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Seroconversion after COVID-19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants pose an increasing threat to these patients. In this observational cohort study, we measured anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies three weeks after a third mRNA vaccine dose in 49 kidney transplant recipients and compared results to 25 age-matched healthy controls. In addition, vaccine-induced neutralization of SARS-CoV-2 wild-type, the B.1.617.2 (delta), and the B.1.1.529 (omicron) variants was assessed using a live-virus assay. After a third vaccine dose, anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies were significantly lower in kidney transplant recipients compared to healthy controls. Only 29/49 (59%) sera of kidney transplant recipients contained neutralizing antibodies against the SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant and neutralization titers were significantly reduced compared to healthy controls (p < 0.001). Vaccine-induced cross-neutralization of the B.1.1.529 (omicron) variants was detectable in 15/35 (43%) kidney transplant recipients with seropositivity for anti-S1 IgG, surrogate neutralizing, and/or anti-RBD antibodies. Neutralization of the B.1.1.529 (omicron) variants was significantly reduced compared to neutralization of SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant for both, kidney transplant recipients and healthy controls (p < .001 for all)., Dietmar Hopp Stiftung; Heidelberg Faculty of Medicine Rahel Goitein-Straus Program; Heidelberg Faculty of Medicine Physician Scientist Program; German Federal Research Network Applied Surveillance and Testing (BFAST); Network University Medicine; Helmholtz Association Initiative and Networking Fund Project Virological and Immunological Determinants of COVID-19 Pathogenesis

The Microbiota-gut-brain axis describes the bidirectional communication between central nervous system and microorganisms in the gastrointestinal tract. Increasing evidence has suggests that the vagus nerve, a major neural connection between the gut and brain, plays a key role in facilitating signaling along the microbiota-gut-brain axis. Much of this evidence has come from studies employing surgical subdiaphragmatic vagotomy. Here we provide a review of the use of vagotomy as a tool to explore the role of the vagus nerve in gut to brain signaling and the knowledge this approach has provided. We also examine how, more recently, vagotomy has contributed to the understanding of the vagus nerve as a bridge for multi-systemic communication; linking microbiota, immune and central nervous systems. Finally, we address limitations to surgical vagotomy and identify such limitations may be mitigated in future studies.

Respiratory allergic disorders are a global public health problem that are responsible for substantial morbidity and healthcare expenditure. Despite the availability of allergen immunotherapy (AIT), its efficacy is suboptimal and regimens are lengthy, with a significant risk of potentially severe side effects. Studies on the recognition of allergens by immune cells through carbohydrate-lectin interactions, which play a crucial role in immune modulation and pathogenesis of allergy, have paved the way for improvements in AIT. We highlight innovative approaches for more effective and safer AIT, including the use of allergens conjugated to specific carbohydrates that bind to C-type lectins (CLRs) and sialic acid-binding immunoglobulin-type lectins (Siglecs) on immune cells to induce suppressive responses.

Radiation is a known immune modulator that drives both local and systemic immunologic effects. There is increasing interest and investigation into harnessing the pro-immunogenic effects of radiation for patients with metastatic cancer to improve systemic disease control and clinical outcomes. Here, we review fundamental immunology concepts in the context of our current understanding of both the pro-immunogenic and the less well-appreciated immunosuppressive effects of radiation therapy. Our aim is to offer the radiation oncology community a lens into the progress the field has made understanding the complex interaction between tumor-directed irradiation and immune-mediated tumor control, thus promoting further discovery and translation of radio-immuno-oncology innovation.

Seizures are frequently triggered by an inciting event and result from uninhibited excitation and/or decreased inhibition of a pool of neurons. If physiologic seizure abortive mechanisms fail, the ensuing unrestrained synchronization of neurons-status epilepticus-can be life-threatening and is associated with the potential for marked morbidity in survivors and high medical care costs. Prognosis is intimately related to etiology and its response to therapeutic measures. Timely implementation of pharmacologic therapy while concurrently performing a stepwise workup for etiology are paramount. Neurodiagnostic testing should guide titration of pharmacologic therapies, and help determine if there is a role for immune modulation.

Lentinan, a β-1,3-D-glucan, is clinically used as an immune enhancement drug for tumor therapy. Dectin-1 is a cell-surface immune receptor, which plays an important role in immunological defense against fungal pathogens and β-glucan-mediated immune modulation. Herein we attempted to study the advanced structure of lentinan and how lentinan interacts with dectin-1 for its immune enhancement effect. We firstly used MD simulation and rigid macromolecule docking, combining some spectral techniques, to uncover the complex 3D conformation of a typical polysaccharide - lentinan, and the detailed interaction mode of lentinan with dectin-1. We proved by computational simulation that lentinan can maintain its triple-helix through hydrogen network and disclosed some structural properties of lentinan. We also characterized the affinity of lentinan to dectin-1 by LSPR and binding free energy calculation, and we found out that hydrogen bonds and CH-π interaction are the major contributors for lentinan's binding to dectin-1. Besides, after bound with lentinan, dectin-1 might surprisingly go through a conformational change. In summary, our work provided insights into lentinan's advanced structure and β-glucan recognition by dectin-1.

