Altered Basal Lipid Metabolism Underlies the Functional Impairment of Naive CD8+ T Cells in Elderly Humans.

Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8+ T cells in elderly humans were prone to apoptosis and proliferated suboptimally in response to stimulation via the TCR. These abnormalities were associated with dysregulated lipid metabolism under homeostatic conditions and enhanced levels of basal activation. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the Ag responsiveness of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against targetable cancers and emerging pathogens, such as seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.

Entinostat induces antitumor immune responses through immune editing of tumor neoantigens.

Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti-PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell-autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.

Evaluation of the digestion and transport profiles and potential immunocompetence of puerarin and its acylated derivatives.

Acylation has become one of the most widely used methods to improve the lipid solubility and bioavailability of flavonoids. In this study, puerarin acid esters (PAES) with different chain lengths were synthesized via biocatalytic acylation. This was the first study to evaluate the digestion and transport profiles and immunocompetence of PAES. The relationship between the digestion and transport profiles and potential immunocompetence of the acylated derivatives in Caco-2 cell monolayers was also explored. Puerarin and PAES remained stable in gastric phases, whereas different degrees of hydrolysis of PAES were found in the intestine. PAES with less than 12 carbon chains were positively correlated with the degree of hydrolysis, while those with more than 12 carbon chains showed higher resistance to hydrolysis by the artificial human digestive juice. The apparent permeability coefficients of puerarin, puerarin acetate, puerarin propanoate, puerarin butyrate, puerarin hexanoate, puerarin octanate and puerarin laurate were 1.62 ± 0.09, 1.70 ± 0.15, 1.89 ± 0.19, 1.86 ± 0.18, 2.29 ± 0.12, 4.06 ± 1.01 and 2.32 ± 0.88 × 10-6 cm s-1, respectively, in Caco-2 cell monolayers. The results of the immune factor assays indicated that puerarin propanoate, puerarin hexanoate and puerarin myristate could significantly promote the secretion of IL-6, TNF-α and IL-10. These findings suggested that a better absorption could be predicted after oral intake using PAES. Meanwhile, the concentration of esters and their metabolites (puerarin) found in the digestion and transport profiles directly affected their potential immunocompetence.

Oligodeoxynucleotides containing unmethylated cytosine-guanine motifs are effective immunostimulants against pneumococcal meningitis in the immunocompetent and neutropenic host.

BACKGROUND: Bacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae. METHODS: Three days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9)-/- mice received an intraperitoneal injection of 100 µg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed. RESULTS: Pre-treatment with 100 µg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9-/- mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection. CONCLUSIONS: Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.

Vertebral tuberculosis as a paradoxical reaction to the treatment of pulmonary and meningeal tuberculosis in an immunocompetent patient: A case report.

INTRODUCTION: Paradoxical reaction in tuberculosis (TB) is defined as the reappearance of general symptoms, aggravation of pre-existing diseases, or appearance of new lesions despite adequate anti-TB therapy. It may result from the hyperactivity of the immune response, resulting in an intense inflammation. There are few cases of vertebral TB reported as paradoxical reaction, mainly among immunocompetents patients. PATIENT CONCERNS: We describe a male immunocompetent patient with confirmed pulmonary and meningeal TB. He was readmitted after 60 days of adequate treatment, with vertebral TB and paravertebral abscess, despite clinical improvement of the other locations. We defined as an uncommon case of a paradoxical reaction, confirmed by nuclear magnetic resonance and molecular rapid test for TB. DIAGNOSIS: Mycobacterium tuberculosis (MTB) was detected in cerebrospinal fluid by molecular rapid test (Gene Xpert MTB/ rifampicina method). Sputum research and culture were positive for the same agent. Lumbosacral spine nuclear magnetic resonance revealed bone destruction from T8 to T11, and a paravertebral collection was found. Gene Xpert MTB/rifampicina and culture were positive for M tuberculosis in the drained material of the paravertebral abscess. INTERVENTIONS: The paravertebral abscess was drainage by tomography-guided. Treatment with 4 anti-TB drugs was extended for 60 days and 2 anti-TB drugs was maintained for 10 months. There was a complete clinical improvement. OUTCOME: After draining the paravertebral abscess, the patient progressively improved and was discharged for outpatient follow-up. He was on antituberculous drugs for 1 year; subsequently, complete resolution of the infection was reported. CONCLUSION: Paradoxical reaction may be a difficult diagnosis in immunocompetent patient. Vertebral TB as a paradoxical reaction is an uncommon presentation. Therapeutic failure or resistance to treatment should be ruled out to confirm the diagnosis of paradoxical reaction.

