bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering of Antibody Conjugated Nanogel Platform for Targeted Drug Delivery to CD4+ T lymphocytes
Authors: Canakci Mine O , Thayumanavan Sankaran , Osborne Barbara A 
Published: January 2023

Abstract
In an ideal systemic therapy, therapeutic agents travel through the bloodstream, reaching cells all over the body and preferentially killing abnormal cells. However, hydrophilic or lipophilic properties of a potential drug affects its ability to reach cells from the bloodstream. Thus, only a small amount of the drug reaches the diseased tissue. Moreover, selective killing approaches to minimize side effects usually fail and many normal cells and tissues are exposed to the drug upon treatment. Development of antibody drug conjugates (ADC) revolutionized the targeted approach for drug delivery. ADCs are composed of cytotoxic drugs covalently linked to monoclonal antibodies which selectively bind to tumor-markers and, by doing so, decrease the side effect of the drug on healthy tissue. Currently there are two FDA approved ADCs in the market. The number of ADCs in clinical trials continuously increases however some fail in efficacy studies. Our approach is to use antibody-nanogel conjugates in order to increase the drug load by avoiding modifications on the therapeutic agent. Nanogels are chemically cross-linked, water-soluble polymer nanoparticles and can encapsulate or trap the lipophilic drug molecules. Selective uptake of these nanogels can be achieved by functionalization of the surface of the nanogel with monoclonal antibodies that can recognize the surface markers of the abnormal cells in which the drug needs to be delivered. Overall aim of this project it to engineer anti-CD4 conjugated nanogels to enhance the antibody mediated targeted drug delivery approach by combining our knowledge in both immunology and polymer chemistry for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) in mouse models.
Understanding how immune checkpoint modulators alter pre-existing rheumatologic disorders in cancer patients
Authors: Nelson Michelle , Shirai Keisuke , Gupta Ridhi , Gilkeson Gary , Paulos Chrystal M 
Published: January 2023

Abstract
The aim of cancer immunotherapy is to reinvigorate an exhausted immune system. Checkpoint modulators PD1/PDL1 and CTLA4 antagonists “release the breaks” on ineffective T cells and subsequently bolster tumor-targeted T cells. These checkpoint modulators are increasingly available for numerous cancers and therefore the number of patients on immunotherapy are ever increasing. In contrast, patients with autoimmune diseases are prescribed immune therapies that dampen the immune system. Of note, immune suppressive therapies increase the incidence of various cancers. The interesting question that has not been fully addressed- what is happening immunologically in patients who have pre-existing autoimmune diseases and are treated with checkpoint modulators for cancer? We have been evaluating the immune correlates in patients with pre-existing rheumatoid arthritis (RA; often being treated with TNF-α blocker) who later receive checkpoint therapy when diagnosed with cancer. Following checkpoint therapy, we saw an increase in central memory T cells, a decrease in PD1 and CTLA4 expression, and a decrease in Th1 and Th17 cells in the peripheral blood. Additionally, we have been working on a dual disease animal model- collagen-induced arthritis (CIA) and lung cancer models. This will has allowed us to study the direct immunological consequences of giving treatments that either dampen or boost the immune system on both cancer and CIA disease states. Outcomes from this work will continue to expand our understanding of the immune system in patients with dual diseases and thus be better equipped to evaluate immunological correlates for exacerbated autoimmune disease and to productively treat patients with both autoimmune and cancer diagnoses.
Autocrine IL-2 programs survival of exhausted CD8 T cells during chronic infection
Authors: Yuzefpolskiy Yevgeniy , Barman Soumik , Smith Kendall A , Sarkar Surojit , Kalia Vandana 
Published: January 2023

