Suppression Of Immune System Research Articles

Saikosaponin d alleviates high-fat-diet induced hepatic steatosis in hybrid grouper (Epinephelus lanceolatus♂ × Epinephelus fuscoguttatus♀) by targeting AMPK/PPARα pathway

High-fat diets generally cause the accumulation of hepatic steatosis in farmed fish tissues, which results in metabolic disorders, abnormal oxidative status and immune system suppression, seriously affecting sustainable aquaculture development. The main bioactive components of Bupleurum are saikosaponins, saikosaponins d (SSd) exhibiting the strongest pharmacological activity. The aim of this research was to examine the preventive and therapeutic benefits of SSd on hepatic steatosis, in addition to the underlying processes of hybrid groupers in vitro and in vivo. SSd was found to enhance cell survival in vitro by lowering apoptosis and decrease lipid accumulation in hepatocytes by reducing oxidative stress, restricting lipogenesis and enhancing lipid oxidation. In vivo, 300 hybrid groupers were fed SSd at dosages of 0, 100, 200, 400, and 800 mg/kg that was supplemented with a high-lipid basal diet for eight weeks. Pretreatment with SSd caused a raised expression in lipolysis-related genes (AMPKα, PPARα, CPT1, LPL) while decreasing the expression of adipogenesis-related genes in the liver of hybrid groupers (G6PD, ME1, FAS and DGAT2). Furthermore, kinsenoside was found to increase ATGL-mediated lipolysis, amplified by AMP-activated protein kinase (AMPK) activation, in addition to the hydrolysis of triglycerides to glycerol and fatty acids, which require transit into mitochondria for further oxidation. AMPK activation was found to increase ATGL expression for lipolysis, while also increasing CPT1 expression for fatty acid transport to the mitochondria. The findings of this study add to a growing body of evidence suggesting SSd therapy can be used for the prevention hepatic steatosis in hybrid groupers via the AMPK/PPAR pathway.

MicroRNAs and drug resistance in colorectal cancer with special focus on 5-fluorouracil.

Colorectal cancer is globally one of the most common cancers in all age groups. The current chemotherapy combinations for colorectal cancer treatment include 5-fluorouracil-based regimens; however, drug resistance remains one of the main reasons for chemotherapy failure and disease recurrence. Many studies have determined colorectal cancer chemoresistance mechanisms such as drug efflux, cell cycle arrest, DNA damage repair, apoptosis, autophagy, vital enzymes, epigenetic, epithelial-mesenchymal transition, stem cells, and immune system suppression. Several microRNAs affect drug resistance by regulating the drug resistance-related target genes in colorectal cancer. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with colorectal cancer. This work reviews and discuss the role of selected microRNAs in 5-fluorouracil resistance and their molecular mechanisms in colorectal cancer.

Cell-based immunotherapy of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary glial brain tumor. It has an unfavorable prognosis and relatively ineffective treatment protocols, with the median survival of patients being ~15 months. Tumor resistance to treatment is associated with its cancer stem cells (CSCs). At present, there is no medication or technologies that have the ability to completely eradicate CSCs, and immunotherapy (IT) is only able to prolong the patient's life. The present review aimed to investigate systemic solutions for issues associated with immunosuppression, such as ineffective IT and the creation of optimal conditions for CSCs to fulfill their lethal potential. The present review also investigated the main methods involved in local immunosuppression treatment, and highlighted the associated disadvantages. In addition, novel treatment options and targets for the elimination and regulation of CSCs with adaptive and active IT are discussed. Antagonists of TGF-β inhibitors, immune checkpoints and other targeted medication are also summarized. The role of normal hematopoietic stem cells (HSCs) in the mechanisms underlying systemic immune suppression development in cases of GBM is analyzed, and the potential reprogramming of HSCs during their interaction with cancer cells is discussed. Moreover, the present review emphasizes the importance of the aforementioned interactions in the development of immune tolerance and the inactivation of the immune system in neoplastic processes. The possibility of solving the problem of systemic immunosuppression during transplantation of donor HSCs is discussed.

Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO trial).