Graphical abstract, The Streptococcal C5a peptidase (ScpA) specifically inactivates the human complement factor hC5a, a potent anaphylatoxin recently identified as a therapeutic target for treatment of COVID-19 infections. Biologics used to modulate hC5a are predominantly monoclonal antibodies. Here we present data to support an alternative therapeutic approach based on the specific inactivation of hC5a by ScpA in studies using recombinant hC5a (rhC5a). Initial characterization of ScpA confirmed activity in human serum and against rhC5a desArg (rhC5adR), the predominant hC5a form in blood. A new FRET based enzyme assay showed that ScpA cleaved rhC5a at near physiological concentrations (Km 185 nM). Surface Plasmon Resonance (SPR) and Isothermal Titration Calorimetry (ITC) studies established a high affinity ScpA-rhC5a interaction (KD 34 nM, KDITC 30.8 nM). SPR analyses also showed that substrate binding is dominated (89% of ΔG°bind) by interactions with the bulky N-ter cleavage product (PN, ’core’ residues 1-67) with interactions involving the C-ter R74 contributing most of the remaining ΔG°bind. Furthermore, reduced binding affinity following mutation of a subset of positively charged Arginine residues of PN and in the presence of higher salt concentrations, highlighted the importance of electrostatic interactions. These data provide the first in-depth study of the ScpA-C5a interaction and indicate that ScpA’s ability to efficiently cleave physiological concentrations of C5a is driven by electrostatic interactions between an exosite on the enzyme and the ‘core’ of C5a. The results and methods described herein will facilitate engineering of ScpA to enhance its potential as a therapeutic for excessive immune response to infectious disease.

Immunosuppression devoid of corticosteroids has been investigated to avoid long-term comorbidities. Likewise, alternatives to calcineurin inhibitors have been investigated as a strategy to improve long-term kidney function following transplanion. Costimulatory blockade strategies that include corticosteroids have recently shown promise, despite their higher rates of early acute rejection. We designed a randomized clinical trial utilizing depletional induction therapy to mitigate early rejection risk while limiting calcineurin inhibitors and corticosteroids. This trial, Clinical Trials in Organ Transplantation 16 (CTOT-16), sought to evaluate novel belatacept-based strategies employing tacrolimus and corticosteroid avoidance. Sixty-nine kidney transplant recipients were randomized from 4 US transplant centers comparing a control group of with rabbit antithymocyte globulin (rATG) induction, rapid steroid taper, and maintenance mycophenolate and tacrolimus, to 2 arms using maintenance belatacept. There were no graft losses but there were 2 deaths in the control group. However, the trial was halted early because of rejection in the belatacept treatment groups. Serious adverse events were similar across groups. Although rejection was not uniform in the belatacept maintenance therapy groups, the frequency of rejection limits the practical implementation of this strategy to avoid both calcineurin inhibitors and corticosteroids at this time.

B cell lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics are targeted therapeutic agents that allow response prediction and patient stratification. BH3 mimetics are prototypical activators of the mitochondrial death program in cancer. They emerged as important modulators of cellular mechanisms contributing to poor therapeutic responses, including cancer cell stemness, cancer-specific metabolic routes, paracrine signaling to the tumor microenvironment, and immune modulation. We present an overview of the antagonism between BH3 mimetics and antiapoptotic BCL2 proteins. We focus on acute myeloid leukemia (AML), a cancer with reduced therapeutic options that have recently been improved by BH3 mimetics.

Poxviruses and herpesviruses encode secreted versions of cytokine receptors as a unique strategy to evade the host immune response. Recent advances in the field have shown the great impact of some of these proteins in immune modulation and viral pathogenesis, and have uncovered unique properties of these viral proteins not found in the cellular counterparts. These modifications inspired by viruses lead to improved immune modulatory activity of the soluble cytokine receptors, information that has been used to develop more efficient therapeutics to treat inflammatory conditions.

Reliable in vitro expansion protocols of regulatory T cells (Tregs) are needed for clinical use. We studied the biology of Mauritian Cynomolgus macaque (MCM) Tregs and developed four in vitro Treg expansion protocols for translational studies. Tregs expanded 3000-fold when artificial antigen presenting cells (aAPCs) expressing human CD80, CD58 and CD32 were used throughout the culture. When donor peripheral blood mononuclear cells (PBMCs) were used as the single source of APCs followed by aAPCs, Tregs expanded 2000-fold. Tregs from all protocols suppressed the proliferation of anti-CD2CD3CD28 bead-stimulated autologous PBMCs albeit with different potencies, varying from 1:2-1:4 Treg:PBMC ratios, up to >1:32. Reculture of cryopreserved Tregs permitted reexpansion with improved suppressive activity. Occasionally, CD8 contamination was observed and resolved by resorting. Specificity studies showed greater suppression of stimulation by anti-CD2CD3CD28 beads of PBMCs from the same donor used for stimulation during the Treg cultures and of autologous cells than of third-party PBMC responders. Similar to humans, the Treg-specific demethylated region (TSDR) within the Foxp3 locus correlated with suppressive activity and expression of Foxp3. Contrary to humans, FoxP3 expression did not correlate with CD45RA or CD127 expression. In summary, we have characterized MCM Tregs and developed four Treg expansion protocols that can be used for preclinical applications.

Defensins have been long recognized as natural antimicrobial peptides, but they also possess diverse and versatile immune functions. Defensins can both induce inflammation and suppress inflammatory responses by acting on specific cells through distinct mechanisms. Defensins can also modulate the immune response by forming a complex with cellular molecules including proteins, nucleic acids, and carbohydrates. The mechanisms of defensin-mediated immune modulation appear to be cell-type and context specific. Because the levels of human defensins are often altered in response to infection or disease states, suggesting their clinical relevance, this review summarizes the complex immune functions of human defensins and their underlying mechanisms of action, which have implications for the development of new therapeutics.

Sialylation plays important roles in tumor-related physiological process. Therefore, intervention of sialylation has great potential to explore new paths for tumor therapy. In view of the immune modulation of sialic acid (SA) on tumor, this work designs a multifunctional mesoporous silica nanoparticle (MFMSN) to derail intracellular sialylation for tumor suppression. The galactose groups covered on MFMSN act as sialylation substrates to bind intracellular SAs competitively, which inhibits the SA expression on tumor cell surface. The derailed intracellular sialylation can be visualized on living cells and in vivo by specifically binding the sialylated galactose with phenylboronic acid labeled ssDNA probe released from the pore of MFMSN to induce DNA strand displacement, which recovers the fluorescence of dsDNA probe covered on MFMSN surface. The derailment of sialylation efficiently suppresses tumor growth on mice, demonstrating the great potentials of the designed strategy for revealing SA-related biological processes and clinical cancer therapy.