Cannabis in the Time of Coronavirus Disease 2019: The Yin and Yang of the Endocannabinoid System in Immunocompetence.

Editor's Note: For those whose response to COVID-19 includes exploring beyond vaccines, conventional pharmaceuticals, and the watchful or healthy waiting until such tools might arrive, interest in cannabinoids has been high - and controversial. It has already stimulated one journal, the Liebert Cannabis and Cannabinoid Research, to issue a call for papers on COVID-19. The unique place of cannabis in the culture seems to always mark the herb with an exponential asterisk whenever basketed with the other natural health strategies that are both widely used, and as broadly derided. In this invited commentary, JACM Editorial Board member Michelle Sexton, ND starts by describing the multiple immune modulating effects associated with the herb. The University of California San Diego Assistant Adjunct Professor in Anesthesiology then asks: "Given these effects, can phytocannabinoids be either helpful, or harmful for immune competency, in the context of the current COVID-19 pandemic?" A skilled edge-walker, Sexton lets the research fall where it may in wending a path through this evidentiary maze. -John Weeks, Editor-in-Chief, JACM.

Effects of Humic Acids, Isolated from High-Moor Pine-Peat Moss-Cotton Grass Peat on the Production of Cytokines by Mouse and Human Immunocompetent Cells and on Humoral Immune Response.

A course of treatment with humic acids extracted with sodium pyrophosphate from high-moor pine-peat moss-cotton grass peat improves humoral immune response of C57BL/6 mice, stimulates the production of TNFα, IL-1ß, and IL-12 by the animal peritoneal macrophages and the production of IFNγ and TNFα by donor peripheral blood mononuclears, causing no changes in the production of IL-10 in vitro.

Pleuritis por Cryptococcus neoformans en paciente inmunocompetente / Cryptococcus neoformans pleuritis in an immunocompetent patient

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Human mesenchymal stem cell sheets in xeno-free media for possible allogenic applications.

Cell-based therapies are increasingly focused on allogeneic stem cell sources because of several advantages in eliminating donor variability (e.g., aging and disease pathophysiology) affecting stem cell quality and in cell-banked sourcing of healthy donors to enable "off-the-shelf" products. However, allogeneic cell therapy is limited by host patient immunologic competence and inconsistent performance due to cell delivery methods. To address allogeneic cell therapy limitations, this study developed a new allogeneic stem cell sheet using human umbilical cord mesenchymal stem cells (hUC-MSC) that present low antigenicity (i.e., major histocompatibility complex, MHC). Optimal conditions including cell density, passage number, and culture time were examined to fabricate reliable hUC-MSC sheets. MHC II antigens correlated to alloimmune rejection were barely expressed in hUC-MSC sheets compared to other comparator MSC sheets (hBMSC and hADSC). hUC-MSC sheets easily graft spontaneously onto subcutaneous tissue in immune-deficient mice within 10 minutes of placement. No sutures are required to secure sheets to tissue because sheet extracellular matrix (ECM) actively facilitates cell-target tissue adhesion. At 10 days post-transplantation, hUC-MSC sheets remain on ectopic target tissue sites and exhibit new blood vessel formation. Furthermore, implanted hUC-MSC sheets secrete human HGF continuously to the murine target tissue. hUC-MSC sheets described here should provide new insights for improving allogenic cell-based therapies.

Necrotic skin ulcers in an immunocompromised patient / Úlceras de piel necróticas en un paciente inmunocomprometido

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A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies.