Abstract
Loss of T cell function is a hallmark of chronic infections (such as HIV, HCV) and cancers. Chronic antigenic stimulation leads to a progressive, hierarchical loss of function in T cells – properties such as autocrine IL-2 production and ability to lyse infected target cells are lost first, followed by the loss of TNF-α and then IFN-γ production. The sum total of these events, known as exhaustion, is followed by the eventual physical deletion of antigen-specific CTLs. Our current clinical checkpoint blockade therapies are heavily hinged upon the very presence of the exhausted T cells that can be re-invigorated to regain function. Hence, it is critical to define the survival signals that prevent the deletion of exhausted antigen-specific T cells.
While IL-2 is historically known to be a key survival cytokine for T cells, autocrine expression of IL-2 is extinguished early during T cell exhaustion. Thus, it has been long believed that IL-2 is dispensable for the maintenance of exhausted CTLs during chronic infections. Surprisingly, deletion of il2 specifically in antigen-specific CD8 T cells (CD8IL2−/−) led to a precipitous decline in the numbers of these exhausted CD8 T cells compared to their wild-type counterparts (CD8IL2+/+) within the same environment. This paradoxical need for autocrine IL-2 in the long-term sustenance of an exhausted CD8 T cell pool is ascribed to its instructional role in programming key aspects of CD8 T cell survival and metabolism early during priming. These findings are of high consequence to checkpoint blockade immunotherapeutic strategies, where success is heavily dependent on the presence of an exhausted T cell population that can be re-functionalized to fight off the chronic infection or tumor.
A spontaneous mutation in NCR1 locus reveals an inhibitory role for IFNγ response by NCR1 via inhibiting dok-1 phosphorylation
Authors: Jang Youngsoon , Gerbec Zachary , Choi Bongkum , Subramaniam Malarkannan , Moore Bethany , Laouar Yasmina 
Published: January 2023

Abstract
Immunosurveillance by Natural killer (NK) cells provides an efficient effector mechanism to eliminate tumor and virally infected cells. A well-defined characteristic of NK cells is their ability to lyse target cells deficient in MHC class I expression or target cells that express non-MHC ligands as a result of infection or transformation. This observation has been the basis for identification of a number of inhibitory and activatory NK cell receptors. Although the collective effort during the last decade shed light on the function of many NK cell receptors, the role of NCR1 in NK cell biology remains highly controversial. We have recently identified a spontaneous mutation of NCR1 in our C57BL/6 mouse colony. In this mutant, NCR1 expression was absent on conventional NK cells of all lymphoid organs as well as on innate lymphocytes (ILC3) of the gut lamina propria. Of note, NCR1 expression was absent on the surface as well as in the intracellular compartment of NK cells. Likewise, lack of NCR1 expression was confirmed in mixed BM chimera indicating a cell intrinsic phenotype. Only genetic backcrossing could correct the lack of NCR1 in these mice. ORF sequencing of NCR1 gene in mutant mice revealed a point mutation (C14R) in the region of signal peptide of NCR1 protein. However, while development and homeostasis of NK cells was not affected by the lack of NCR1, infection of NCR1C14R mutant mice with murine cytomegalovirus resulted in increased resistance, an advantage that correlated with NK cell hyperresponsive production of IFN-γ, but not cytotoxic activity. Moreover, NCR1 limits NK cell IFNγ response via regulation of Dok-1 phosphorylation and p38 activation. Collectively, our data reveal the role for NCR1 in IFNγ production of NK cell.
ADAMTS5 and its substrate versican play a critical role in influenza virus immunity
Authors: Stambas John , Ye Siying , Izzard Leonard , Dlugolenski Daniel Aaron , Tripp Ralph A , McCulloch Daniel , McMahon Meagan 
Published: January 2023

Abstract
Members of the ADAMTS (A disintegrin-like and metalloproteinase with thrombospondin-1 motifs) metalloproteinase family remodel the extracellular matrix (ECM). In this current study we demonstrate that Adamts5−/− mice infected with X31 influenza virus (104pfu/mouse) show enhanced weight loss, have higher virus titres and perturbed T cell immunity when compared to WT counterparts. These responses correlate with the accumulation of a key ADAMTS5 substrate, versican, in the MLN of Adamts5−/− mice and underpin disruption of T cell migration as evidenced through the use of both in vitro and in vivo models. Our research emphasizes the importance of ADAMTS5 activity in the control of influenza virus infection and highlights the potential for development of ADAMTS5-based therapeutic strategies to reduce overall morbidity and mortality.
Performance of the HIV diagnosis screening algorithm using two immunoassays and a molecular test
Authors: Balada-Llasat Joan-Miquel , Dougherty Jenna , Goldenbaum Brian , Wang Shu-Hua 
Published: January 2023