Probiotics play important roles on sustaining or reconstructing the homeostasis of intestinal microbiota, which is one of the key factors in alleviating diseases and maintaining the healthy condition of the host. Preclinical trials indicate that Bacteroides genus is widely considered as source of novel beneficial candidates for attenuating inflammation by regulating lymphocytes and cytokine expression, controlling metabolism and preventing cancer. Furthermore, the first case of authorization of Bacteroides xylanisolvens in food by the European Commission opens the gate for further investigation and application of this promising community. With this paper, we summarized current investigations of discovering beneficial Bacteroides strains, exploring their interaction mechanisms with the host, and evaluating the potential safety risks during commercialization.

Restoration of insulin-independence and normoglycemia has been the overarching goal in diabetes research and therapy. While whole organ and islet transplantation have become gold standard procedures in achieving glucose control in diabetic patients, the profound lack of suitable donor tissues severely hampers the broad application of these therapies. Here, we describe current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation and present state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies.

Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1-/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR.

Prevention or early detection is one of the most promising strategies against colorectal cancer (CRC), the second leading cause of cancer death in the US. Recent studies indicate that antitumor immunity plays a key role in CRC prevention. Accumulating evidence suggests that immunosurveillance represents a critical barrier that emerging tumor cells have to overcome in order to sustain the course of tumor development. Virtually all of the agents with cancer preventive activity have been shown to have an immune modulating effect. A number of immunoprevention studies aimed at triggering antitumor immune response against early lesions have been performed, some of which have shown promising results. Furthermore, the recent success of immune checkpoint blockade therapy reinforces the notion that cancers including CRC can be effectively intervened via immune modulation including immune normalization, and has stimulated various immune-based combination prevention studies. This review summarizes recent advances to help better harness the immune system in CRC prevention.

Choosing whether or not to initiate neuraxial anesthesia in pregnant women with immune system defects may be challenging. Anesthesiologists have the responsibility of making the best decision in terms of anesthesia management for both mother and baby during the labor and delivery process. Whether neuraxial anesthesia is associated with an increased risk of central nervous system infection in immunocompromised compared with healthy patients is unknown. It is also unclear if maternal immune modulation required for fetal tolerance makes pregnant women susceptible to pathogens and causes an altered immune response. Infection-related complications of neuraxial anesthesia are rare but may be severe, especially in immunocompromised parturients. There are no guidelines regarding the indications and limitations of regional anesthesia procedures in these patients. Immunocompromised patients are now seen more commonly, and it is essential to adopt a multidisciplinary approach to their care while tailoring anesthetic plans to the individual. We present the case of a 37-year-old parturient who had a congenital immune deficiency and who developed aseptic meningitis after receiving spinal anesthesia for cesarean delivery.

Glucocorticoid hormones allow individuals to rapidly adjust their physiology and behavior to meet the challenges of a variable environment. An individual's baseline concentration of glucocorticoids can reflect shifts in life history stage and resource demands while mediating a suite of physiological and behavioral changes that include immune modulation and resource allocation. Thus, glucocorticoids could facilitate a response to parasites that is optimized for an individual's specific challenges and life history stage. We investigated the relationship between endogenous circulating glucocorticoids and measures of resistance and tolerance to Haemosporidian parasites (including those that cause avian malaria) in red-winged blackbirds (Agelaius phoeniceus). We found that higher endogenous concentrations of circulating glucocorticoids were associated with reduced costs of parasite infection, which is indicative of higher tolerance, but were unrelated to parasite burden in free ranging, breeding male birds. Post-breeding, both males and females with higher glucocorticoid concentrations had higher measures of tolerance to Haemosporidian infection. Our findings suggest a potentially adaptive role for glucocorticoids in shifting the response to parasites to align with an individual's current physiological state and the challenges they face.

Previous studies demonstrated that the extracellular polysaccharides (EPSs) produced by Lactobacillus delbrueckii OLL1073R-1 (LDR-1) improve antiviral immunity, especially in the systemic and respiratory compartments. However, it was not studied before whether those EPSs are able to beneficially modulate intestinal antiviral immunity. In addition, LDR-1-host interaction has been evaluated mainly with immune cells while its interaction with intestinal epithelial cells (IECs) was not addressed before. In this work, we investigated the capacity of EPSs from LDR-1 to modulate the response of porcine IECs (PIE cells) to the stimulation with the Toll-like receptor (TLR)-3 agonist poly(I:C) and the role of TLR2, TLR4, and TLR negative regulators in the immunoregulatory effect. We showed that innate immune response triggered by TLR3 activation in porcine IECs was differentially modulated by EPS from LDR-1. EPSs treatment induced an increment in the expression of interferon (IFN)-α and IFN-β in PIE cells after the stimulation with poly(I:C) as well as the expression of the antiviral factors MxA and RNase L. Those effects were related to the reduced expression of A20 in EPS-treated PIE cells. EPS from LDR-1 was also able to reduce the expression of IL-6 and proinflammatory chemokines. Although further in vivo studies are needed, our results suggest that these EPSs or a yogurt fermented with LDR-1 have potential to improve intestinal innate antiviral response and protect against intestinal viruses. Fil: Kanmani, Paulraj. Tohoku University; Japón Fil: Albarracín, Leonardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina. Tohoku University; Japón Fil: Kobayashi, Hisakazu. Tohoku University; Japón Fil: Iida, Hikaru. Tohoku University; Japón Fil: Komatsu, Ryoya. Tohoku University; Japón Fil: Kober, Humayun A. K. M.. Tohoku University; Japón. Chittagong Veterinary and Animal Sciences University. Department of Dairy & Poultry Science; Bangladesh Fil: Ikeda-Ohtsubo, Wakako. Tohoku University; Japón Fil: Suda, Yoshihito. Miyagi University. Department of Food, Agriculture and Environment; Japón Fil: Aso, Hisashi. Tohoku University; Japón Fil: Makino, Seiya. Meiji Co., Ltd. Food Science Research Laboratory; Japón Fil: Kano, Hiroshi. Meiji Co., Ltd. Food Science Research Laboratory; Japón Fil: Saito, Tadao. Tohoku University; Japón Fil: Villena, Julio Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina. Tohoku University; Japón Fil: Kitazawa, Haruki. Tohoku University; Japón