TPS407 Background: Renal cell carcinoma (RCC) is the 6° most common cancer in men and the 8° in women in the USA. In Italy RCC incidence was 11,500 new cases in 2017, while mortality was 3,371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel treatment option aimed to restore healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection. Preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a double-blinded placebo-controlled randomized clinical trial, the efficacy of targeted FMT (from donors who are responding to ICIs) in improving response rates to ICIs in subjects with aRCC. Methods: 50 patients who are about to receive, or have started by <8 weeks, pembrolizumab + axitinib as first-line therapy for aRCC will be enrolled. Exclusion criteria include major comorbidities, concomitant GI or autoimmune disorders, or HIV, HBV, HCV infection, continuative corticosteroid therapy, previous treatment with systemic immune-suppressants or immune-modulatory drugs, antibiotic therapy within 4 weeks prior to enrollment. Stool samples and clinical data will be collected at baseline. Then, patients will be randomized to donor FMT or placebo FMT. They will receive the first infusion by colonoscopy and then oral frozen fecal or placebo capsules (8 capsules t.i.d.) 90 and 180 days after the first FMT. Stool donors will be searched among long-term (>12 months) responders to ICIs, and will be selected by following protocols recommended by international guidelines. Patients in the FMT group will always receive feces from the same donor throughout the three fecal transplants. Frozen fecal batches and frozen fecal capsules will be manufactured according to international guidelines. Patients will be followed-up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of stool samples. Patients will also undergo radiological assessment at 90, 180, 270 and 360 days after randomization. Microbiome analysis will be performed with shotgun metagenomics. The primary endpoint is the progression-free survival (PFS) at 12 months. Secondary endpoints are: objective response rate at 12 months; overall survival at 12 months; adverse events after FMT; microbiome changes after FMT. Sample size calculation was based on the hypothesis that FMT can improve the 1-year PFS rate from 60% (reported 1-year PFS for SOC) to 80% wen associated to SOC. Clinical trial information: NCT04758507.

Inhibiting WEE1 and IKK-RELA Crosstalk Overcomes TNFα Resistance in Head and Neck Cancers.

Inhibiting WEE1 and IKK-RELA crosstalk could potentially enhance the effects of therapies mediated by TNFα with less systemic immune suppression and toxicity than observed with direct interruption of IKK-NF-κB/RELA signaling.

Prenatal and neonatal complications of COVID-19: A systematic review.

Background and AimsThe outbreak of coronavirus disease 2019 (COVID‐19) over the past year has affected public health worldwide. During pregnancy, the maternal immune system and inflammatory responses are widely suppressed. Pregnancy‐related immune system suppression could make the mother vulnerable to infectious diseases like SARS‐COV‐2. However, current data suggest little to no possibility of COVID‐19 transmission in pregnant women to the fetus during pregnancy or childbirth. This systematic review focused on the possible complications of COVID‐19 infection in the fetus and newborn babies including the possibility and evidence of vertical transmission by reviewing articles published during the first year of the COVID‐19 pandemic.MethodsWe conducted a systematic search using keywords on PubMed, Embase, and Scopus databases. The studies followed a title/abstract and a full‐text screening process, and the eligible articles were included in the study.ResultsIn total, 238 published papers were identified using a systematic search strategy (44 articles met the inclusion criteria and were included in the final review). In all studies, a total of 2375 women with signs and symptoms of COVID‐19, who were in the second and third trimester of pregnancy, were assessed mild to moderate pneumonia was one of the most common symptoms. Seventy‐three percent of the women did not present any comorbidity, 19% had a fever, 17% had to cough as the most frequent clinical signs and symptoms, 7.5% had pulmonary changes with chest scans, 8% had increased C reactive protein, and 9.4% had decreased lymphocytes (lymphocytopenia). A total of 2716 newborns and fetal were assessed; the delivery method of 1725 of them was reported, 913 (53%) through C‐section delivery, and 812 through normal vaginal delivery (47%). Of total newborns, 13 died (five died along with the mother), and 1965 were tested for SARS‐CoV‐2:118 tested positive. In a study, vertical transmission in seven cases was reported in total of 145 cases assessed.ConclusionIt appeared that most pregnant COVID patients were mildly ill, and there is currently no convincing evidence to support the vertical transmission of COVID‐19 disease. Therefore, neonates do not represent any additional risk for adverse outcomes neither during the prenatal period nor after birth.

Central nervous system injury-induced immune suppression.

