Iranian Journal of Allergy, Asthma and Immunology

Grading Histopathology Features of Graft-versus-host Disease in Animal Models; A Systematic Review

Hami Ashraf, Farid Kosari — Wed, 05 Jun 2024 03:42:20 +0000

Graft-versus-host disease (GvHD), a frequent and severe complication following allogeneic hematopoietic stem cell transplantation, presents substantial morbidity and mortality risks. The crucial role of histopathological examination in diagnosing and grading GvHD, particularly within animal models, is pivotal for elucidating disease mechanisms and assessing emerging therapies. This systematic review aims to critically evaluate the various grading systems for GvHD in animal models, emphasizing histopathological characteristics. In this endeavor, we meticulously examined original research articles sourced from PubMed, Scopus, Web of Science, and Google Scholar. Our findings reveal a diverse array of grading systems, each differing in the tissues examined, criteria evaluated, severity scoring scales, and the granularity of the information provided. Predominantly, skin, liver, and gut tissues are assessed, though some systems also incorporate lung and thymus evaluations. This review will delve into the alignment between clinical and histological grading in animal models of GvHD, also casting light on prospective advancements and the impact of technological progress. In conclusion, our analysis underscores the imperative need for uniform criteria and consistent application of grading systems. Such standardization is essential to foster comparability across studies and enhance the translation of preclinical discoveries into clinical applications.

The Efficacy of Omalizumab in Patients with Chronic Rhinosinusitis with Nasal Polyps and Comorbid Severe Allergic Asthma

Emel Atayik, Gokhan Aytekin, Isa Aydin, Ethem Omeroglu — Wed, 05 Jun 2024 03:44:34 +0000

Chronic rhinosinusitis whit nasal polyps (CRSwNP) is the most common comorbid disease accompanying asthma. Omalizumab is a recombinant anti-immunoglobulin (Ig) E antibody, and studies suggest that omalizumab may also affect CRSwNP regardless of asthma. We aimed to assess the effect of omalizumab treatment on CRSwNP accompanying severe allergic asthma (SAA) patients.

Clinical data including spirometry measurements, serum/nasal secretion biomarker levels were collected. NP scores and CRS scores (Lund-Mancay [LM] scores) were also recorded before omalizumab treatment, as well as at the 4th and 12th months of omalizumab treatment.

Twenty-one patients with both CRSwNP and SAA who underwent omalizumab therapy were assessed. There was a significant difference among forced expiratory volume (FEV1), ACT scores, NP scores, LM scores, serum IgE, and blood eosinophil levels of the patients before omalizumab therapy at the 4th and 12th months of omalizumab treatment. A significant negative correlation was observed between ∆FEV1 and ∆NP scores (r=−0.485), between ∆ACT and ∆NP scores (r=−0.469), and ∆ACT and ∆LM scores (r=−0.436). When we grouped the patients who benefited from 1 year of omalizumab therapy and those who did not in terms of NP, there was no difference between the two groups related to local eosinophil and local IgE levels in the nasal polyp biopsy.

Omalizumab treatment is effective for asthma and CRSwNP in patients with CRSwNP accompanied by SAA. Improvement in asthma is associated with improvement in CRSwNP. The efficacy of omalizumab on NP in patients with CRSwNP accompanied by SAA is independent of local IgE and eosinophil counts.

High-expression of V-domain Imuunoglobulin Suppressor of T-cell Activation (VISTA) Is Correlated with Advanced Pathological Features in Patients with Pancreatic Ductal Adenocarcinoma

Wed, 05 Jun 2024 03:47:53 +0000

V-domain Imuunoglobulin suppressor of T-cell activation (VISTA) seems a promising immune checkpoint target in cancer treatment; however, its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) remains unknown.

Herein, 29 fresh PDAC tissue samples were used to evaluate the mRNA expression level of VISTA by real-time polymerase chain reaction (PCR). Besides, 40 formalin-fixed paraffin-embedded PDAC tissues were collected to evaluate VISTA protein expression by immunohistochemistry.

Real-time PCR indicated that high expression of VISTA was significantly correlated with advanced stages of the cancer, based on the tumor/node/metastasis (TNM) stagingand tumor cell differentiation. Immunohistochemistry results also showed significant correlation of the elevated cytoplasmic expression of VISTA with advanced TNM stages, older age of the patients and was a worsening indicator, regarding the disease-specific survival.