There is strong evidence that the immune system changes dramatically during pregnancy in order to prevent the developing fetus from being "attacked" by the maternal immune system. Due to these alterations in peripheral immune function, many women that suffer from autoimmune disorders actually find significant relief from their symptoms throughout pregnancy; however, these changes can also leave the mother more susceptible to infections that would otherwise be mitigated by the inflammatory response (Robinson and Klein, 2012). Only one other study has looked at changes in microglial number and morphology during pregnancy and the postpartum period (Haim et al., 2016), but no one has yet examined the neuroimmune response following an immune challenge during this time. Therefore, in this study, we investigated the impact of an immune challenge during various time-points throughout pregnancy and the postpartum period on the expression of immune molecules in the brain of the mother and fetus. Our results indicate that similar to the peripheral immune suppression measured during pregnancy, we also see significant suppression of the immune response in the maternal brain, particularly during late gestation. In contrast to the peripheral immune system, immune modulation in the maternal brain extends moderately into the postpartum period. Additionally, we found that the fetal immune response in the brain and placenta is also suppressed just before parturition, suggesting that cytokine production in the fetus and placenta are mirroring the peripheral cytokine response of the mother.

A new cycloartane sapogenol and a new cycloartane xyloside were isolated from Astragalus karjaginii BORISS along with thirteen known compounds. The structures of the new compounds were established as 3-oxo-6α,16β,24(S),25-tetrahydroxycycloartane (1) and 6-O-β-D-xylopyranosyl-3β,6α,16β,24(S),25-pentahydroxycycloartane (2) by 1D- and 2D-NMR experiments as well as ESIMS and HRMS analyses. The presence of the keto function at position 3 was reported for the first time for cyclocanthogenol sapogenin of Astragalus genus. In vitro immunomodulatory effects of the new compounds (1 and 2) along with the n-BuOH and MeOH extracts of A. karjaginii at two different doses (3 and 6 μg) were tested on human whole blood for in vitro cytokine release (IL-2, IL-17A and IFN-γ) and hemolytic activities. The results confirmed that compound 2, a monodesmosidic saponin, had the strongest effect on the induction of both IL-2 (6 μg, 6345.41 ± 0.12 pg/mL (× 5), P < 0.001) and a slight effect upon IL-17A (3 μg, 5217.85 ± 0.72 pg/mL, P < 0.05) cytokines compared to the other test compounds and positive controls (AST VII: Astragaloside VII; and QS-21: Quillaja saponin 21). All tested extracts and molecules also induced release of IFN-γ remarkably ranging between 5031.95 ± 0.05 pg/mL, P < 0.001 for MeOH extract (6 μg) and 5877.08 ± 0.06 pg/mL, P < 0.001 for compound 1 (6 μg) compared to QS-21 (6 μg, 5924.87 ± 0.1 pg/mL, P < 0.001). Administration of AST VII and other test compounds did not cause any hemolytic activity, whereas QS-21 resulted a noteworthy hemolysis., Ege University BAP Research Foundation (15-FBE-001)

Adjunctive therapies have been proposed for use in at least 5 inflammation pathobiology phenotypes in pediatric sepsis-induced multiple organ failure (MOF). Here, we provide host-pathogen interaction prototypes to facilitate understanding of the rationale for personalized therapy in these phenotypes. Meningococcemic sepsis and Shiga-like toxin-associated atypical Hemolytic Uremic Syndrome sepsis result in thrombocytopenia and MOF due to endothelial dysfunction and formation of small vessel thromboses that can respond to plasma exchange and C5a monoclonal antibody therapy. H1N1 Influenza A sepsis is associated with immune paralysis that can result in opportunistic secondary infection with invasive methicillin resistant Staphylococcus aureus (MRSA) and MOF that can respond to Granulocyte Macrophage Colony Stimulating Factor therapy. Hyperleukocytosis-associated MOF is associated with critical Bordetella Pertussis pulmonary hypertension and cardiovascular collapse which can respond to leukoreduction therapy. Epstein Barr Virus lymphoproliferative disease-associated sequential MOF has high levels of soluble-Fas Ligand that cause liver failure, and can respond to anti-CD20 monoclonal antibody therapy. Viral hemorrhagic fevers such as Ebola or Dengue can lead to macrophage activation syndrome characterized by hyperferritinemia, hepatobiliary dysfunction and disseminated intravascular coagulation (DIC)-related MOF that can theoretically respond to anti-inflammatory therapies. We discuss the literature on adjunctive anti-inflammatory and immune modulation therapies that, in addition to traditional organ support and infection source control, might be part of a personalized precision medicine approach to reverse of each of these inflammatory pathobiology phenotypes.