Central nervous system trauma is a common cause of morbidity and mortality. Additionally, these injuries frequently occur in younger individuals, leading to lifetime expenses for patients and caregivers and the loss of opportunity for society. Despite this prevalence and multiple attempts to design a neuroprotectant, clinical trials for a pharmacological agent for the treatment of traumatic brain injury (TBI) or spinal cord injury (SCI) have provided disappointing results. Improvements in outcome from these disease processes in the past decades have been largely due to improvements in supportive care. Among the many challenges facing patients and caregivers following neurotrauma, posttraumatic nosocomial infection is a significant and potentially reversible risk factor. Multiple animal and clinical studies have provided evidence of posttraumatic systemic immune suppression, and injuries involving the CNS may be even more prone, leading to a higher risk for in-hospital infections following neurotrauma. Patients who have experienced neurotrauma with nosocomial infection have poorer recovery and higher risks of long-term morbidity and in-hospital mortality than patients without infection. As such, the etiology and reversal of postneurotrauma immune suppression is an important topic. There are multiple possible etiologies for these posttraumatic changes including the release of damage-associated molecular patterns, the activation of immunosuppressive myeloid-derived suppressor cells, and sympathetic nervous system activation. Postinjury systemic immunosuppression, particularly following neurotrauma, provides a challenge for clinicians but also an opportunity for improvement in outcome. In this review, the authors sought to outline the evidence of postinjury systemic immune suppression in both animal models and clinical research of TBI, TBI polytrauma, and SCI.

Targets of immunotherapy for hepatocellular carcinoma: An update.

Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.

Myeloid Diagnostic and Prognostic Markers of Immune Suppression in the Blood of Glioma Patients

BackgroundAlthough gliomas are confined to the central nervous system, their negative influence over the immune system extends to peripheral circulation. The immune suppression exerted by myeloid cells can affect both response to therapy and disease outcome. We analyzed the expansion of several myeloid parameters in the blood of low- and high-grade gliomas and assessed their relevance as biomarkers of disease and clinical outcome.MethodsPeripheral blood was obtained from 134 low- and high-grade glioma patients. CD14+, CD14+/p-STAT3+, CD14+/PD-L1+, CD15+ cells and four myeloid-derived suppressor cell (MDSC) subsets, were evaluated by flow cytometry. Arginase-1 (ARG1) quantity and activity was determined in the plasma. Multivariable logistic regression model was used to obtain a diagnostic score to discriminate glioma patients from healthy controls and between each glioma grade. A glioblastoma prognostic model was determined by multiple Cox regression using clinical and myeloid parameters.ResultsChanges in myeloid parameters associated with immune suppression allowed to define a diagnostic score calculating the risk of being a glioma patient. The same parameters, together with age, permit to calculate the risk score in differentiating each glioma grade. A prognostic model for glioblastoma patients stemmed out from a Cox multiple analysis, highlighting the role of MDSC, p-STAT3, and ARG1 activity together with clinical parameters in predicting patient’s outcome.ConclusionsThis work emphasizes the role of systemic immune suppression carried out by myeloid cells in gliomas. The identification of biomarkers associated with immune landscape, diagnosis, and outcome of glioblastoma patients lays the ground for their clinical use.

Lysosomal storage diseases in the era of COVID-19: a report of an Egyptian case of alpha-fucosidosis and a summary of the lysosomal storage diseases-COVID-19 relationship

BackgroundWe present a case of alpha-fucosidosis, a lysosomal storage disorder, from Egypt. The report also includes a brief review of the COVID-19 and lysosomal storage diseases relationship.Case presentationA female patient aged 18 years, diagnosed with type II fucosidosis, based on the cutaneous signs, characteristic facies, and systemic symptoms, and diagnosis was confirmed using genetic analysis. The patient died from COVID-19 pneumonia during the COVID-19 pandemic after getting the infection from her father and being hospitalized.ConclusionsPatients with lysosomal storage diseases with local or systemic immune suppression may be predisposed to respiratory complications of COVID-19. Intense care with protective guidelines should be applied to those patients.

The Liver-Immunity Nexus and Cancer Immunotherapy.

The impact of liver metastases on immune checkpoint-inhibitor effectiveness in patients with solid-tumor malignancies has been the focus of several recent clinical and translational studies. We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and non-small cell lung cancer (NSCLC) patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a two-site MC38 model appear to delete CD8+ T cells in a FasL-dependent manner. In addition, regulatory T-cell (Treg) activation was observed and contributed to the distal immunosuppression. Finally, we discuss some of the interventions reported to address liver immune suppression, such as radiation therapy, combination checkpoint blockade, and Treg depletion.

Immune Modulation by Antigenic Peptides and Antigenic Peptide Conjugates for Treatment of Multiple Sclerosis.

