Burrack Adam , Nelsen Michelle , Coulombe Marilyne , Kupfer Tinalyn , Gill Ronald 
Published: January 2023

Abstract
NOD mice, a well-characterized model of type 1 diabetes, provide a stringent model in which to test transplant tolerance-promoting therapies. We studied the failure of T cell-directed therapies in the autoimmune recipient. When we blocked T cell co-stimulation with a CD154 antibody in NOD isograft recipients transplant survival time doubled (MST 22 days), and we observed a profound decrease in ex vivo cytokine production of graft infiltrating CD4+ T cells. These results suggest that autoimmune CD8+ T cells can mediate disease recurrence with minimal help from CD4+ T cells and that CD154 antibody does not impede the reactivation of primed autoreactive CD8+ T cells. Graft survival was significantly prolonged in NOD mice grafted with syngeneic islets and the combination treatment of CD154 antibody and transient CD8+ T cell depletion (MST 58 days). In the clinically relevant model of islet allografts in NOD mice, anti-CD154 antibody treatment had less effect on graft rejection (MST 10 days), and minimal effect on ex vivo CD4+ T cell cytokine production. Unfortunately, our combination therapy demonstrated minimal allograft survival benefits (MST 12 days). Interestingly, CD4+ T cell depletion therapy yielded superior allograft survival results (MST 24 days). These results highlight clinically relevant differences in the mechanisms of autoimmune disease recurrence and islet allograft rejection by the autoimmune recipient.