In conclusion, we found that the expression levels of VISTA can be a potential prognostic biomarker in PDAC patients and its elevated levels are correlated with poor prognostic outcomes.

Polyomavirus BK-Specific CD4+ T Cells Response to VP1 Stimulation in Kidney Transplant Recipients

Wed, 05 Jun 2024 04:00:00 +0000

Reactivation of Polyomavirus BK (BKPyV) is related to reduction of T cells response in kidney transplant recipients (KTRs). Here, we examined the differentiation of CD4⁺ T cells subsets in response to BKPyV KTRs, using the BKPyV VP1 (viral capsid protein 1) as a stimulator.

We categorized our samples into three distinct groups: 1. Reactive BKPyV (BKPyV⁺), 2. non-reactive (BKPyV^-) KTRs and 3. Healthy controls. BKPyV^-KTRs and healthy controls stimulated with VP1 and BKPyV+ unstimulated with VP1. The human CD4⁺ T cells was stimulation with VP1-Ag. The proportion of CD4⁺ T lymphocytes and their various subsets, including naive T cells, central memory T cells (TCM), and effector memory T cells (TEM) was measured using flowcytometry.

BKPyV^- KTRs VP1⁺ indicated significantly lower TCM CD4⁺ T cells in contrast with both BKPyV⁺ KTRs VP1^-, and healthy controls VP1⁺. This indicates that VP1 stimulation may reduce TCM cell levels in these patients. The percentage of TEM in the BKPyV^- KTRs VP1⁺ group was significantly less prevalent than the BKPyV⁺ KTRs VP1^- group. The percentage of TEM cells in BKPyV⁺ KTRs VP1^- was significantly lower than the healthy controls VP1⁺. Stimulation with VP1 protein significantly increased the frequency of cytotoxic CD4⁺ T cells in BKPyV^- KTRs VP1⁺ compared to BKPyV⁺ KTRs VP1^-.

The present research has shown that the VP1 stimulation of CD4⁺ T cells can induce cytotoxic CD4⁺ T cells responses that may help overcome BKPyV infection in KTRs. However, VP1 stimulation may also differentially affect TCM and TEM CD4⁺ T cells subsets.

The Effect of Exosomes Isolated from Poly (I:C) Treated Human Wharton's Jelly Mesenchymal Stem Cells on CD4+CD25+Foxp3+ Regulatory T Cells

Ava Misaghian, Ata A Ghadiri, Ali Asadirad, Sareh Amirzadeh, Afshin Amari — Wed, 05 Jun 2024 04:02:39 +0000

Mesenchymal stem cells (MSCs) are a potential cell therapy candidate for autoimmune and inflammatory diseases due to their multilineage capacity and immune modulating function. MSCs exert immunomodulatory effects on target cells through the secretion of exosomes. Inflammatory conditions such as Toll-like receptors (TLRs) engagement can change the biological functions and immunomodulatory activities of MSCs and the contents of exosomes derived from MSCs are changed. Regulatory T-cells (Treg) are crucial for maintaining immune cell homeostasis and self-tolerance. Our study aimed to investigate the impact of isolated exosomes from hWJ-MSCs that were treated with Poly (I:C) on regulatory CD4 CD25 Foxp3 T-cells.

MSCs were harvested from human umbilical cord Wharton’s Jelly by explant method. Stem cells were treated by Polyinosinic-polycytidylic acid sodium salt (Poly (I:C)) for 48 hours. Exosomes were extracted from supernatant of cells and Scanning electron microscopy (SEM) and Dynamic light scattering (DLS) were performed for them. Peripheral blood mononuclear cells (PBMCs) isolated from the healthy donors were stimulated with PHA (Phytohemagglutinin) and co-cultured with Poly (I:C) treated hWJ-MSCs derived exosome and untreated hWJ-MSCs derived exosome or without hWJ-MSCs-derived exosome for 6 days. Then, frequency of CD4+CD25+ Foxp3+ regulatory T cells was measured by flow cytometry.

Our results showed that exosomes isolated from Poly (I:C) treated hWJ-MSCs significantly increased frequency of CD4+CD25+ Foxp3+ regulatory T cells compared to the untreated hWJ-MSCs derived exosome group and control group.

