bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage Persistence in Adipose Tissue of Rhesus Macaques
Authors: Fahlberg Marissa , Alvarez Xavier , Midkiff Cecily , Didier Elizabeth , Kuroda Marcelo J 
Published: January 2023

Abstract

BACKGROUND
HIV/SIV establishes lifelong infection by integrating proviral DNA into the genome of susceptible long-lived immune cells. In order to eliminate the virus, cellular reservoirs must be removed. Long-lived macrophages are permissible to SIV infection and replication. Given recent publications describing adipose as a tissue reservoir for HIV in HAART-treated patients, we chose to investigate the abundance of macrophages in adipose tissue and the proportion that are long-lived to determine their potential as viral reservoirs.

METHODS
Mesenteric adipose tissue from three RM infected with SIVmac239 intravenously and three uninfected RM were analyzed by confocal microscopy to determine frequency of CD163+ macrophages among nucleated cells. An additional two macaques (one SIVmac239-infected, one uninfected) were injected with dextran intravenously, an inert molecule which can be phagocytosed by macrophages and detected at later time points. Tissues were analyzed by IHC and flow cytometry.

RESULTS
CD163+ macrophages constituted 10.5% ± 2.0 of all nucleated cells in the adipose of three uninfected macaques, which differed significantly from infected macaques where macrophages made up 22.0% ± 3.1 of all nucleated cells. We detected dextran in cells within adipose tissue from both injected rhesus macaques at the time of death. The time points at which they died were 43 days (uninfected animal) and 50 days (infected animal) post-injection. Macrophages constitute a significant proportion of nucleated cells in adipose tissue of both uninfected and infected macaques, and their incorporation of dextran is indicative of a long-lived tissue-resident macrophage subtype with potential to be a reservoir for HIV/SIV.
Do T cells from HIV-infected individuals have normal metabolic function?
Authors: Clutton Genevieve Tyndale , Council Olivia , Xu Yinyan , Warren Joanna , Lee De’Ashia , Fernandez Maria Abad , Archin Nancie , Kuruc JoAnn , Eron Joseph , Gay Cindy , Margolis David , Goonetilleke Nilu 
Published: January 2023

Abstract
Untreated HIV infection is characterized by generalized immune activation, T cell dysfunction, and ultimately the exhaustion of HIV-specific CD8 T cell responses. Durable virus suppression resulting from anti-retroviral therapy (ART) is associated with greatly improved immune function, but some phenotypic and functional abnormalities persist even after years of suppressive ART. We have observed that, relative to HIV-seronegative individuals, CD8 T cells from HIV+ participants on ART are skewed toward a more effector-like (T-bethigh Eomeslow) phenotype and have significantly reduced proliferative capacity in response to antigenic stimulation.
Metabolic pathways play a key role in shaping T cell maturation, phenotype, and function, and the ability to produce ATP via both glycolytic and oxidative phosphorylation (mitochondrial) pathways is critical to T cell function and longevity. However, whether underlying metabolic abnormalities contribute to residual CD8 T cell dysfunction in HIV+ individuals on ART has not been fully explored. Here we compare the metabolic phenotype of T cells from HIV+ participants on ART with those from HIV-seronegative participants. We are using MitoTracker® dyes to assess mitochondrial mass and polarization in T cell memory subsets, ex vivo and in response to antigen, and measuring expression of the glucose transporter GLUT1 and the mitochondrial biogenesis master regulator PGC-1α in different CD8 T cell effector subsets. Our findings will inform whether phenotypic and functional abnormalities in CD8 T cells from HIV+ individuals on ART reflect underlying metabolic dysfunction and if metabolic interventions could improve T cell function.
CD8+ T cells from healthy blood bank donors secrete antiviral levels of interferon-alpha
Authors: Killian M. Scott , Wegehaupt Abby , Roufs Ellen 
Published: January 2023

Abstract

Background
CD8+ T cells play important roles in the antiviral immune response to HIV-1 infection. Variation in the antiviral activities of CD8+ T cells among HIV-1-infected persons has been associated with disease state and clinical prognosis. However, the anti-HIV activities of CD8+ T cells from healthy uninfected blood donors have not been fully established.

Methods
In this study we assessed the ability of peripheral blood CD8+ T cells from healthy blood bank donors to inhibit HIV-1-replication. Co-culture assays were performed with CD8+ T cells and acutely HIV-1-infected primary CD4+ T cells. Also, CD8+ T cells were cultured and the derivative supernatants were evaluated in virus inhibition assays, ELISAs, and multiplex cytokine arrays.