The immune system defends our body by fighting infection from pathogens utilizing both the innate and adaptive immune responses. The innate immune response is generated rapidly as the first line of defense. It is followed by the adaptive immune response that selectively targets infected cells. The adaptive immune response is generated more slowly, but selectively, by targeting a wide range of foreign particles (i.e., viruses or bacteria) or molecules that enter the body, known as antigens. Autoimmune diseases are the results of immune system glitches, where the body's adaptive system recognizes self-antigens as foreign. Thus, the host immune system attacks the self-tissues or organs with a high level of inflammation and causes debilitation in patients. Many current treatments for autoimmune diseases (i.e., multiple sclerosis (MS), rheumatoid arthritis (RA)) have been effective but lead to adverse side effects due to general immune system suppression, which makes patients vulnerable to opportunistic infections. To counter these negative effects, many different avenues of antigen specific treatments are being developed to selectively target the autoreactive immune cells for a specific self-antigen or set of self-antigens while not compromising the general immune system. These approaches include soluble antigenic peptides, bifunctional peptide inhibitors (BPI) including IDAC and Fc-BPI, polymer conjugates, and peptide-drug conjugates. Here, various antigen-specific methods of potential treatments, their efficacy, and limitations will be discussed along with the potential mechanisms of action.

Analysis of Aflatoxins in South Carolina Farm’s Corn, Peanut, Wheat, Soybean, and Cottonseed

The mold Aspergillus grows on several raw food commodities and produces highly toxic compounds known as aflatoxins. These compounds can cause developmental and immune system suppression, cancer, and death if ingested. The aim of this study was to determine the aflatoxin levels in various crops obtained from farms in South Carolina, USA. Aflatoxin levels were measured using the Vicam Virtu Reader and High-Performance Liquid Chromatography (HPLC). The Vicam Virtu Reader utilized five grams of corn and peanuts blended and placed into an extraction tube containing 25 ml of 70% methanol. The sample mixture was placed on the AlfaV test strip for readings. For use of the HPLC, the samples were analyzed by isocratic using 60:20:20 water/methanol/acetonitrile mixture as the mobile phase. Results from the Vicam Virtu Reader indicated corn samples and peanut samples had aflatoxin levels below 25 ppb established by the USDA. When the HPLC analysis was done on soybean, wheat, and cottonseed, all results were below 25 ppb as well. A food safety survey was administered to 190 farmers to ascertain their familiarity with aflatoxins. Sixteen percent (16%) reported they heard about it. In conclusion, storage conditions of the crops can affect the level of aflatoxins. The Vicam Virtu Reader is a fast method to identify aflatoxin levels in crops. The HPLC has the advantage of separating aflatoxins into subgroups even at low levels. The aflatoxin levels were low and safe for export and consumption.

Al-Muddaththir of the Quran Linked to the Covid-19 and Spanish Flu Pandemics: Circumstantial Evidence

Recently there have been speculations concerning a possible link between the covid-19 pandemic and al-Muddaththir, the 74th chapter of the Quran. An examination of this chapter presented in this article shows further evidences in support of these speculations. It is shown that indications of not only the current Covid-19 pandemic, but also the horrific 1918 Spanish flu can be detected in chapter 74. The main emphasis of this article will be to demonstrate the timings of the pandemic events as they appear to have been encoded in four of the chapter verses. The concept of Translational-Coding and in particular, its use in decoding one of the time-informing verses will be explained. A remarkable scheme of al-Muddaththir to announce the exact occurring years of the two major pandemics, will also be exposed. Coincidences of the Super Moon occurrences with major events of both, Covid-19 and Spanish flu pandemics, will be shown as the possible reason for “by the moon” swearing in verse 74:32. In connection with these observed coincidences, possible effect of the moon’s differential gravity on suppression of the human immune system during a Super Moon occurrence will be addressed. Some other verses in al-Muddaththir with possible relevance to the pandemic perspective of this chapter will also be discussed.

Tumor-associated macrophages: An important player in breast cancer progression.

Breast cancer is the most common form of malignant tumor in females, accounting for the second highest mortality among cancer patients. In the breast tumor microenvironment, tumor‐associated macrophages (TAMs) are the most abundant immune cells, which regulate the progression of breast cancer. During breast cancer tumorigenesis and progression, TAMs support breast tumor growth by promoting angiogenesis and cancer cell metastasis, inducing cancer stemness, regulating energy metabolism, and supporting immune system suppression. TAMs exhibit a high degree of cellular plasticity. Repolarizing tumor‐related macrophages into M1 macrophages can promote tumor regression. This study reviews the role and mechanism of action of TAMs in the development of breast cancer and establishes TAMs as effective targets for breast cancer treatment.

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions.