Stimulation by TLR3 improved the anti-inflammatory features of exosomes that were derived from hWJ-MSCs by increasing the frequency of Treg cells.

Invariant Natural Killer Cells Regulate Conventional Dendritic Cell Maturation to Re-establish Immune Tolerance to Rheumatoid Arthritis in DBA/1 Mice

Yaqi Wang, Min Zhang, Shengde Chen, Zheng Li, Ming Meng — Wed, 05 Jun 2024 04:05:19 +0000

Rheumatoid arthritis (RA) is a type of autoimmune disease that results in immune disorder and excessive inflammatory response due to a reduction of self-tolerance. Invariant natural killer T (iNKT) cells can effectively alleviate clinical symptoms and hyper-inflammation in RA, but their mechanism of action is not well-defined. This study aims to investigate the mechanism of iNKT cell therapy for RA.

We established a DBA/1 mouse model for RA and treated it with specific iNKT cells. A cytometric bead array was used to measure the amounts of cytokines in the serum. Flow cytometry was then employed to identify different subsets of helper T cells (Th), the frequency of conventional dendritic cells (cDC), the expression of CD80, CD86, programmed cell death ligand 1 (PD-L1), and PD-L2 on cDC surfaces, and associated pathway proteins.

iNKT cell treatment reduced Th1/Th2 and Th17/ regulatory T (Treg) cell ratios while increasing interleukin-4 (IL-4) and IL-10. It enhanced the generation of immature cDCs, and it upregulated the level of PD-L2 by stimulating the Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Meanwhile, it activated the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and inhibited the nuclear factor kappa B (NF-κB) pathway.

According to our findings, iNKT cell treatment increased the expression of phosphates STAT3 in lymph node cDC, causing them to upregulate PD-L2 molecules. While activating the ERK1/2 pathway and inhibiting the NF-κB pathway, tolerogenic cDC was produced, restoring immune homeostasis and correcting excessive inflammation. These results deliver new insights into the treatment of RA by iNKT cells.

Moderate-intensity Exercise Alleviates Rat’s Systemic Inflammation Induced by Repeated Exposure to Lipopolysaccharide

Wed, 05 Jun 2024 04:07:47 +0000

The protective impacts of physical activity against inflammatory and oxidative stress
conditions have been demonstrated. In this study, the impacts of moderate-intensity exercise on oxidative stress-associated factors and proinflammatory cytokines levels as well as the count of white blood cells (WBC) were assessed in a lipopolysaccharide (LPS)-triggered model of inflammation.

Wistar rats were randomized into these groups (8 rats in each): (1) control; (2) LPS; (3) moderate exercise (EX); and (4) moderate exercise + LPS (EX+LPS). Exercise groups were trained for 8 weeks (30 min, 6 days/week) at 15 m/min speed. During the final week of the experiment, 1 mg/kg/day of intraperitoneal LPS was administered for 5 days. On day 56, from the rats’ hearts, peripheral blood was taken for biochemical evaluation.

LPS enhanced serum levels of C-reactive protein (CRP), interleukin (IL)- 1β, tumor necrosis factor-α (TNF-α), metabolites of nitric oxide, and malondialdehyde (MDA), as well as the counts of total WBC, monocytes, neutrophils, and eosinophils, but decreased serum levels of thiol as well as superoxide dismutase (SOD) and catalase (CAT) activity versus the control rats. Moderate exercise reduced the levels of thiol, CAT, and SOD, but increased TNF-α level, and total WBC, neutrophils, eosinophils, and monocytes counts versus the control group. In the EX+LPS group, moderate exercise decreased cell counts and diminished MDA, TNF-α, IL-1β, and CRP levels, while increasing thiol level, CAT, and SOD versus the LPS group.

In our study, exercise preconditioning reduced inflammation induced by LPS by ameliorating inflammatory cytokine levels, WBC counts, and oxidative damage, while improving antioxidant
defenses.