Results
Variation was observed among CD8+ T cells from different blood donors in the ability to suppress HIV-1 replication. In the absence of stimulation, the CD8+ T cells, or their derivative fluids, lacked any appreciable anti-HIV activity. After PHA or anti-CD3/CD28 stimulation, the majority of CD8+ T cells and derivative fluids exhibited anti-HIV activity. Low levels of interferon-alpha were present in the CD8+ T cell fluids having increased anti-HIV activity, whereas CD8+ T cell fluids lacking anti-HIV activity contained undetectable levels of interferon-alpha. Other soluble factors present at increased levels in CD8+ T cell fluids having anti-HIV activity included TNF-beta, IL-8, IP-10, and TRAIL.

Conclusions
Our findings indicate that the secretion of antiviral levels of interferon-alpha is a normal function of CD8+ T cells in response to activation and stimulation. Variation in this immune response may influence host susceptibility to infection and disease.
Determining the effects of CCL21 nanomedicine therapeutic modalities in cancer
Authors: Poelaert Brittany J , Romanova Svetlana , Smits Kaitlin , Sliker Bailee , Moffitt Alexandra , Smith Lynette , Bronich Tatiana K , Solheim Joyce 
Published: January 2023

Abstract
Solid tumors demonstrate varying levels of immunogenic potential as well as the proficiency to undergo immune evasion, thus there is a need for novel therapies capable of augmenting the patient’s anti-tumor immune response in a concentrated and durable manner. We hypothesized that therapeutic modalities utilizing the chemoattractant C-C motif chemokine ligand 21 (CCL21) in a novel alginate nanoformulation will provide prolonged release of CCL21 and subsequent steady infiltration of immune cells into the tumor, which will abrogate disease progression and delay tumor growth significantly better than CCL21 alone. Nanoformulations of CCL21 were first analyzed for rates of release in vitro. We found that intratumoral administration of nanoformulation CCL21 significantly prolonged the survival of A/J mice with subcutaneous neuroblastoma tumors, compared to controls. Furthermore, we also determined that the tumor growth rate for nanoformulation CCL21-treated mice was significantly lower in comparison to the tumor growth rates of mice treated with buffer control, empty nanoparticles, or CCL21 alone. Notably, four out of nine nanoformulation CCL21-treated mice demonstrated complete tumor regression. When rechallenged, these four mice failed to produce tumors within a two-week period, therefore suggesting that a protective memory immune response had been induced by the nanoformulation CCL21 treatment. These results indicate that nanoformulation CCL21 therapy may be clinically relevant for the treatment of children and adolescents diagnosed with neuroblastoma. In addition, this novel nanoformulation may also have potential for future development as a means for slow-release delivery of other immunotherapies besides CCL21.
Leukemic cell expressed CTLA-4 suppresses T cells via down-modulation of CD80 by trans-endocytosis
Authors: Do Priscilla , Beckwith Kyle A , Beaver Larry , Griffin Brittany G , Mo Xiaokui , Liu Yang , Jones Jeffrey A , Hertlein Erin , Muthusamy Natarajan , Byrd John C 
Published: January 2023

Abstract
Despite clinical utility in targeting the immune checkpoint, Cytotoxic T Lymphocyte Antigen 4 (CTLA-4), on T cells, its function on non-T cells remains unaddressed, especially in the context of therapy. We define an immunosuppressive role for tumor expressed CTLA-4 in Chronic Lymphocytic Leukemia (CLL). Most primary CLL samples were intracellularly CTLA-4+ (12/14) but surface CTLA-4− (14/14). Co-culture with activated T cells induced surface expression of CTLA-4 on CLL B cells. To mechanistically study CLL B cell expressed CTLA-4, we generated CLL-derived Mec1 and OSU-CLL cell lines to inducibly express CTLA-4. These cell lines express the ligands for CTLA-4, CD80 and CD86. Expression of CTLA-4 on Mec1 and OSU-CLL resulted in decreased CD80 expression on CD80+ cells with rescue upon CTLA-4 blockade (N=3). Co-culture of CTLA-4+ Mec1 and CTLA-4+ primary CLL cells with CD80-GFP+ Hek293 cells revealed transfer of CD80-GFP into primary CLL cells (N=2) and the Mec1 cell line. This finding was consistent with the ability of CTLA-4+ T cells to trans-endocytose CD80. Co-culture of T cells with Mec1 CTLA-4+ cells resulted in decreased IL2 production (N=3, p=0.0172). The loss of IL2 signified decreased co-stimulation as a result of tumor expressed CTLA-4. We generated an in vivo model to study tumor CTLA-4 using the TCL1 murine model of CLL. Murine CTLA-4+ (mCTLA-4) TCL1 tumor cells were engrafted into human CTLA-4+/+mFcγR−/− immune competent mice. MCTLA-4 on the tumor cells but not human CTLA-4 on the host cells was blocked with an anti-mCTLA-4 antibody. Effect on disease progression and overall survival are currently being assessed. We present a paradigm shift whereby CTLA-4 is an immunosuppressive protein irrespective of expression on T cells.
Anti-viral immune responses within the tumor microenvironment decrease tumor progression
Authors: Chesson Charles Brent , Newman Jenna H , Dobias Natalie S , Sadimin Evita , Schenkel Jason M , Zloza Andrew 
Published: January 2023