The field of vascularized composite allotransplantation-combining advances in reconstructive surgery, transplantation, and immunology-offers great promise for patients with heretofore unsolvable problems. In the last 30 years, hand transplantation has progressed through the phases of being a research subject, a controversial clinical procedure, a more widely accepted and expanding field, and now a promising endeavor undergoing refined indications. Although many lessons have been learned, few procedures in the author's experience have been as life-transformative in restoring the body image, motor and sensory functions, activities of daily living, and personal autonomy as successful hand transplantation.

Author(s): Nguyen, Tanya; Kosciolek, Tomasz; Daly, Rebecca; Vazquez-Baeza, Yoshiki; Swafford, Austin; Knight, Rob; Jeste, Dilip

More than 95years ago Schistosoma pigment had been deemed as a degradation product of haemoglobin. Until the 1950s, scientists initiated to pay attention to understand the hematophagous habit of schistosomes, and to study the degradation of haemoglobin as well as the formation of hemozoin inside the gut of the worms. For a long time, the formation of hemozoin in both Plasmodium and in Schistosoma was considered to be the major route of heme detoxification, and hemozoin served a role in waste disposal. At the beginning of this century, the chemical structure of Schistosoma pigment was confirmed to be identical to that of malarial pigment (hemozoin) and its synthetic analogue, β-hematin. Since then, studies on Schistosoma hemozoin have been investigated by some workers and the results showed that Schistosoma hemozoin may play important roles in pathogenicity, immune modulation, iron supply for egg formation, and interaction with some anti-schistosomal drugs. In this review, we briefly review and discuss the hematophagous habit of schistosomes, degradation of haemoglobin, formation of hemozoin in the worm gut, and possible roles of hemozoin.

Ethnopharmacological relevance Withania somnifera (L.) Dunal (Ashwagandha, WS) is one of the extensively explored Ayurvedic botanicals. Several properties including immunomodulation, anti-cancer and neuro-protection of the botanical have been reported. Even though, in indigenous medicine, WS is well known for its immunomodulatory activity, the molecular mechanism of immunomodulation has not been elucidated. Aim of the study This study aimed the evaluation of the immunomodulatory effect of WS using network ethnopharmacology technique to elucidate the in silico molecular mechanism. Materials and methods Databases- DPED, UNPD, PubChem, Binding DB, ChEMBL, KEGG and STRING were used to gather information to develop the networks. The networks were constructed using Cytoscape 3.2.1. Data analysis was performed with the help of Excel pivot table and Cytoscape network analyzer tool. Results Investigation for WS immune modulation mechanism identified five bioactives that are capable of regulating 15 immune system pathways through 16 target proteins by bioactive-target and protein-protein interactions. The study also unveils the potential of withanolide-phytosterol combination to achieve effective immunomodulation and seven novel bioactive-immune target combinations. Conclusion The study elucidated an in silico molecular mechanism of immunomodulation of WS. It unveils the potential of withanolide-phytosterol combination to achieve a better immunomodulation. Experimental validation of the network findings would aid in understanding the rationale behind WS immunomodulation as well as aid in bioactive formulation based drug discovery.

It is currently unknown whether and how mammalian pathogen recognition receptors (PRRs) respond to biophysical patterns of pathogen-associated molecular danger signals. Using synthetic pathogen-like particles (PLPs) that mimic physical properties of bacteria or large viruses, we have discovered that the quality and quantity of Toll-like receptor 9 (TLR9) signaling by CpG in mouse dendritic cells (mDCs) are uniquely dependent on biophysical attributes; specifically, the surface density of CpG and size of the presenting PLP. These physical patterns control DC programming by regulating the kinetics and magnitude of MyD88-IRAK4 signaling, NF-κB-driven responses, and STAT3 phosphorylation, which, in turn, controls differential T cell responses and in vivo immune polarization, especially T helper 1 (Th1) versus T helper 2 (Th2) antibody responses. Our findings suggest that innate immune cells can sense and respond not only to molecular but also pathogen-associated physical patterns (PAPPs), broadening the tools for modulating immunity and helping to better understand innate response mechanisms to pathogens and develop improved vaccines.

Background Soybean oligosaccharides (SBOSs) are potential prebiotics that may be used to improve immune function. Here, we investigated the effects of intragastric administration of SBOSs in mice to determine the effects on autochthonous intestinal microbial communities and immunological parameters. Results E: After 22-day administration, 4.0 g kg body weight (BW) − 1 SBOSs significantly enhanced the proliferation of bifidobacteria and lactic acid bacteria (LAB) as compared to the control. This dose of SBOSs also significantly increased numbers of enterococci and decreased numbers of Clostridium perfringens. Treatment with 4.0 g kg BW −1 SBOSs also significantly increased the percentage of T-lymphocytes and lymphocyte proliferation as compared to the control, suggesting that SBOSs promoted cellular immunity in mice. Additionally, 4.0 g kg BW −1 SBOSs induced significant differences in hemolysin production, natural killer (NK) cell activity, phagocytic activity, cytokine production, and immunoglobulin levels compared to the control. Conclusion: Our data demonstrated that intragastric administration of SBOSs at a dose of 4.0 g kg BW −1 improved the numbers of beneficial intestinal microbes and enhanced immunological function of mice. Therefore, these data supported that SBOSs may have applications as a prebiotic to improve immune responses in humans. Further studies are warranted.