Assessment of the Anti-cancer Effects of Camel Milk Exosomes (CMEXOs) on Murine Colorectal Cancer Cell Line (CT-26)

Wed, 05 Jun 2024 04:10:50 +0000

Today, camel milk consumption in the Middle East is trendy because it is believed that it reduces the risk of cancer. Recently, studies have discovered that most of milk's beneficial effects are because of its nanoparticles, especially exosomes. The objective of the present research was to investigate the anti-cancer effects of camel milk exosomes (CMEXOs) in the murine colorectal cancer cell line (CT-26).

Our findings verified the existence of exosomes measuring approximately 114.1±3.4 nm in diameter. Through MTT and migration assays, we established that CMEXOs exhibit dose-dependent anti-proliferative and anti-migration effects on the CT-26 cell line. Furthermore, our study showed that treatment with CMEXOs led to a reduction in TNF-α and IL-6 gene expression in CT-26 cells.

While additional in vivo studies are required, our data demonstrate that CMEXOs have anti-proliferative and anti-migration effects on CT-26, possibly by influencing crucial genes within the inflammation pathway.

Nebulized Dexmedetomidine Alleviates Oxidative Stress in Ventilator-induced Lung Injury via Keap1-Nrf2-ARE Pathway

Jun Zha, Youjia Yu, Ji Zhu, Guiru Li, Xiaolin Deng, Hong Xie — Wed, 05 Jun 2024 04:13:49 +0000

This study aimed to explore the underlying mechanism of nebulized dexmedetomidine (DEX) in ameliorating ventilator-induced lung injury (VILI)-induced oxidative stress in rats.

Forty 7 to 8-week-old Sprague-Dawley rats at the specific pathogen-free level were randomized into the control group, model group, nebulized dexmedetomidine (WH-YM) group, and dexmedetomidine intravenous infusion (JM-YM) group, each containing 10 rats. Except for the control group, rats in the other groups underwent mechanical ventilation (tidal volume, 40 mL/kg; respiratory rate, 70 breaths per minute; inspiratory-to-expiratory ratio, 1:2; fraction of inspired oxygen, 21%; positive end-expiratory pressure, 0 cmH2O). Nebulized DEX (6.3 µg/kg), and isodose intravenous DEX were given to rats of WH-YM and JM-YM groups prior to ventilation. Post 4-hour ventilation, rats were euthanized. Lung tissue wet-to-dry weight ratio, H&E staining for assessing diffuse alveolar damage (DAD), and expression levels of Nrf2 and Keap1 detected by qRT-PCR and Western blot were compared. Inflammatory markers TNF-α, IL-2, and IL-6, and oxidative stress indices malondialdehyde (MDA) and superoxide dismutase (SOD), were quantified in lung tissues and serum samples using commercial kits.

Rats in the WH-YM and JM-YM groups demonstrated significant ameliorations in the wet-to-dry weight ratio and DAD score, decreased Keap1, TNF-α, IL-2, and IL-6 levels in lung tissues and serum samples, but increased Nrf2 and SOD level than those of controls. These changes were more pronounced in the WH-YM group than in the JM-YM group.

DEX effectively alleviates VILI-induced oxidative stress and inflammation via the Keap1-Nrf2-ARE signaling pathway., especially in the nebulized administration.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and Myocarditis: A Case Report and Literature Review on Fatal Complications of Reactivated Viral Infections

Wed, 05 Jun 2024 04:18:45 +0000

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a complex and potentially fatal hypersensitivity condition. We present a unique case report and literature review focusing on DRESS syndrome-associated myocarditis resulting from reactivated viral infections in a 21-year-old female.

3 weeks after 5-day oral co-trimoxazole consumption due to acne, she developed symptoms consistent with DRESS syndrome, including a generalized maculopapular rash. Despite prednisolone treatment, the patient developed fatal fulminant myocarditis linked to HHV-6 and CMV reactivation.

The patient's death highlights the importance of early recognition and careful management of DRESS syndrome, especially considering the potential viral reactivation that can lead to severe complications. Postmortem investigations revealed that viral reactivation caused myocarditis. Careful consideration must be given to corticosteroid usage in DRESS treatment, as inappropriate prescribing may promote viral reactivation and subsequent complications.

While high-dose corticosteroids initiated within the first week effectively suppress HHV-6 reactivation. Conversely, low-dose or late-start high-dose corticosteroids prove ineffective in preventing HHV-6 viremia. Late- onset or low- dose corticosteroids may lead to fatal complications following the primary viral reactivation.