Abstract
We recently reported that acute concomitant infection in a tissue distant from the tumor results in the trafficking of tumor-specific CD8+ T cells from the tumor microenvironment to the infection site and to accelerated tumor growth and host death. However, we hypothesized that anti-viral responses within the tumor (rather than distant from it), possibly even without productive viral replication, can reprogram the local tumor microenvironment and lead to long-term tumor regression. Indeed, we discovered in a mouse model of melanoma (B16-F10), that injection of live influenza (A/H1N1/PR8), heat-inactivated influenza, or live vesicular stomatis virus (VSV) results in no observable mordibity or mortality, but significantly inhibits tumor growth (with 60% of the mice surviving more than 50 days). We observed similar results in a 4T1 breast cancer model where, likewise, such virus-associated treatments significantly decreased the tumor area compared to vehicle-treated controls. Interestingly, prior influenza exposure completely abrogated the anti-tumor response after local re-exposure, suggesting that primary anti-viral responses, but not secondary immune responses, at the tumor site may be a novel type of immunotherapy. This finding may explain why infections in cancer patients have been reported to both decrease and increase cancer-specific mortality. Future studies will seek to determine if combination immunotherapies utilizing anti-viral immune responses may augment tumor regression and whether specific viruses are favored based on the cancer type. The overall goal of our work is to translate these findings into clinical trials and cancer patient treatment regimens that improve and save cancer patient lives.
Human gingiva-derived mesenchymal stem cells modulate the fate of macrophages and alleviate atherosclerosis
Authors: Wang Julie , Zhang Ximei , Zheng Song Guo 
Published: January 2023

Abstract
Atherosclerosis is the major cause of cardiovascular diseases. Current evidence indicates that macrophages and inflammation are involved in the pathogenesis of atherosclerosis. Human gingiva-derived mesenchymal stem cells(GMSCs) have displayed anti-inflammatory and immunomodulatory effects on autoimmune and inflammatory diseases. However, whether GMSCs can modulate macrophages and eventually prevent and treat atherosclerosis is far from clear. Here, we show that GMSCs markedly inhibited the foam cell formation and the inflammatory macrophages activation, converting inflammatory macrophages to anti-inflammatory macrophages in vitro. Additionally, infusion of GMSC to AopE−/− mice significantly reduced the frequency of inflammatory monocytes and decreased the size of plaque and lipid deposition. Thus, our study has revealed an unexpected role of GMSCs in modulating the function of macrophages and alleviating atherosclerosis. Transplantation of GMSCs to atherosclerotic patients might be a new therapeutic strategy to improve atherosclerosis.
Using transgenic MHC class II/self-peptide reactive cytotoxic T cells as a method of ameliorating established EAE
Authors: Lees Jason R , Nurmukhambetova Saule , Kim Yong Chan , Zhang Ai-Hong , Blanchfield Jennifer Lori , Evavold Brian D , Scott David W. 
Published: January 2023

Abstract
In multiple sclerosis (MS) CD4+ T cells are thought to coordinate initiation and maintenance of neuroinflammation following recognition of central nervous system (CNS) antigens in the context of MHC class II molecules. Re-activation of these CNS antigen specific CD4+ T cells within the CNS is thought to be crucial to recruitment of secondary immune effector cells and resultant tissue inflammation. MHC class II is thought to be expressed on professional antigen presenting cells (APC) but not on oligodendrocytes and neurons, two cellular targets for MS pathology. Here we examine the use of defined MHC class II/peptide restricted transgenic T cell receptor expression in mature CD8 T cells to generate cytotoxic cells specific for CNS antigen presenting APC. We suggest that auto-antigen/MHC class II specific APC elimination can ameliorate disease while sparing MHC II negative neurons and oligodendrocytes. This study examines a novel potential therapeutic modality for its efficacy in neuroinflammation.
Erdr1 is a potential therapeutic molecule in inflammatory skin disease, psoriasis
Authors: Houh Youn Kyung , Kim Kyung Eun , Cho Daeho 
Published: January 2023