Abstract
Advances in HIV diagnostic testing have improved detection of HIV infections. HIV can be detected earlier so patients benefit from treatment and negative results reassure uninfected patients. Because first line immunoassays lack specificity, positive results need to be confirmed. The aim of this study was to evaluate the algorithm used at The Ohio State Wexner Medical Center for the diagnosis of HIV infection. The algorithm begins with a combination immunoassay that detects HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen [ADVIA Centaur® HIV Ag/Ab Combo (CHIV), Siemens]. All positive specimens are confirmed with an immunoassay that differentiates HIV-1 from HIV-2 antibodies [Geenius HIV-1/HIV-2 Confirmatory assay (GHIV), Bio-Rad]. Specimens that are positive by CHIV and negative or indeterminate by GHIV proceed to HIV-1 nucleic acid testing for resolution. A total of 14,994 patients were evaluated using CHIV assay, of these 99.7% were negative (n= 14,950) and 0.3% were positive (n=44). The 44 positive specimens were tested by GHIV, only 4 confirmed positive and 40 were negative. Of the 40 that tested negative, only 32 had enough serum left to be tested by RNA HIV molecular test and all tested negative. Of the 8 that there was not enough serum left, 6 patients had a follow up viral load and they were all negative. In summary, of the 44 CHIV positive, only 4 were confirmed by GHIV, and 38 confirmed negative by the molecular tests, questioning the utility of the additional molecular step.
T follicular helper cell-derived IL-10 sustains humoral immunity during chronic viral infection
Authors: Zander Ryan A , Xin Gang , Schauder David , Cui Weiguo 
Published: January 2023

Abstract
Although it is well-appreciated that Tfh cells play a critical role in regulating antiviral humoral immunity, the detailed cellular and molecular pathways that govern their differentiation and function during chronic viral infection remains incompletely understood. In this study, we generated IL-10 and IL-21 double-reporter mice to study the dynamic expression of the immunoregulatory cytokines IL-10 and IL-21, which are known to differentially regulate T cell-mediated control over viral replication. Infection of these double-reporter mice with either an acute or chronic strain of LCMV, revealed a unique subset of IL-10+IL-21+co-producing Tfh cells that arise only during chronic viral infection. Notably, compared to IL-21-single producing Tfh cells, IL-10+IL-21+co-producing Tfh cells exhibited an enhanced germinal center (GC) Tfh-like profile, as exemplified by their increased per cell expression of PD-1, CXCR5, and Bcl-6. Additional analyses identified that IL-10-producing Tfh cells have an increased capacity to form stable Tfh-B cell conjugates compared to their IL-10− Tfh counterparts, suggesting that IL-10+ Tfh cells may specialize in providing help signals to B cells during chronic infection. Importantly, depletion of IL-10+IL-21+ co-producing CD4 T cells or deletion of Il10 specifically from Tfh cells resulted in impaired GC B cell responses, LCMV-specific antibody production and viral control. Mechanistically, we show that B cell intrinsic IL-10 signaling is indispensable for GC B cell differentiation and function. Collectively, our findings delineate a heterogeneous population of Tfh cells and elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection.
CD8 T cells initiate blood-brain barrier disruption during experimental cerebral malaria through non-cytotoxic alterations to endothelial cells
Authors: Huggins Matthew A , Jin Fang , Johnson Aaron J 
Published: January 2023

Abstract
Cerebral malaria is a serious health complication that can arise during Plasmodium infections. Symptoms of human cerebral malaria (HCM) include coma, permanent neurological deficits, and potentially death. While the mechanism is not well understood, brain swelling and edema have been shown to correlate with a poor disease outcome for afflicted individuals. This work attempts to identify the cellular changes occurring during breakdown of the blood-brain barrier (BBB) by utilizing the murine model of experimental cerebral malaria (ECM). Previous work determined that the tight junctions claudin-5 and occludin, proteins essential for regulating BBB integrity, were disorganized on cerebral endothelial cells during ECM. Here, we focus on the constituents of the BBB to characterize the changes occuring within endothelial cells during disease progression. Importantly, endothelial cell changes were not strictly induced by parasitic infection itself, but also required the presence of functional CD8 T cells. Using perforin deficient mice to impair CD8 T cell effector function, we demonstrate that brain endothelial cells retain the characteristics of uninfected animals in contrast to wild-type infected mice. Interestingly, the CD8 T cells appear to be acting independently of direct killing as there is not an increase in activation of the apoptotic pathway nor is there an increase in dead or dying endothelial cells. From these data we propose that non-cytotoxic CD8 T cell functions are required for ECM induction.
Activation of histone acetyltransferase p300 by MAPK pathway is required for optimal production of PGE2 in primary human monocytes activated with muramyl dipeptide adjuvant (MDP).
Authors: Liu Fengjie , Romantseva Tatiana , Golding Hana , Zaitseva Marina 
Published: January 2023