Alterations of the microbial composition in the gut and the concomitant dysregulation of the mucosal immune response are associated with the pathogenesis of opportunistic infections, chronic inflammation, and inflammatory bowel disease. To create a platform for the investigation of the underlying mechanisms, we established a three-dimensional microphysiological model of the human intestine. This model resembles organotypic microanatomical structures and includes tissue resident innate immune cells exhibiting features of mucosal macrophages and dendritic cells. The model displays the physiological immune tolerance of the intestinal lumen to microbial-associated molecular patterns and can, therefore, be colonised with living microorganisms. Functional studies on microbial interaction between probiotic Lactobacillus rhamnosus and the opportunistic pathogen Candida albicans show that pre-colonization of the intestinal lumen of the model by L. rhamnosus reduces C. albicans-induced tissue damage, lowers its translocation, and limits fungal burden. We demonstrate that microbial interactions can be efficiently investigated using the in vitro model creating a more physiological and immunocompetent microenvironment. The intestinal model allows a detailed characterisation of the immune response, microbial pathogenicity mechanisms, and quantification of cellular dysfunction attributed to alterations in the microbial composition.

[Antimicrobial therapy in cancer patients and hematopoietic stem cell transplantation receptors]. / Parte IV. Terapia antimicrobiana en pacientes con cáncer y receptores de trasplante de precursores hematopoyéticos.

This manuscript includes the antiinfective therapeutic resources for immunocompromised patients under chemotherapy by cancer or hematopoietic stem cells transplant (HSCT) receptors. The document presents the antimicrobial therapy indicated in the most prevalent clinical situations in this population and the primary and alternative therapy for some specific microorganisms. The clinical situations included in the analysis are: febrile neutropenia without focus, sepsis, infections of the central nervous system, pneumonia, skin and soft tissue infections, neutropenic enterocolitis and urinary tract infection. The therapeutic resources, recommended doses and special precautions for the use of antimicrobial recommended in bacterial, viral, fungal and parasitic infections in this population are described, including the measurement of plasma concentrations of certain drugs in specific situations.

Growth performance and immune status in common carp Cyprinus carpio as affected by plant oil-based diets complemented with ß-glucan.

Omnivorous fish species such as the common carp (Cyprinus carpio) are able to biosynthesise long chain polyunsaturated fatty acids (LC-PUFAs) from plant oil PUFA precursors, but the influence of the amount and quality of the LC-PUFAs biosynthesised from these oils on the immunocompetence status of the fish has received little attention. This study aims to evaluate whether the conversion of PUFA by carp induces a sufficient biosynthesis of LC-PUFA to maintain a good immunocompetence status in this species. Six iso-nitrogenous (crude protein = 39.1%) and iso-lipidic (crude lipids = 10%) diets containing three different lipid sources (cod liver oil (CLO) as fish oil; linseed oil (LO) and sunflower oil (SFO) as plant oils) were formulated with or without ß-glucan supplementation at 0.25 g/kg diet. Juvenile carp (16.3 ±â€¯0.6 g initial body weight) were fed a daily ration of 4% body weight for 9 weeks and then infected at day 64 with the bacteria Aeromonas hydrophyla. No significant differences in survival rate, final body weight, specific growth rate and feed conversion rate were observed between diets. After bacterial infection, mortality rate did not differ between fish fed CLO and plant oil-based diets, indicating that the latter oils did not affect the overall immunocompetence status of common carp. Plant oil-based diets did not alter lysozyme activity in healthy and infected fish. No negative effects of plant oils on complement activity (ACH50) were observed in healthy fish, even if both plant oil-based diets induced a decrease in stimulated fish two days after infection. Furthermore, the levels of various immune genes (nk, lys, il-8, pla, pge, alox) were not affected by plant oil-based diets. The expression of pla and pge genes were higher in SFO-fed fish than in CLO ones, indicating that this plant oil rich in linoleic acid (LA) better stimulated the eicosanoid metabolism process than fish oil. In response to ß-glucan supplementation, some innate immune functions seemed differentially affected by plant oil-based diets. LO and SFO induced substantial LC-PUFA production, even if fish fed CLO displayed the highest EPA and DHA levels in tissues. SFO rich in LA induced the highest ARA levels in fish muscle while LO rich in α-linolenic acid (ALA) sustained higher EPA production than SFO. A significantly higher fads-6a expression level was observed in SFO fish than in LO ones, but this was not observed for elovl5 expression. In conclusion, the results show that common carp fed plant oil-based diets are able to produce substantial amounts of LC-PUFA for sustaining growth rate, immune status and disease resistance similar to fish fed a fish oil-based diet. The differences in the production capacity of LC-PUFAs by the two plant oil-based diets were associated to a differential activation of some immune pathways, explaining how the use of these oils did not affect the overall immunocompetence of fish challenged with bacterial infection. Moreover, plant oil-based diets did not induce substantial negative effects on the immunomodulatory action of ß-glucans, confirming that these oils are suitable for sustaining a good immunocompetence status in common carp.