Les avancees recentes dans la prise en charge de la douleur perioperatoire concernent principalement la reconnaissance du risque de chronicisation. L’existence d’une douleur preoperatoire, la prise de morphiniques en preoperatoire et l’intensite de la douleur postoperatoire sont les facteurs de risque les mieux identifies. La gestion de la douleur perioperatoire en 2016 doit permettre d’optimiser la prise en charge postoperatoire, de detecter, en preoperatoire, les risques de chronicisation de la douleur et de detecter les facteurs precoces de chronicisation. En termes de traitement, l’utilisation systematique et large de la morphine a montre ses limites, notamment avec une efficacite moindre sur les douleurs au mouvement, des effets secondaires pouvant etre tres invalidants pour le patient et retarder la rehabilitation postoperatoire, un effet hyperalgesique dose-dependante source de douleur aigue et chronique, une immunomodulation pouvant avoir un impact negatif sur des pathologies infectieuses ou cancereuses (Sacerdote et al., 2012) et enfin, un doute sur une possible neurotoxicite. C’est pourquoi, l’analgesie moderne est basee sur la recherche d’une epargne morphinique en per- et postoperatoire. L’objectif en 2016 est donc une analgesie optimale permettant une rehabilitation rapide sans sequelles ou chronicisation utilisant des medicaments et/ou techniques permettant de s’affranchir des morphiniques. Recent advances in the management of perioperative pain principally concern the recognition of the risk of developing pain chronicity. The best identified risk factors for pain chronicity are the presence of pain preoperatively, preoperative opioid use, and the intensity of postoperative pain. Ideal management of perioperative pain in 2016 aims to optimize postoperative pain management, to detect the risk of pain chronicity begins preoperatively with early detection of risk factors for chronicity. In terms of treatment, the systematic and generous use of morphine has shown its limitations, particularly due to reduced efficacy for movement-related pain. Meanwhile, opioid side effects can be very debilitating for the patient, leading to delay in postoperative rehabilitation, a dose-dependent hyperalgesic effect resulting in both acute and chronic pain, immune modulation that may have a deleterious impact on infectious complications or cancer (Sacerdote et al., 2012), and, finally, some question of possible neurotoxicity. Therefore, modern analgesia depends on both intraoperative and postoperative morphine sparing. The goal at the present time is to obtain optimal analgesia that allows rapid rehabilitation without sequelae or chronicity through the use of drugs and/or techniques to avoid the need for opioid medications.

Characterization of the implanting human fetus as an allograft prompted a field of research in reproductive immunology that continues to fascinate and perplex scientists. Paternal- or partner-derived alloantigens are present in the maternal host at multiple times during the reproductive process. They begin with exposure to semen, continue through implantation and placentation, and may persist for decades in the form of fetal microchimerism. Changes in maternal immune responses that allow allogenic fertilization and survival of semiallogenic concepti to delivery must be balanced with a continued need to respond appropriately to pathogenic invaders, commensals, cell or tissue damage, and any tendency toward malignant transformation. This complex and sophisticated balancing act is essential for survival of mother, fetus, and the species itself. We will discuss concepts of alloimmune recognition, tolerance, and ignorance as they pertain to mammalian reproduction with a focus on human reproduction, maternal immune modulation, and the very earliest events in the reproductive process, fertilization and implantation.

Background Tuberculosis (TB) remains a health-related problem worldwide, and certain malignancies are known to be associated with an increased risk of TB. Lung cancer is the leading cause of cancer-related death, and the number of patients with lung cancer has been reportedly increasing. As the prognosis of lung cancer remains poor, aggressive comprehensive therapies have been used. The immunosuppression caused by cancer itself and treatment-associated immune modulation may increase the risk of TB. The present study was conducted to investigate the cumulative incidence of TB in lung cancer patients. Methods This observational study included 904 consecutive patients diagnosed with histologically confirmed lung cancer from March 2007 to March 2013 and followed until March 2015 (mean 25.2 months). The cumulative incidence of TB was estimated using the Kaplan–Meier method. Results Nine lung cancer patients (1.00%) developed TB during the observation period. In all cases, TB occurred within 2 years of the diagnosis of lung cancer. The cumulative incidence of TB at 6 months, 1 year, and 2 years was 0.65%, 1.15%, and 1.38%, respectively. Conclusions The cumulative incidence of TB in lung cancer patients was 1.38% in Japan.

Particles make extensively physical contact with cells after entering the body, which mediate a series of particle-cell interaction processes. These interaction processes induce different physiological responses of cells and indicate the potential biomedical applications of particles. Hence, controlling the particle-cell interaction processes have been attracting more and more attentions. Among factors that affect particle-cell interaction processes, regulating particle multiscale structures is the most dominant. To date, numerous principles have been developed, including integrating particles with different physicochemical properties such as size, shape, elasticity and surface chemistry by various preparation technologies, coating particle surface with cell membrane to endow its biomimetic properties, taking advantage of the particle's dimensional effect, etc. In this review, we will highlight recent progresses on these principles, and corresponding biomedical applications in drug delivery, immune modulation and tissue engineering. The challenges and perspectives of regulating particle multiscale structures for controlling interaction processes will also be discussed.

International audience; Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by vasculopathy, dysregulation of innate and adaptive immune responses, and progressive fibrosis. SSc remains an orphan disease, with high morbity and mortality in SSc patients. The mesenchymal stromal cells (MSC) demonstrate in vitro and in vivo pro-angiogenic, immuno-suppressive, and anti-fibrotic properties and appear as a promising stem cell therapy type, that may target the key pathological features of SSc disease. This review aims to summarize acquired knowledge in the field of :1) MSC definition and in vitro and in vivo functional properties, which vary according to the donor type (allogeneic or autologous), the tissue sources (bone marrow, adipose tissue or umbilical cord) or inflammatory micro-environment in the recipient; 2) preclinical studies in various SSc animal models , which showed reduction in skin and lung fibrosis after MSC infusion; 3) first clinical trials in human, with safety and early efficacy results reported in SSc patients or currently tested in several ongoing clinical trials.