Abstract
Prostaglandin E2 (PGE2) is a proximal mediator of fever produced by human monocytes and macrophages activated by microbial pathogens and, in some cases, by adjuvants that contain analogues of microbial products. Here we studied the signaling pathway of PGE2 production in primary human monocytes activated with MDP, the minimal structure unit responsible for the adjuvant activity of peptidoglycans.
MDP alone did not induce COX-2 mRNA expression and PGE2 protein production in monocytes. However, COX-2 mRNA and PGE2 were dramatically up-regulated when MDP was combined with T cell conditioned medium (TCM) prepared from CD3 bead-purified human T cells. MDP-induced nuclear NF-kB was not further increased by TCM. However, TCM induced increase in cytosolic Ca2+ and in phosphorylated ERK1/2 in monocytes, suggesting a role for MAPK signaling. In agreement with this, inhibition of Ca2+, of Ca2+-dependent PKC, and of MAPK kinase enzymes MEK1/2 suppressed PGE2 production in MDP/TCM-treated monocytes. Chromatin immunoprecipitation analysis showed that TCM alone or combined with MDP facilitated association of histone acetyltransferase p300 to the promoter regions of COX-2, IL-1b, and of IL-6 genes. Inhibition of p300 by C646 suppressed the recruitment of p300 and the acetylation of H3 and H4 histones at the COX-2 promoter, prevented COX-2 gene transcription, and PGE2 production. Taken together these results demonstrate that MDP-induced COX-2 gene transcription and PGE2 protein production in primary monocytes requires a second signal delivered by a TCM through a Ca2+-dependent activation of PKC/MEK1/2 signaling pathway followed by phosphorylation of ERK1/2 and p300-facilitated acetylation of histones H3 and H4 at the COX-2 promoter.
Antiretroviral drugs and tobacco smoke dysregulate human platelets: A novel investigation into the etiology of HIV co-morbid cardiovascular disease.
Authors: Loelius Shannon G , Lannan Katie L , Casey Ann E , Spinelli Sherry L , Phipps Richard P 
Published: January 2023

Abstract
While antiretroviral drugs (ARVs) successfully suppress Human Immunodeficiency Virus (HIV), HIV-infected persons still have a shorter lifespan and are at higher risk of developing cardiovascular disease (CVD) compared to uninfected persons. CVD is the number one cause of death globally, and is now appreciated as an inflammatory disease. HIV-infected persons experience chronic inflammation, thought to be caused by low levels of HIV proteins, daily use of ARVs, and increased rates of smoking. The impact of ARVs on CVD risk remains unclear, with some studies linking ARVs to CVD. Additionally, when controlled for smoking status HIV-infected persons were still at greater risk for CVD. Platelets are important in the development of CVD, but the effects of ARVs on platelets are unstudied. Additionally, cigarette smoke is known to activate platelets, inducing inflammation. Our novel study investigates the effects of ARVs and cigarette smoke, alone and in combination, on human platelet function. Our striking in vitro findings demonstrate that the ARVs Ritonavir and Darunavir, as well as cigarette smoke, dysregulate platelet function. Treatment with the protease inhibitor Ritonavir resulted in a dose-dependent increase in platelet production of proinflammatory mediator prostaglandin E2 (PGE2) (p&lt;0.001). Additionally, when combined with cigarette smoke, Darunavir induced production of PGE2 (p&lt;0.01). Combined doses of Ritonavir and Darunavir at physiological concentrations inhibited platelet spreading, similar to the effect of cigarette smoke. We hypothesize that cigarette smoke and ARVs act in combination to activate platelets and thus contribute to the chronic inflammation which leads to CVD.
Inducing a human atypical memory B cell phenotype in vitro
Authors: Ambegaonkar Abhijit A , Pierce Susan K. , Sohn Haewon 
Published: January 2023