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

The Association between Tumor-associated Macrophages and Glioblastoma: A Potential Target for Therapy

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults, causing many deaths each year. The life expectancy of patients from the time of diagnosis does not exceed 15 months. Tumoral cells are generally surrounded by a bed of tumor microenvironment (TME), composed of various components such as different immune cells, stromal cells, and blood vessels. Previous studies on the treatment of this tumor have generally focused on cancerous cells and, therefore, have introduced conventional therapies for eradicating this tumor, including maximal safe surgery, chemotherapy with temozolomide (TMZ), and radiotherapy. Despite treatment with this method, tumors almost always recur, and life expectancy has not increased much. Recently, due to the discovery of the various roles of immune cells (including tumor-associated macrophages or TAMs) in the pathogenesis of this disease, the path of studies has moved towards targeting them as a treatment for glioblastoma. In this review, we aimed to investigate recent studies on the different roles of TME components, the role of TAM in the pathogenesis, and novel methods that target TAMs, including induction of TAM repolarization, inhibition of TAM-produced cytokines, and prohibition of immune system suppression induced by TAMs. In this regard, various targets, including colony-stimulating factor-1 (CSF- 1) receptors, Nuclear factor-kappa B (NF-κB), or chemokine receptor (CXCR) pathways, are investigated.

POLY-COMPONENT FAT EMULSIONS IN THE PARENTAL NUTRITION OF PATIENTS IN THE INTENSIVE CARE UNIT

One of the main problems in the departments of anesthesiology and intensive care is the lack of energy in patients. In order to solve it, parenteral nutrition, which contains fat emulsions is prescribed for critical patients. It is known that fat emulsions consist of essential fatty acids which can have both pro-inflammatory (linoleic acid) and anti-inflammatory (linolenic acid) effects. In order to reduce the impact on the immune system, the use of alternative fat emulsions is recommended, as this may provide better clinical results. The first generation of fat emulsions consisted of soybean oil, but it was proven that this oil can increase the risk of purulentseptic complications. Second-generation fat emulsions contain medium-chain triglycerides, the metabolism of which can lead to acidosis, so their use is limited, especially in patients with diabetes. Third-generation fat emulsions contain olive oil, which reduces the risk of thrombosis, is considered immunoneutral and less sensitive to lipid peroxidation. Fourth-generation fat emulsions contain fish oil, which has anti-inflammatory properties and can reduce the duration of patients staying in critical condition. The most promising is the usage of balanced fats, among which there is a 20% SMOFlipid available in Ukraine. For patients who require parenteral nutrition, fat emulsions are an integral part of it, and for critically ill patients fat emulsions containing fish oil are recommended. However, it is recommended to assess baseline triglycerides prior to administration. Thus, lipids provide the delivery of fatty acids that affect important body processes, including metabolism, immune response, blood clotting. Alternative fat emulsions can be a better source of energy, also showing antioxidant effects and less suppression of immune system.

Retinoic Acid-Containing Liposomes for the Induction of Antigen-Specific Regulatory T Cells as a Treatment for Autoimmune Diseases.

The current treatment of autoimmune and chronic inflammatory diseases entails systemic immune suppression, which is associated with increased susceptibility to infections. To restore immune tolerance and reduce systemic side effects, a targeted approach using tolerogenic dendritic cells (tolDCs) is being explored. tolDCs are characterized by the expression of CD11c, the major histocompatibility complex (MHC)II and low levels of co-stimulatory molecules CD40 and CD86. In this study, tolDCs were generated using a human-proteoglycan-derived peptide (hPG) and all-trans retinoic acid (RA). RA-tolDCs not only display a tolerogenic phenotype but also can induce an antigen-specific regulatory T cell (Treg) response in vitro. However, further analysis showed that RA-tolDCs make up a heterogeneous population of DCs, with only a small proportion being antigen-associated tolDCs. To increase the homogeneity of this population, 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG)-containing liposomes were used to encapsulate the relevant antigen together with RA. These liposomes greatly enhanced the proportion of antigen-associated tolDCs in culture. In addition, in mice, we showed that the liposomal co-delivery of antigen and RA can be a more targeted approach to induce antigen-specific tolerance compared to the injection of RA-tolDCs, and that these liposomes can stimulate the generation of antigen-specific Tregs. This work highlights the importance of the co-delivery of an antigen and immunomodulator to minimize off-target effects and systemic side effects and provides new insights in the use of RA for antigen-specific immunotherapy for autoimmune and chronic inflammatory diseases.

Post-Transplant Cyclophosphamide Is Associated with Improved Clinical Outcomes in HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Post-Transplant Cyclophosphamide Is Associated with Improved Clinical Outcomes in HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation