Vitexin-2-O-rhamnoside improves immunosuppression, oxidative stress, and phosphorylation of PI3K/Akt signal pathway in cyclophosphamide treated mice.

Vitexin-2-O-rhamnoside (VR) is an important active substance in hawthorn, which is widely used as a food or functional food raw material; however, its immunomodulatory activities have not been extensively studied. In this study, BALB/c mice immunocompromised by cyclophosphamide (CY) were used as models to explore the effects of VR on the immunity and antioxidant capacity of mice. The results revealed that VR can restore weight to the immunosuppressed mice to varying degrees, improve spleen and thymus injury, and restore peripheral blood levels. Furthermore, it can effectively promote the proliferation of T and B lymphocytes, natural killer (NK) and cytotoxic T lymphocyte (CTL) cell activities, and the secretion and mRNA expression of cytokines IFN-γ, IL-2, IL-6, and IL-12 to 0.36, 0.34, 50.25%, 45.74%, 28.36 pg/mL or 0.68, 31.81 pg/mL or 0.74, 20.40 pg/mL or 0.75, and 19.81 pg/mL or 0.55, respectively. Moreover, it can upregulate the phosphorylation level of PI3K/Akt signaling pathway in mice immunosuppressed by CY, increase the activities of glutathione peroxidase (GSH-Px), chloramphenicol acetyltransferase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), and decrease the level of malondialdehyde (MDA). This study provides a theoretical and experimental basis for the research and development of health products with targeted efficacy, and the development of diversified products in the hawthorn deep-processing industry.

A Rare Case of Epstein-Barr Virus-Positive T-Cell Lymphoma in the Skin of an Immunocompromised Patient.

ABSTRACT: Immunodeficiency-associated lymphoproliferative disorders are associated with latent infection by Epstein-Barr virus (EBV). Most cases of EBV-positive immunodeficiency-associated lymphoproliferative disorders arise from B cells, although some are of T-cell or natural killer origin. Cutaneous involvement is unusual and sporadically reported in the literature. We describe a rare case of an EBV-positive T-cell lymphoma presenting in the skin of a 32-year-old woman using adalimumab for neurosarcoidosis.

The antibody response of haematological malignancies to COVID-19 infection and vaccination.

Cancer patients with COVID-19 have reduced survival. While most cancer patients, like the general population, have an almost 100% rate of seroconversion after COVID-19 infection or vaccination, patients with haematological malignancies have lower seroconversion rates and are far less likely to gain adequate protection. This raises the concern that patients with haematological malignancies, especially those receiving immunosuppressive therapies, may still develop the fatal disease when infected with COVID-19 after vaccination. There is an urgent need to develop Guidelines to help direct vaccination schedules and protective measures in oncology patients, differentiating those with haematological malignancies and those in an immunocompromised state.

Comparison of water- and alkali-extracted polysaccharides from Fuzhuan brick tea and their immunomodulatory effects in vitro and in vivo.

In the present study, the purpose is to compare the effect of water extraction and alkali-assisted extraction on the structural characteristics and immunomodulatory activity of polysaccharides from Fuzhuan brick tea (FBTPs). The results indicated that water-extracted FBTPs (W-FBTPs) and alkali-extracted FBTPs (A-FBTPs) had similar molecular weights but different monosaccharide compositions, of which A-FBTPs had a higher yield and uronic acid groups corresponding to galacturonic acid (GalA). Moreover, A-FBTPs had stronger ability to promote phagocytic capacity, acid phosphatase activity and nitric oxide (NO) secretion in macrophages in vitro. In the in vivo study, A-FBTPs exhibited a promising effect to adjust the immune imbalance by enhancing the body features, antioxidant activities, immune response and intestinal mucosal barrier in cytoxan (CTX)-induced immunosuppressive mice. Besides, A-FBTP supplementation effectively improved CTX-induced gut microbiota dysbiosis, including promoting the abundance of beneficial bacteria (e.g., Lactobacillus) and short chain fatty acid (SCFA)-producing bacteria (e.g., Lachnospiraceae, Prevotellaceae and Ruminococcaceae), along with reducing the growth of potentially pathogenic microbes (e.g., Desulfovibrionaceae and Helicobacter). These findings suggested that alkaline extraction might be a promising way to obtain high-quality acidic polysaccharides from Fuzhuan brick tea (FBT), and A-FBTPs could be developed as novel potential prebiotics and immunomodulators for further application in food formulations.

Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B.

BACKGROUND & AIMS: Regulatory T cell (Treg) depletion increases antitumor immunity. However, severe autoimmunity can occur following systemic loss of Tregs, which could be avoided by selectively depleting intratumoral Tregs. Herein, we aimed to investigate the role of tumor-infiltrating CCR4+ Tregs in hepatocellular carcinoma (HCC) and to provide a potential target strategy for immunotherapy. METHODS: CCR4+ Tregs were analyzed by flow cytometry in murine models and clinical samples. The function of tumor-infiltrating and induced CCR4+ Tregs was interrogated by genetic and epigenetic approaches. To block CCR4+ Treg chemotaxis, we developed an N-terminus recombinant protein of CCR4 (N-CCR4-Fc) as a neutralizing pseudo-receptor that effectively bound to its ligand CCL22. The efficacy of CCR4 antagonism as an immunotherapeutic agent was evaluated by tumor weights, growth kinetics and survival curves. RESULTS: CCR4+ Tregs were the predominant type of Tregs recruited to hepatitis B-associated HCC (HBV+ HCC), correlating with sorafenib resistance and HBV load titers. Compared with CCR4- Tregs, CCR4+ Tregs exhibited increased IL-10 and IL-35 expression, and enhanced functionality in suppressing CD8+ T cells. CCR4+ Tregs also displayed PD-1+TCF1+ stem-like properties. ATAC-seq data revealed substantial chromatin remodeling between tumor-infiltrating Tregs (TIL-Tregs) and induced Tregs, suggesting that long-term chromatin reprogramming accounted for the acquisition of enhanced immunosuppressive stem-like specificity by CCR4+ TIL-Tregs. Treatment with a CCR4 antagonist or N-CCR4-Fc blocked intratumoral Treg accumulation, overcame sorafenib resistance, and sensitized tumors to PD-1 checkpoint blockade. CONCLUSIONS: Intratumoral stem-like CCR4+ Tregs orchestrated immunosuppressive resource cells in the tumor microenvironment. CCR4 could be targeted to enhance antitumor immunity by specifically blocking infiltration of Tregs into the tumor microenvironment and inhibiting maintenance of the TIL-Treg pool. LAY SUMMARY: Targeting regulatory T cells is a promising approach in cancer immunotherapy; however, severe autoimmunity can occur following systemic regulatory T cell loss. This could be avoided by selectively depleting intratumoral regulatory T cells. Herein, targeting intratumoral stem-like CCR4+ regulatory T cells helped to overcome sorafenib resistance and sensitize tumors to immune checkpoint blockade in mouse models of liver cancer. This approach could have wide clinical applicability.

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.

Immunomodulatory Activity of Carboxymethyl Pachymaran on Immunosuppressed Mice Induced by Cyclophosphamide.

The effects of immunomodulatory activity of two types of carboxymethyl pachymaran (CMP-1 and CMP-2) on cyclophosphamide (CTX)-induced mice were investigated. Both CMP-1 and CMP-2 were found to restore the splenomegaly and alleviate the spleen lesions and the mRNA expressions of TLR4, MyD88, p65 and NF-κB in spleen were also increased. CMP-1 and CMP-2 could enhance the immunity by increasing the levels of TNF-α, IL-2, IL-6, IFN-γ, Ig-A and Ig-G in serum. In addition, CMP-1 could increase the relative abundance of Bacteroidetes and reduce the relative richness of Firmicutes at the phylum level. CMP-1 and CMP-2 could reduce the relative abundance Erysipelatoclostridum at the genus level. CMP-1 and CMP-2 might enhance the immune function of immunosuppression mice by regulating the gene expression in the TLR4/NF-κB signaling pathway and changing the composition and abundance of the intestinal microbiota. The results suggested that CMP-1 and CMP-2 would be as potential immunomodulatory agents in functional foods.

Assessment of clinical outcomes in renal transplant recipients with COVID-19.

The coronavirus disease 2019 (COVID-19) has affected more than a hundred million individuals and caused more than three million deaths worldwide. Specific risk groups were defined for increased risk of mortality and morbidity in COVID-19, and renal transplant recipients are at a significantly increased risk regarding outcomes due to their immunosuppressed conditions. This study evaluated the general characteristics of kidney transplant recipients with COVID-19 infection. Among 1257 transplant cases, 56 had COVID-19 infection, and 23 (41%) were hospitalized during the 9-month study period. Among all COVID-19 cases, 58% were male with a mean age of 45.5 (±13.2, 19-71) years, and the most frequent comorbidities were hypertension (70.9%) and diabetes (23.6%). Hospitalized patients were older (p = 0.03) and had higher rates of hypertension (p = 0.008), diabetes (p = 0.002), and ischemic heart disease (p = 0.03). Therapeutic management included antimetabolite withdrawal and prednisolone increase in 71%, calcineurin inhibitor withdrawal in 8% and decrease in 58%, hydroxychloroquine in 17%, tocilizumab in 3%, and antivirals in 67% of patients. Acute kidney injury and respiratory failure developed in 34% and 85%, respectively. The mortality rate was 23%. These results emphasized that the COVID-19 infection in renal transplant recipients significantly increases the risk of morbidity and mortality. Therefore, these patients should be intervened earlier and monitored closely to prevent poor outcomes.

Analysis of antibody responses after COVID-19 vaccination in liver transplant recipients and those with chronic liver diseases.

BACKGROUND & AIMS: Liver transplant (LT) recipients or other immunocompromised patients were not included in the registration trials studying the efficacy of vaccines against SARS-CoV-2. Although the clinical efficacy of COVID-19 vaccines in immunocompromised patients is unknown, many societies have recommended vaccination of this highly vulnerable patient population. METHODS: In this prospective study, we determined antibody responses to spike protein, 4 weeks after the 2nd dose of mRNA vaccines or after the single dose of Johnson & Johnson vaccine, in LT recipients and those with chronic liver disease (CLD) with and without cirrhosis. RESULTS: Of the 233 patients enrolled so far, 62 were LT recipients, 79 had cirrhosis (10 decompensated) and 92 had CLD without cirrhosis. Antibody titers were defined as undetectable (<0.40 U/ml), suboptimal (0.40-250 U/ml) and adequate (>250 U/ml). Of the 62 patients who had LT, antibody levels were undetectable in 11 patients and suboptimal (median titer 17.6, range 0.47-212 U/ml) in 27 patients. Among 79 patients with cirrhosis, 3 had undetectable antibody levels and 15 had suboptimal (median titer 41.3, range 0.49-221 U/L) antibody responses. Of the 92 patients without cirrhosis, 4 had undetectable antibody levels and 19 had suboptimal (median titer 95.5, range 4.9-234 U/L) antibody responses. Liver transplantation, use of 2 or more immunosuppression medications and vaccination with a single dose of the Johnson & Johnson vaccine were associated with poor immune response on multivariable analysis. No patient had any serious adverse events. CONCLUSIONS: Poor antibody responses after SARS-CoV-2 vaccination were seen in 61% of LT recipients and 24% of those with CLD. LAY SUMMARY: The clinical efficacy of COVID-19 vaccines in immunocompromised patients is unknown. We performed a prospective study to evaluate immune responses to COVID-19 vaccines (Moderna, Pfizer or Johnson & Johnson) in 62 liver transplant recipients, 79 patients with cirrhosis and 92 with chronic liver diseases without cirrhosis. We found that 17.8% of liver transplant recipients, 3.8% of those with cirrhosis and 4.3% of those with chronic liver diseases without cirrhosis had undetectable antibody levels. In total, 61.3% of liver transplant recipients and 24% of those with chronic liver diseases (with or without cirrhosis) had poor antibody responses (undetectable or suboptimal). Liver transplantation, use of immunosuppressive medications and vaccination with a single dose of Johnson & Johnson vaccine were associated with poor antibody responses when adjusted for other factors.

The immunoenhancement effects of sea buckthorn pulp oil in cyclophosphamide-induced immunosuppressed mice.

In this study, the immunomodulatory effect of sea buckthorn (SBT) pulp oil was elucidated in immunosuppressed Balb/c mice induced by cyclophosphamide (CTX). The results showed that SBT pulp oil could reverse the decreasing trend of body weight, thymus/spleen index and hematological parameters induced by CTX. Compared with immunosuppressive mice induced by CTX, SBT pulp oil could enhance NK cytotoxicity, macrophage phagocytosis, and T lymphocyte proliferation, and regulate the proportion of T cell subsets in mesenteric lymph nodes (MLN), and promote the production of secretory immunoglobulin A (sIgA), IFN-γ, IL-2, IL-4, IL-12 and TNF-α in the intestines. In addition, SBT pulp oil can promote the production of short fatty acids (SCFAs), increase the diversity of gut microbiota, improve the composition of intestinal flora, increase the abundance of Alistipes, Bacteroides, Anaerotruncus, Lactobacillus, ASF356, and Roseburia, while decreasing the abundance of Mucispirillum, Anaeroplasma, Pelagibacterium, Brevundimonas, Ochrobactrum, Acinetobacter, Ruminiclostridium, Blautia, Ruminiclostridium, Oscillibacter, and Faecalibaculum. This study shows that SBT pulp oil can regulate the diversity and composition of intestinal microflora in CTX-induced immunosuppressive Balb/c mice, thus enhancing the intestinal mucosa and systemic immune response. The results can provide a basis for understanding the function of SBT pulp oil and its application as a new probiotic and immunomodulator.

Vaccination and their importance for lung transplant recipients in a COVID-19 world.

INTRODUCTION: Lung transplant patients are immunocompromised because of the medication they receive to prevent rejection, and as a consequence are susceptible to (respiratory) infections. Adequate vaccination strategies, including COVID-19 vaccination, are therefore needed to minimize infection risks. AREAS COVERED: The international vaccination guidelines for lung transplant patients are reviewed, including the data on immunogenicity and effectivity of the vaccines. The impact on response to vaccination of the various categories of immunosuppressive drugs, used in the posttransplant period, on response to vaccination is described. A number of immunosuppressive and/or anti-inflammatory drugs also is used for controlling the immunopathology of severe COVID-19. Current available COVID-19 vaccines, both mRNA or adenovirus based are recommended for lung transplant patients. EXPERT OPINION: In order to improve survival and quality of life, infections of lung transplant patients should be prevented by vaccination. When possible, vaccination should start already during the pre-transplantation period when the patient is on the waiting list. Booster vaccinations should be given post-transplantation, but only when immunosuppression has been tapered. Vaccine design based on mRNA technology could allow the design of an array of vaccines against other respiratory viruses, offering a better protection for lung transplant patients.

COVID-19 vaccines: concerns beyond protective efficacy and safety.

INTRODUCTION: Several vaccine candidates have been developed using different platforms, including nucleic acids (DNA and RNA), viral vectors (replicating and non-replicating), virus-like particles, peptide-based, recombinant proteins, live attenuated, and inactivated virus modalities. Although many of these vaccines are undergoing pre-clinical trials, several large clinical trials investigating the clinical efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines have produced promising findings. AREAS COVERED: In this review, we provide a status update on COVID-19 vaccines currently undergoing clinical trials and discuss issues of concern beyond vaccine efficacy and safety, including dosing regimens, the mixed vaccine strategy, prior severe acute respiratory syndrome coronavirus-2 infection, antibody levels, cellular immunity and protection, variants of concern, COVID-19 vaccine distribution, vaccination willingness, herd immunity, immunity passports, and vaccine indications. EXPERT OPINION: Four vaccines have obtained emergency use authorization, 87 are at the clinical development stage, and 186 are in pre-clinical development. While the knowledge and development of COVID-19 vaccines is rapidly expanding, the benefits of COVID-19 vaccines must outweigh the potential risks of adverse events. To combat the COVID-19 pandemic, clinicians should consistently update COVID-19-associated information, and healthcare authorities and manufacturers should work together to provide adequate and appropriate vaccinations for the prevention of COVID-19. PLAIN LANGUAGE SUMMARY: What is the context?Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic: the coronavirus disease 2019 (COVID-19) outbreak. The development and implementation of the COVID-19 vaccine could be an important measure to control the COVID-19 pandemic.What is new?Several phase 3 clinical trials have demonstrated the effectiveness and safety of COVID-19 vaccines for the prevention of SARS-CoV-2 infections. Several COVID-19 vaccines have obtained emergency use authorization and been implemented in many countries. Although concerns regarding unusual blood clots and low platelet counts have been raised, the benefits of COVID-19 vaccines outweigh the potential risks of adverse events.What is the impact?Except for children, the COVID-19 vaccine is recommended for all people, including those pregnant or immunocompromised. Healthcare authorities should advise people receiving the vaccine that they must seek medical attention if they have associated thromboembolism and thrombocytopenia symptoms. More studies are necessary to determine the appropriate vaccine dose and regimen strategy, as well as the effectiveness of COVID-19 vaccines against variants of concerns. A global effort must be made to achieve widespread vaccination and herd immunity.

Safety and efficacy of COVID-19 vaccines in multiple sclerosis patients.

COVID-19 vaccination is recommended for multiple sclerosis patients. Disease-modifying therapies can influence the safety and efficacy of COVID-19 vaccines. RNA, DNA, protein, and inactivated vaccines are likely safe for multiple sclerosis patients. A few incidences of central demyelination were reported with viral vector vaccines, but their benefits likely outweigh their risks if alternatives are unavailable. Live-attenuated vaccines should be avoided whenever possible in treated patients. Interferon-beta, glatiramer acetate, teriflunomide, fumarates, and natalizumab are not expected to impact vaccine efficacy, while cell-depleting agents (ocrelizumab, rituximab, ofatumumab, alemtuzumab, and cladribine) and sphingosine-1-phosphate modulators will likely attenuate vaccine responses. Coordinating vaccine timing with dosing regimens for some therapies may optimize vaccine efficacy.

Treatment of B-cell depleted COVID-19 patients with convalescent plasma and plasma-based products.

Severe acute respiratory syndrome coronavirus 2 infected patients, receiving background anti-CD20 therapy, were treated with convalescent plasma or plasma-based products. Eight patients were included in the study, presenting with prolonged disease course and delayed viral clearance. CP/plasma-based products were offered as an add-on therapy to standard medical treatment. All patients showed remarkable clinical and laboratory improvement. In addition, polymerase chain reaction from nasopharyngeal swabs rapidly converted to negative following plasma administration. This study emphasizes the therapeutic efficacy of convalescent plasma and plasma-based products in a subgroup of immunocompromised patients with iatrogenic B-cell depletion.

Immune-Enhancing Effects of Lactobacillus plantarum 200655 Isolated from Korean Kimchi in a Cyclophosphamide-Induced Immunocompromised Mouse Model.

In this study, we evaluated the immune-enhancing activity of kimchi-derived Lactobacillus plantarum 200655 on immune suppression by cyclophosphamide (CP) in ICR mice. Animals were fed distilled water or 1×109 colony-forming unit/kg B.W. 200655 or Lactobacillus rhamnosus GG as a positive control for 14 days. An in vivo model of immunosuppression was induced using CP 150 and 100 mg/kg B.W. at 7 and 10 days, respectively. Body weight, spleen index, spleen weight, and gene expression were measured to estimate the immune-enhancing effects. The dead 200655 (D-200655) group showed an increased spleen weight compared to the sham control (SC) group. Similarly, the spleen index was significantly higher than that in the CP-treated group. The live 200655 (L-200655) group showed an increased mRNA expression of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in splenocytes. Also, the iNOS and COX-2 mRNA expression was upregulated in the L-200655 group compared to the CP-only (SC) group. The phosphorylation of ERK and MAPK was also upmodulated in the L-200655 group. These results indicate that L. plantarum 200655 ameliorated CP-induced immune suppression, suggesting that L. plantarum 200655 may have the potential to enhance the immune system.

Improvement of Myelopoiesis in Cyclophosphamide-Immunosuppressed Mice by Oral Administration of Viable or Non-Viable Lactobacillus Strains.

Myelosuppression is the major dose-limiting toxicity of cancer chemotherapy. There have been many attempts to find new strategies that reduce myelosuppression. The dietary supplementation with lactic acid bacteria (LAB) improved respiratory innate immune response and the resistance against respiratory pathogens in immunosupressed hosts. Although LAB viability is an important factor in achieving optimal protective effects, non-viable LAB are capable of stimulating immunity. In this work, we studied the ability of oral preventive administration of viable and non-viable Lactobacillus rhamnosus CRL1505 or L. plantarum CRL1506 (Lr05, Lr05NV, Lp06V or Lp06NV, respectively) to minimize myelosuppressive and immunosuppressive effects derived from chemotherapy. Cyclophosphamide (Cy) impaired steady-state myelopoiesis in lactobacilli-treated and untreated control mice. Lr05V, Lr05NV and Lp06V treatments were the most effective to induce the early recovery of bone marrow (BM) tissue architecture, leukocytes, myeloid, pool mitotic and post-mitotic, peroxidase positive, and Gr-1Low/High cells in BM. We selected the CRL1505 strain for being the one capable of maintaining its myelopoiesis-enhancing properties in its non-viable form. Although the CRL1505 treatments do not modify the Cy ability to induce apoptosis, both increased the incorporation of BrdU in BM cells. Consequently, Lr05NV and Lr05V treatments were able to promote early recovery of LSK cells (Lin-Sca-1+c-Kit+ cells), multipotent progenitors (Lin-Sca-1+c-Kit+CD34+ cells), and myeloid cells (Gr-1+Ly6G+Ly6C- cells) with respect to the untreated Cy control. In addition, these treatments were able to increase the frequency of IL17A-producing innate lymphoid cells in the intestinal lamina propria (IL-17A+RORγt+CD4-NKp46+ cells) after Cy injection. These results were correlated with an increase in the IL-17A serum levels, a GM-CSF high expression and a CXCL12 lower expression in BM. Therefore, both Lr05V and Lr05NV treatments are able to activate beneficially the IL-17A/GM-CSF axis and accelerate the recovery of Cy-induced immunosuppression by increasing BM myeloid precursors. We demonstrated for the first time the beneficial effect of CRL1505 strain on myelopoiesis affected by a chemotherapeutic drug. Furthermore, Lr05NV could be a good and safe resource for reducing chemotherapy-induced leukopenia. The results are a starting point for future research and open up broad prospects for future applications of the immunobiotics.

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.

Histoplasmosis diseminada en paciente inmunosuprimido / Disseminated histoplasmosis in immunosuppressed patient

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Injectable Hydrogel as a Unique Platform for Antitumor Therapy Targeting Immunosuppressive Tumor Microenvironment.

Cancer immunotherapy can boost the immune response of patients to eliminate tumor cells and suppress tumor metastasis and recurrence. However, immunotherapy resistance and the occurrence of severe immune-related adverse effects are clinical challenges that remain to be addressed. The tumor microenvironment plays a crucial role in the therapeutic efficacy of cancer immunotherapy. Injectable hydrogels have emerged as powerful drug delivery platforms offering good biocompatibility and biodegradability, minimal invasion, convenient synthesis, versatility, high drug-loading capacity, controlled drug release, and low toxicity. In this review, we summarize the application of injectable hydrogels as a unique platform for targeting the immunosuppressive tumor microenvironment.

Progressive multifocal leukoencephalopathy in multiple myeloma. A literature review and lessons to learn.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection with high mortality rate usually seen in the context of immunosuppression. Although cases have been reported largely in patients with HIV/AIDS, following the use of monoclonal antibodies and occasionally in haematological malignancies, there is no review to date of patients with smouldering or treated myeloma who developed PML. Here, we conducted a literature search of PML cases in patients with multiple myeloma (MM), analyse patient and disease characteristics and describe the possible mechanisms that could lead to the development of PML. The lack of data and case reports until 2010 may indicate that PML in MM is underdiagnosed. Simultaneously, with an expanding field of new therapeutic options, patients with MM live longer, albeit continually immunosuppressed, and at risk of opportunistic infections. Emerging new treatments for PML in the horizon render the need to look out for this complication mandatory, and more case reports are needed to enrich our knowledge in this field.