The present study evaluated the effects of a commercial phytogenic feed additive (PFA) on Salmo salar growth, immune response and its susceptibility to Piscirickettsia salmonis infection. Preliminary in vitro trials in SHK-1 cells showed higher expression levels for il-12 and ifn-I genes at 12 h post-treatment, also a protective cellular effect against the P. salmonis infection was observed. Subsequently, in vivo trials with the PFA supplemented diet (0.5 g/Kg) were conducted to corroborate the fish immune modulation and protection against P. salmonis. Diets with and without the PFA were used to fed triplicate groups of 35 juveniles salmon during 14 days. Afterwards, fish from all dietary groups were equally redistributed in tanks and challenged by cohabitation with P. salmonis infected fish (donors), recording mortalities after 70 days post-infection. Survival percentages of 79.1 ± 3.7 and 52.7 ± 2.78% were observed in the cohabitant fish fed with PFA and control diets, respectively. PFA dietary administration, preceding the cohabitation challenge, contributed significantly in the protection against P. salmonis as suggested by the Relative Percent Survival (RPS) values of 48.1% after 70 days post-infection. Furthermore, we also demonstrate that dietary supplementation with the PFA stimulates the expression of keys genes involved in the S. salar immune response against P. salmonis infection.

SUMMARY Phosphatidylserine (PS) is exposed on the surface of apoptotic cells and is known to promote immunosuppressive signals in the tumor microenvironment (TME). Antibodies that block PS interaction with its receptors have been shown to repolarize the TME into a proinflammatory state. Radiation therapy (RT) is an effective focal treatment of isolated solid tumors but is less effective at controlling metastatic cancers. We found that tumor-directed RT caused an increase in expression of PS on the surface of viable immune infiltrates in mouse B16 melanoma. We hypothesize that PS expression on immune cells may provide negative feedback to immune cells in the TME. Treatment with an antibody that targets PS (mch1N11) enhanced the anti-tumor efficacy of tumor-directed RT and improved overall survival. This combination led to an increase in proinflammatory tumor-associated macrophages. The addition of anti-PD-1 to RT and mch1N11 led to even greater anti-tumor efficacy and overall survival. We found increased PS expression on several immune subsets in the blood of patients with metastatic melanoma after receiving tumor-directed RT. These findings highlight the potential of combining PS targeting with RT and PD-1 pathway blockade to improve outcomes in patients with advanced-stage cancers., In Brief Budhu et al. show that tumor-directed irradiation of murine B16 melanoma causes an increase in PS on the surface of infiltrating immune cells. Blocking PS and RT improves the anti-tumor efficacy and overall survival, which can be further improved with the addition of anti-PD-1. Melanoma patients exhibit increased PS on their PBMCs after RT., Graphical Abstract

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal condition that can be primary or secondary. Secondary HLH due to Mycobacterium tuberculosis (TB) is uncommon. We report a case of tuberculosis-associated HLH in an umbilical cord blood transplant (UCBT) recipient and discuss its clinical characteristics and challenges. Methods Hematologic investigations, bone marrow aspirates, Xpert MTB/RIF test of TB with peripheral blood were performed. Immune modulation with anti-TB therapy was initiated. Results Subsequent treatment with anti-TB treatment resulted rapid clinical response and disease remission. Conclusion It is important to consider TB as one of the underlying cause of HLH in high-risk patients, particularly those in immunodeficient states. Early diagnosis and treatment can improve the survival rates of patients with tuberculosis-associated HLH.

Summary Immunotherapeutics are frequently associated with adverse side effects due to the elicitation of global immune modulation. To lower the risk of these side effects, recombinant DNA technology is employed to enhance the selectivity of cell targeting by genetically fusing different biomolecules, yielding new species referred to as multi-specific biologics. The design of new multi-specific biologics is a central challenge for the realization of new immunotherapies. To understand the molecular determinants responsible for regulating the binding between multi-specific biologics and surface-bound membrane receptors, we developed a multiscale computational framework that integrates various simulation approaches covering different timescales and spatial resolutions. Our model system of multi-specific biologics contains two natural ligands of immune receptors, which are covalently tethered by a peptide linker. Using this method, a number of interesting features of multi-specific biologics were identified. Our study therefore provides an important strategy to design the next-generation biologics for immunotherapy., Graphical Abstract, Highlights • Two proteins are connected by different linkers as a model of bispecific biologics • Conformational dynamics of biologics are captured by microsecond MD simulations • Coarse-grained simulations are used to test binding between biologics and receptors • Biologics with long and flexible linkers are more efficient in targeting receptors, Immunology; Therapeutics

To date only small animal models have been employed to assess the effect of mesenchymal stromal cell (MSC) therapy on acute pancreatitis (AP), the most common cause of hospitalization for gastrointestinal diseases worldwide. We outline the challenges inherent in the small animal models of AP. We also point to specific benefits afforded by the adoption of larger animal models. The potential for MSC therapeutics in the treatment of AP was recognized over a decade ago. With sharper focus on the form of AP and development of new MSC delivery routes in larger animals, we believe the challenge can be engaged.

14 pages, 9 figures, 2 tables, Although iron has been proved as a vital element for the development of living organisms, high levels of this element can impact the normal function of different biological processes, including immune response. Therein, this study aimed to characterize the transcriptional changes in Atlantic salmon during the exposure to iron overload, evaluating the susceptibility to bacterial infection. Atlantic salmon were injected with 1 or 5 mg of iron dextran and an iron chelator (DFOM), and subsequently challenged with the intracellular bacterium Piscirickettsia salmonis. Iron levels in plasma and the transcriptional responses of the head kidney, liver, and spleen during the infection processes were evaluated. Here, iron transport, response to oxidative stress, and immune related genes were strongly modulated in individuals exposed to the metal. Fish overloaded with iron showed significant downregulation of CD83, IL-17, IL-1, Toll-like receptors, immunoglobulin, and T-cell receptors genes, suggesting an overall deleterious effect on the immune system. Furthermore, histopathological analysis evidenced that iron overdoses can strongly increase the clinical signs during the P. salmonis infection. Notably, fish exposed to 1 mg of iron and infected with P. salmonis evidenced high mortality and bacterial burden. Also, this group showed significant downregulation of immune-related genes comparing with fish with 5 mg of iron. In addition, Atlantic salmon injected with deferoxamine mesylate salt (DFOM) showed high tolerance to P. salmonis infection and an increase of IL-1b expression, suggesting a cytokines response activation. These results suggest that iron overload disrupts fish immune response although not in a doses dependent manner, and when a chelator is injected, fish present higher resistance to P. salmonis. This study reveals novel insights about teleost's immune system modulation by iron availability, This study was funded by FONDAP grant #15110027 and Fondecyt grant #1180867, granted by CONICYT-Chile