Abstract
Psoriasis is a common skin disease accompanied by chronic inflammation. Pro-inflammatory cytokines are increased in psoriatic lesional skin and have important roles in psoriasis pathogenesis. Especially, as a representative pro-inflammatory cytokine, IL-18 has been known as a biomarker for psoriasis activity. In previous studies, erythroid differentiation regulator 1 (Erdr1) was shown to have a negative correlation with IL-18 in several inflammatory skin diseases such as melanoma and rosacea, suggesting the opposite effects with IL-18. The present study investigated whether Erdr1 in negatively regulated by IL-18 in human keratinocytes in vitro and the level of cutaneous expression of Erdr1 was compared in skin tissues from psoriasis patients and healthy donors. Erdr1 expression was significantly reduced in psoriatic lesional skin whereas enhanced IL-18 expression. Based on the negative correlation, It was hypothesized that Erdr1 may exert anti-inflammatory effects in contrast to the pro-inflammatory effect of IL-18. To investigate the anti-inflammatory effects of Erdr1 in psoriasis, recombinant Erdr1 was injected intraperitoneally into a psoriasis mouse model. Recombinant Erdr1 (rErdr1) significantly alleviated the symptoms of psoriasis-like skin inflammation and reduced the mRNA of various psoriasis-related markers. Additionally, rErdr1 inhibits Th17 cell distribution in psoriatic lesional skin through regulation of CCL20 expression. Taken together, this results provides the first clinical evidence that Erdr1 is downregulated in lesional skin and acts as a novel regulator for psoriasis pathogenesis which can be a potential therapeutic molecule.
The impact of using web conferencing system on student learning, engagement and performance in Immunology Course
Authors: Hussein Mohamed , Reda Betlhem , Bizuayehu-Mekonnen Menorwork , Fazal Nadeem 
Published: January 2023

Abstract
The increasing complexity of pharmacy curricula has been a continuing challenge for both students and faculty. The technology learning platforms currently used in Chicago State University College of Pharmacy are Moodle, Livetext and ExamSoft. The aim of this study was to develop and investigate certain tools instituted by Moodle. We wanted to study the impact of using podcasts on student learning, engagement and performance in Immunology. Our focus was on assessing the full functionality of Moodle features and study its effects in improving learning outcomes, classroom performance and student involvement. Our objective was to explore Moodle-based web conferencing system called BigBlueButton (BBB) in learning immunology. The study was an observational, cohort study with 86 students who were enrolled in Microbiology/Immunology offered to P-1 students at Chicago State University College of Pharmacy. BBB is a web conferencing system, which allows for distant lecture delivery and stores audio/visual content into Moodle. Delivery time was set up according to lecture time. Recordings were automatically uploaded into the course in Moodle within 30 minutes. BBB module was available at no charge on the Moodle service to supplement lecture information. Students have the ability to review recorded lectures at any time, anywhere and on any device with satisfactory picture and sound quality. Recorded podcasts can remain on the Moodle course for a year, and are easily transferable to an upcoming lecture course. Our data shows a positive correlation between the BBB videos watched by the students and their performance. Further studies may need to be done to assess the duration of time spent by students outside of the classroom in reviewing the podcasts.
Fc-fusion drugs have C1q/FcγR binding and signaling properties that can affect their immunogenicity.
Authors: Lagasse H.A. Daniel , Levin Ditza , Hengel Hartmut , Golding Basil , Sauna Zuben E. 
Published: January 2023