Abstract
Chronic human infectious diseases such as malaria are associated with expansion of an unusual population of memory B cells (MBCs) referred to as atypical MBCs. In malaria, atypical MBCs are CD21−, CD27−, highly express the transcription factor, T-bet, and also express a variety of inhibitory receptors, including FcRL5 and Siglec6. These atypical MBCs signal poorly through their B cell receptors (BCRs) and exhibit poor B cell function. We concluded from these studies that atypical MBCs contribute to the slow, inefficient acquisition of immunity to malaria in African children. However, the mechanisms by which atypical MBCs are induced during chronic infectious diseases are not known. Acute febrile malaria in African children is correlated with expansion of less-functional TH1-type T follicular helper T cells which secrete IFN-γ and are impaired in their helper function, suggesting that they may contribute to the generation of atypical MBCs. We investigated the conditions under which human naïve B cells were induced to express an atypical MBC phenotype in vitro. Studying human tonsillar B cells we showed that BCR cross linking by anti-Ig in the presence of IFN-γ and CpG, induced high levels of T-bet and FcRL5. Moreover, expression of these markers was further enhanced by the persistent engagement of B cells with membrane bound anti-Ig. We also found that atypical MBCs induced in vitro by persistent antigen, CpG and IFN-γ showed severely reduced early BCR signaling when re-challenged with soluble antigen, characteristic of atypical MBCs. Taken together these results suggest that atypical MBCs may be the product of persistent antigen engagement by B cells in the highly inflammatory environments that develop during chronic malaria exposure.
Defining T helper cell immunity in bronchopulmonary dysplasia
Authors: Lao Jason Chun , Pang Merrin A , Malhotra Atul , Tan Kenneth , Beker Friederike , Konig Kai , Collins Clare , Theda Christiane , Kamlin C. Omar , Yeomans Emma , Elsayed Kristy , Noble Elizabeth , Walsh Geraldine , Argus Brenda , Twitchell Emily , Berger Philip , Veldman Alex , Nold-Petry Claudia A , Nold Marcel Friedrich 
Published: January 2023

Abstract

Background
Bronchopulmonary dysplasia (BPD) is a common neonatal lung disease that has been linked to pulmonary inflammation. Previous studies have suggested involvement of various cell types and soluble factors but have thus far failed to reveal a dominant pathway that underpins disease progression. It remains unknown that which T helper (Th) cell polarization, if any, contributes to the pathogenesis of BPD.

Methods
Citrated whole cord and peripheral blood were collected from infants born between 24+0–28+6 gestational weeks at five different time points, namely at birth, on days 1, 7 and 14 and at 36 weeks corrected gestational age (CGA). Cells were stimulated with either PMA, ionomycin and brefeldin A or vehicle and brefeldin A overnight. Cells were then stained for multi-color flow cytometry to enumerate Th cell subsets including Th1, Th2 and Th17 and regulatory T cells. Results were analyzed against BPD disease status at 36 weeks CGA and corrected for confounders.

Results
50 infants were enrolled and 228 unique samples were collected. 36 enrolled infants (72%) had BPD (mild to severe) at 36 weeks CGA. When compared to infants that did not have the disease, the frequency of interleukin(IL)-4 in CD4+ Th cells in peripheral blood was increased in infants with BPD on days 1 (p=0.0449), 7 (p=0.0423), 14 (p=0.0489) and 36 weeks CGA but not within cord blood. There was no difference in the frequency of cells positive for interferon-gamma (IFNγ), IL-17A or FOXP3 among CD4+ cells in blood from BPD and non-BPD infants across all time points.

Conclusions
T helper cells are polarized towards a Th2 phenotype in infants with BPD based on elevated levels of IL-4 in CD4+ cells. We hypothesize that BPD infants may benefit from therapies that target the Th2 pathway.
Culturally appropriate advisory and governance oversight for the study of rheumatic fever and rheumatic heart disease in New Zealand
Authors: Sika-Paotonu Dianne , Azevedo Pedro , Faatoese Allamanda , Wihongi Helen , Nuku Hiueni , Hudson Maui , Havea Palatasa , Parks Tom , Merriman Tony , Lennon Diana 
Published: January 2023

Abstract
Acute rheumatic fever (ARF) is an autoimmune condition caused by untreated Group A Streptococcal (GAS) infection of the upper respiratory tract (and possibly skin). Multiple or severe attacks of ARF can cause cardiac damage, known as Rheumatic Heart Disease (RHD). RHD remains a significant cause of morbidity and mortality is rare in developed countries. In New Zealand, the disease burden of ARF and RHD amongst Indigenous Maori and Pasifika communities is one of the highest in the world, usually affecting children and young adults. Previous work carried out in New Zealand sought to explore the immunogenetics of ARF and RHD and involved candidate gene analysis techniques utilizing samples from individuals diagnosed with RHD where a functional variant in the gene encoding the interleukin IL-6 cytokine known as IL-6 rs1800797 was found to be significantly associated with RHD. Current work seeks to explore the genetic susceptibility to ARF/RHD in greater depth using more advanced genome-wide technology. An international genome wide association study (GWAS) is currently underway to further understand the genetics of ARF/RHD using data obtained from global sources. To undertake the proposed GWAS work and amend the original New Zealand study, an Advisory team comprised of Pasifika and Māori representatives comprised of community leaders, researchers, scientists, and academics is providing the appropriate governance, cultural support and guidance essential for the project work.