Parte IV. Terapia antimicrobiana en pacientes con cáncer y receptores de trasplante de precursores hematopoyéticos / Antimicrobial therapy in cancer patients and hematopoietic stem cell transplantation receptors

Resumen Este documento incluye los recursos terapéuticos antiinfecciosos necesarios para pacientes inmunocomprometidos por terapia de cáncer o receptores de trasplante de precursores hematopoyéticos (TPH). Se aborda la terapia indicada para pacientes con las situaciones clínicas prevalentes en esta población y la terapia indicada para algunos microorganismos específicos. Según presentación clínica, se aborda el manejo de pacientes con: neutropenia febril sin foco, sepsis, infecciones del sistema nervioso central, neumonía, infecciones de piel y tejidos blandos, enterocolitis neutropénica e infección del tracto urinario. Se describe el arsenal terapéutico necesario, las dosis recomendadas y las precauciones especiales para el uso de antibacterianos, antivirales, antifúngicos y antiparasitarios en esta población, incluida la medición de concentraciones plasmáticas de ciertos fármacos en situaciones específicas.

This manuscript includes the antiinfective therapeutic resources for immunocompromised patients under chemotherapy by cancer or hematopoietic stem cells transplant (HSCT) receptors. The document presents the antimicrobial therapy indicated in the most prevalent clinical situations in this population and the primary and alternative therapy for some specific microorganisms. The clinical situations included in the analysis are: febrile neutropenia without focus, sepsis, infections of the central nervous system, pneumonia, skin and soft tissue infections, neutropenic enterocolitis and urinary tract infection. The therapeutic resources, recommended doses and special precautions for the use of antimicrobial recommended in bacterial, viral, fungal and parasitic infections in this population are described, including the measurement of plasma concentrations of certain drugs in specific situations.

Evaluation of a Fully Human, Hepatitis B Virus-Specific Chimeric Antigen Receptor in an Immunocompetent Mouse Model.

Chimeric antigen receptor (CAR) T cell therapy is a promising novel therapeutic approach for cancer but also for chronic infection. We have developed a fully human, second-generation CAR directed against the envelope protein of hepatitis B virus on the surface of infected cells (S-CAR). The S-CAR contains a human B cell-derived single-chain antibody fragment and human immunoglobulin G (IgG) spacer, CD28- and CD3-signaling domains that may be immunogenic in mice. Because immunosuppression will worsen the clinical course of chronic hepatitis B, we aimed at developing a preclinical mouse model that is immunocompetent and mimics chronic hepatitis B but nevertheless allows evaluating efficacy and safety of a fully human CAR. The S-CAR grafted on T cells triggered antibody responses in immunocompetent animals, and a co-expressed human-derived safeguard, the truncated epidermal growth factor receptor (EGFRt), even induced B and T cell responses, both limiting the survival of S-CAR-grafted T cells. Total body irradiation and transfer of T cells expressing an analogous, signaling-deficient S-CAR decoy and the safeguard induced immune tolerance toward the human-derived structures. S-CAR T cells transferred after immune recovery persisted and showed long-lasting antiviral effector function. The approach we describe herein will enable preclinical studies of efficacy and safety of fully human CARs in the context of a functional immune system.

Infección por Saccharomyces cerevisiae en un individuo inmunocompetente / Saccharomyces cerevisiae infection in an immunocompetent host

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Arginine and manganese supplementation on the immune competence of broilers immune stimulated with vaccine against Salmonella Enteritidis.