Clinical administration of Interferon α (IFNα) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8+ T cell responses during IFNα therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFNα subtype 2. To date, the immunomodulatory roles of the remaining 10-13 IFNα subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treatments. Here, we report that virus-specific CD8+ T cell responses were influenced to various extents by individual IFNα subtypes. IFNα4, 6 and 9 had the strongest effects on CD8+ T cells, including antiproliferative effects, improved cytokine production and cytotoxicity. Interestingly, augmented cytokine responses were dependent on IFNα subtype stimulation of dendritic cells (DCs), while antiproliferative effects and cytotoxicity were mediated by IFNAR signaling in either CD8+ T cells or DCs. Thus, precise modulation of virus-specific CD8+ T cell responses may be feasible for specific antiviral immunotherapies through careful selection and administration of individual IFNα subtypes.

Objectives Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. Methods A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. Results Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. Conclusions Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment., Highlights • CC-11050 is an anti-inflammatory molecule targeting host phosphodiesterase-4. • CC-11050 plus isoniazid therapy significantly reduced bacillary load and pathology in a rabbit model pulmonary tuberculosis. • CC-11050 can be a promising candidate for adjunctive host directed therapy of patients with active pulmonary tuberculosis. In 2013, tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) killed 1.5 million people worldwide. Current antibiotic therapy for tuberculosis is ineffective in eliminating the infecting bacilli and/or disease pathology such as lung fibrosis. Therefore, alternate approaches are urgently needed to control the TB epidemic. In this study, using a rabbit model of pulmonary TB, which closely mimics the human disease, we tested the hypothesis that reducing the host inflammatory response during Mtb infection would improve the outcome of antibiotic treatment; we show that adjunctive phosphodiesterase-4 inhibition therapy with isoniazid improves bacterial clearance and lung pathology.

Background Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet β cells. The complexities of overcoming autoimmunity in T1D have contributed to the challenges the research community faces when devising successful treatments with conventional immune therapies. Overcoming autoimmune T cell memory represents one of the key hurdles. Methods In this open-label, phase 1/phase 2 study, Caucasian T1D patients (N = 15) received two treatments with the Stem Cell Educator (SCE) therapy, an approach that uses human multipotent cord blood-derived multipotent stem cells (CB-SCs). SCE therapy involves a closed-loop system that briefly treats the patient's lymphocytes with CB-SCs in vitro and returns the “educated” lymphocytes (but not the CB-SCs) into the patient's blood circulation. This study is registered with ClinicalTrials.gov, NCT01350219. Findings Clinical data demonstrated that SCE therapy was well tolerated in all subjects. The percentage of naïve CD4+ T cells was significantly increased at 26 weeks and maintained through the final follow-up at 56 weeks. The percentage of CD4+ central memory T cells (TCM) was markedly and constantly increased at 18 weeks. Both CD4+ effector memory T cells (TEM) and CD8+ TEM cells were considerably decreased at 18 weeks and 26 weeks respectively. Additional clinical data demonstrated the modulation of C–C chemokine receptor 7 (CCR7) expressions on naïve T, TCM, and TEM cells. Following two treatments with SCE therapy, islet β-cell function was improved and maintained in individuals with residual β-cell function, but not in those without residual β-cell function. Interpretation Current clinical data demonstrated the safety and efficacy of SCE therapy in immune modulation. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects. Funding Obra Social “La Caixa”, Instituto de Salud Carlos III, Red de Investigación Renal, European Union FEDER Funds, Principado de Asturias, FICYT, and Hackensack University Medical Center Foundation., Highlights • We prove the safety and feasibility of a two-treatment approach with SCE therapy. • The percentage of naïve CD4+ and TCM cells were increased, but the percentage of CD4+ TEM and CD8+ TEM cells were declined. • The expression of CCR7 on naïve T and TCM cells were markedly increased. The current studies demonstrated the safety and feasibility of a two-treatment approach with Stem Cell Educator therapy and well tolerated in all subjects, without significantly changing the numbers and ratios of different cell compartments in the subjects' immune system. Both the percentage of CD4+ and CD8+ effector memory T cells were substantially decreased in the peripheral blood of T1D subjects, whereas the percentage of CD4+ central memory T cells was markedly and constantly increased. These findings provide a solution to alter the autoimmune memory compartment in T1D, while mitigating safety and ethical concerns associated with conventional immune therapies.

Despite significant advances in the development of Alzheimer's disease (AD) vaccines effective in animal models, these prototypes have been clinically unsuccessful; apparently the result of using immunogens modified to prevent inflammation. Hence, a new paradigm is needed that uses entire AD-associated immunogens, a notion supported by recent successful passive immunotherapy results, with adjuvants that induce Th2-only while inhibiting without abrogating Th1 immunity. Here, we discuss the obstacles to AD vaccine development and Th2-adjuvants that by acting on dendritic and T cells, would elicit regardless of the antigen a safe and effective antibody response, while preventing damaging neuroinflammation and ameliorating immunosenescence.