Abstract
Fusing the IgG1 constant region (Fc-domain) to therapeutic proteins increases their plasma half-life via neonatal Fc receptor (FcRn) binding. However, potential interactions with other Fc-binding molecules including complement C1q and Fc gamma receptors (FcγR) can have immunological consequences. Our previous studies in a mouse model suggest that engagement of the Fc-Factor IX (FIX) to FcγR on APC and NKT cells could alter the immunogenicity of the FIX moiety. Here, we conducted a comparative study of FDA-approved Fc-fusion proteins to assess their potential for C1q binding as well as FcγR binding and signaling. Binding of soluble drug to C1q was measured by ELISA, and FcγR binding and signaling was evaluated using BW5147:FcγR-ζ reporter cell lines. We demonstrate that rFIXFc and rFVIIIFc bound C1q as well as activating and inhibitory FcγRs (I, IIA, IIB, IIIA). These therapeutic proteins also signaled via FcγRIIIA, and to a lesser extent via FcγRI and FcγRIIB. Other Fc-fusion drugs (TNFR-Fc; CTLA4-Fc) bound FcγRI (TNFR-Fc also bound FcγRIIIA), but did not result in FcγR signaling. As predicted, a control anti-CD20 monoclonal antibody modified for enhanced FcγRIIIA engagement, bound and signaled via FcγRIIIA, while the parent molecule did not; supporting our use of BW5147: FcγR-ζ reporter cells for the assessment of Fc:FcγR interactions. Our studies show that Fc-fusion drugs have distinct C1q/FcγR binding and signaling properties. Moreover, FcγR binding does not predict signaling. Our studies suggest that Fc-FcγR engagement can influence the immunogenicity to Fc-fusion drugs as both fusion partners influence this interaction. Future investigations will elucidate the underlying molecular mechanisms.
‘Arid5a expression is induced through MYD88-independent pathway in response to TLR4 stimulation in IFNγ-sensitized human macrophages.’
Authors: Metwally Hozaifa , Tanaka Toshio , Kishimoto Tadamitsu 
Published: January 2023

Abstract
Sepsis is caused by infection, especially gram-negative bacteria, followed by an inflammatory cascade leading to cytokine storm. High IL-6 serum level in patients with sepsis is correlated with severity and high mortality. However, the exact pathological mechanism(s) in sepsis regulating high IL-6 expression and how Arid5a, a post-transcriptional regulator of IL-6, is related to exaggerated IL-6 expression are not fully understood yet. We found that Arid5a and IL-6 are more markedly expressed in response to Toll-like receptor 4 (TLR4) than TLR2 stimulation in both human primary monocyte-derived macrophages (MDM) as well as human macrophage cell line (THP-1 cells). TLR4 signals through the cell surface as well as the endosomal compartment activating MYD88-indpendent pathway. Pre-treatment of THP-1 cells with endocytosis inhibitor (MiTMAB) significantly decreases the levels of Arid5a, IL-6 and IFNβ, whereas TNFα and IL-8 are marginally affected. Moreover, MYD88 gene-knockout THP-1 cells showed similar expression level of Arid5a compared to the wild type cells. Furthermore, IFNγ pre-treatment of THP-1 cells as well as MDM results in enhancement of TLR4 endocytosis, hence higher expression of Arid5a, IL-6 and IFNβ upon LPS stimulation, while IFNγ pre-treatment has little effect on Arid5a and IL-6 expression upon TLR2 stimulation. On the contrary, IL-4 pre-treatment results in an opposite effect on TLR4 endocytosis. These results taken together indicate that priming of macrophages with IFNγ or IL-4 determines the responsiveness to LPS and that Arid5a expression is regulated by MYD88-independent pathway.
IQGAP1 inhibits type I interferon production via interactions with NLRC3
Authors: Davis Beckley K , Roberts David Michael , Tocker Aaron M , Troiani Zachary , Jacob Kimberly , Trieschman Kate , Durocher Emily , Rechnitzer Alma , Talento Suzanna Marie 
Published: January 2023

Abstract
Nucleotide binding domain, leucine rich repeat CARD containing protein 3 (NLRC3) is a member of the NLR gene family. Members of this family have been associated with human inflammatory diseases such as Crohn’s disease and cryopyrin-associated periodic syndrome. Although NLRC3 is not associated with human diseases, it is expressed preferentially in the immune system and functions in pathogen detection. NLRC3 is an intracellular protein involved in the sensing of lipopolysaccharide and cytosolic nucleic acids. NLRC3 is hypothesized to act as a negative regulator in response to bacterial and viral infection, suggesting that the vertebrate immune system has evolved specific inhibitors to limit the inflammatory response. We performed an unbiased yeast two-hybrid screen using an amino terminal fragment of NLRC3 to identify putative interacting proteins that might help elucidate the mechanism by which NLRC3 might inhibit inflammatory responses. To this end, we identified several interacting proteins. One protein, in particular, IQGAP1, acts as a scaffold important in regulating the cytoskeleton, cell adhesion and proliferation. Structure function analysis has localized the domains necessary and sufficient for interacting with NLRC3. Confocal microscopy demonstrates that these two proteins co-localize in transformed human epithelial cells. Functionally, in the absence of IQGAP1, human monocytic cells are hyperactive in response to cytosolic nucleotides, phenocopying NLRC3 deficiencies. These data suggest that NLRC3 can interact with novel proteins to facilitate squelching of cellular responses to cytosolic nucleotides.