This experiment was conducted to evaluate the combined effects of manganese-amino acid complex and arginine supplementation on the immune competence of broilers. On the day of hatch 640 male Cobb 500 broiler chicks assigned to two study groups (immune stimulate and non-stimulated). A 2 × 2 factorial arrangement of treatments was used with two manganese sources (MnSO4 or manganese-amino acid complex - MnAA) and two digestible Arg:Lys ratios (1.12 or 1.20). The treatments are: IM (80 ppm MnSO4); MnAA (40 ppm MnSO4 + 40 ppm MnAA); IM+Arg: 80 ppm MnSO4+ L-Arg (Arg:DigLys 1.20); MnAA+Arg: 40 ppm MnSO4 + 40 ppm MnAA + L-Arg (Arg:Lys 1.20). For treatments 1 and 2, the digestible Arg:Lys ratio was 1.12, considered normal for corn-soybean meal-based diets. Birds in the immune stimulated group received a dose of Salmonella Enteritidis vaccine. For growth performance and lymphoid organ development, no significant results were observed. Non-stimulated birds fed diets with Arg supplementation had higher percentage of mucosal T helper, T helper and T cytotoxic, compared to the normal Arg:Lys ratio (1.12). In the immune stimulated birds, broilers fed exclusive IM diet had a higher amount of T helper, T cytotoxic, activated T cytotoxic, and APC cells compared to broilers fed MnAA. The inorganic Mn diets, resulted in higher humoral antibody level (increased IgM levels) only when associated with supplementation of L-Arg. However, the use of an associated Mn source, could support high levels of IgM in commercial levels of Arg. No differences were observed to macrophage phagocytic activity analyses.

High-dose corticosteroids for acute cytomegalovirus-associated transverse myelitis in the immunocompetent patient: a case report and systematic review.

We present an immunocompetent patient with transverse myelitis (TM) during acute cytomegalovirus (CMV) infection, as evidenced by a reactive serum CMV IgM and CMV viremia. The patient had an excellent outcome after receiving only high-dose methylprednisolone. Given concerns that practitioners may have around the use of immunosuppressive therapy for this potentially infectious myelopathy, we systematically reviewed the literature to assess outcomes after administration of high-dose corticosteroids to this population. Despite severe disease at clinical nadir with inability to ambulate, immunocompetent patients with acute CMV-associated TM who received high-dose corticosteroids had good clinical outcomes 1 month to 1 year after presentation.

Impact of Rosmarinus officinalis cold-pressed oil on health, growth performance, intestinal bacterial populations, and immunocompetence of Japanese quail.

This study was performed to study the impacts of rosemary cold-pressed oil (RCPO) for biostimulating health, growth performance, and intestinal bacterial populations of Japanese quail. The study included 300 growing 1-wk-old Japanese quails. Birds were divided into 3 groups in a complete randomized design experiment that involved 3 levels of RCPO (0, 1.00 and 2.00 mL/kg diet). Results revealed that the addition of rosemary oil numerically increased values of body weight and body weight gain when compared with the control group, particularly the highest level of RCPO (2.00 mL/kg diet). Birds fed diets supplemented with rosemary oil consumed more feed (P ≤ 0.01) compared with those fed the control diet. Feed conversion ratio tended to be improved in rosemary oil groups during the period 3 to 6 wk of age (P = 0.013). The highest level of rosemary oil (2.00 mL/kg diet) had the best impact on all carcass traits studied. RCPO supplementation showed an increase in serum total protein, metabolic hormones levels, while it reduced serum cholesterol and low-density lipoprotein cholesterol, 8-hydroxy-2'-deoxyguanosine, and protein carbonyl levels. Moreover, RCPO increased antioxidative enzymes, and reduced the lipid peroxidation in quail liver. The supplementation of 2 mL/RCPO kg diet showed significant reduction in populations of total cultural bacterial count, coliforms, Escherichia coli, and Salmonella spp. in the ileum when compared to the control. The current results showed that RCPO supplementation to Japanese quails diet could enhance the growth performance and reduce the intestinal pathogenic bacteria. Therefore, RCPO can be a beneficial antimicrobial and growth-promoting feed supplement for the Japanese quail.