Associations of the neutrophil to lymphocyte ratio with intracranial artery stenosis and ischemic stroke.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has emerged as an inflammatory marker. However, the associations of NLR with intracranial artery stenosis (ICAS) and ischemic stroke remain unclear. This study aimed to examine the associations of NLR with ICAS and ischemic stroke among a large and high-risk population. METHODS: Participants with records of clinical characteristics were prospectively recruited from the Neurology Department and Health & Physical Examination Center of Qingdao Municipal Hospital. Logistic regression analysis was used to examine the associations of NLR with ICAS and ischemic stroke. Moreover, we also conducted parametric mediation analysis to estimate the effect of NLR on the risk of ischemic stroke mediated through ICAS. RESULTS: A total of 2989 participants were enrolled in this study. After adjusting for covariates, NLR (OR = 1.125, 95%CI 1.070-1.183) and ICAS (OR = 1.638, 95%CI 1.364-1.967) were significantly associated with ischemic stroke. Compared with the first quartile NLR, the second, third and fourth quartiles NLR were independent risk predictors for ischemic stroke (P for trend < 0.001); the third and fourth quartiles were independent predictors for ICAS (P for trend < 0.001). The mediation analysis showed that ICAS partially mediated the association between NLR and ischemic stroke, accounting for 14.4% of the total effect (P < 0.001). CONCLUSIONS: NLR was significantly associated with ICAS and ischemic stroke. Besides, ICAS partially mediated the association between NLR and ischemic stroke.

Differing Progression to Posterior Glottic Stenosis in Autoimmune and Idiopathic Subglottic Stenosis.

OBJECTIVES/HYPOTHESIS: We sought to characterize rates of progression to posterior glottic stenosis (PGS) from autoimmune or idiopathic subglottic stenosis. STUDY DESIGN: This was a retrospective review. METHODS: Patients from a tertiary-care laryngology practice over a 10-year period with autoimmune or idiopathic subglottic stenosis (SGS) were included. Patients with a history of prolonged intubation or other causes of iatrogenic stenosis were excluded. PGS was confirmed on videostrobolaryngoscopy recordings by a fellowship-trained laryngologist. PGS type (1-4) was also recorded. Demographic information was recorded, and if applicable, autoimmune disease type was specified. Time until PGS was recorded along with the number of interventions. Chi-squared analysis was used to compare PGS in autoimmune and idiopathic SGS. RESULTS: A total of 77 patients were identified with autoimmune (32 patients) or idiopathic (45 patients) subglottic stenosis. Autoimmune pathologies included systemic lupus erythematosus, granulomatosis with polyangiitis (GPA), rheumatoid arthritis, relapsing polychondritis, and sarcoidosis, with GPA the most common (14/32). Patients with autoimmune SGS had a higher rate of PGS (10 of 32) compared to idiopathic subglottic stenosis (1 of 45) for an odds ratio of 20 (95% CI: 2.4-166.4, P = .006). Patients with idiopathic SGS were more likely to be female (all 45 compared to 29/32 autoimmune, P = .07) and older (mean 53 (range 29-75) compared to 46 (20-82), P = .02). CONCLUSIONS: In this large patient cohort, autoimmune SGS patients were found to have a higher likelihood of developing PGS compared to their idiopathic counterparts, suggesting that counseling for this progression may be warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1816-1820, 2021.

Do Postoperative Oral Corticosteroids Improve Results After Sialendoscopy for Ductal Stenosis?

OBJECTIVES: This study aims to review the effects of short- and long-term oral administration of postoperative corticosteroids in patients undergoing sialendoscopy for the treatment of obstructive sialadenitis due to ductal stenosis. STUDY DESIGN: Prospective comparative study. METHODS: A prospective observational study was conducted at Manukau Surgical Center in Auckland, New Zealand, where patients undergoing sialendoscopic surgery for recurrent obstructive sialadenitis due to ductal stenoses were reviewed. Univariable and multivariable analysis, and also logistic regression were performed to identify variables correlated with the likelihood of the need for revision surgery for persistent or recurrent symptoms. RESULTS: In this study, sialendoscopy was performed in 142 patients: 162 parotid glands (86.6%) and 25 submandibular glands (13.4%). Postoperative oral steroids were prescribed for 48 patients (34%); 19 (13%) were prescribed for less than 7 days and 29 (20%) for more than 7 days. In total, 33 patients (23.2%) required a revision sialendoscopy during follow-up due to recurrence of symptoms. Oral steroids prescribed for more than 7 days after a sialendoscopy reduced the likelihood of a revision procedure by 93% when compared with patients who did not receive this medication, and by 96% when compared with patients who received steroids for less than 7 days. CONCLUSION: The results showed that in our population oral administration of corticosteroids for more than 7 days after sialendoscopy for the treatment of recurrent obstructive sialadenitis due to ductal stenosis markedly reduced the need for later revision surgery. Routine use of corticosteroids for more than 7 days is recommended after sialendoscopy in patients with ductal stenosis. LEVEL OF EVIDENCE: II Laryngoscope, 131:E1503-E1509, 2021.

Mechanism of fibrosis and stricture formation in Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract that leads to substantial suffering for millions of patients. In some patients, the chronic inflammation leads to remodelling of the extracellular matrix and fibrosis. Fibrosis, in combination with expansion of smooth muscle layers, leaves the bowel segment narrowed and stiff resulting in strictures, which often require urgent medical intervention. Although stricture development is associated with inflammation in the affected segment, anti-inflammatory therapies fall far short of treating strictures. At best, current therapies might allow some patients to avoid surgery in a shorter perspective and no anti-fibrotic therapy is yet available. This likely relates to our poor understanding of the mechanism underlying stricture development. Chronic inflammation is a prerequisite, but progression to strictures involves changes in fibroblasts, myofibroblasts and smooth muscle cells in a poorly understood interplay with immune cells and environmental cues. Much of the experimental evidence available is from animal models, cell lines or non-strictured patient tissue. Accordingly, these limitations create the basis for many previously published reviews covering the topic. Although this information has contributed to the understanding of fibrotic mechanisms in general, in the end, data must be validated in strictured tissue from patients. As stricture formation is a serious complication of CD, we endeavoured to summarize findings exclusively performed using strictured tissue from patients. Here, we give an update of the mechanism driving this serious complication in patients, and how the strictured tissue differs from adjacent unaffected tissue and controls.

Early treatment with anti-tumor necrosis factor agents improves long-term effectiveness in symptomatic stricturing Crohn's disease.

BACKGROUND: There is limited evidence on the effectiveness of biological therapy in stricturing complications in patients with Crohn's disease. AIM: The study aims to determine the effectiveness of anti-tumor necrosis factor (TNF) agents in Crohn's disease complicated with symptomatic strictures. METHODS: In this multicentric and retrospective study, we included adult patients with symptomatic stricturing Crohn's disease receiving their first anti-TNF therapy, with no previous history of biological, endoscopic or surgical therapy. The effectiveness of the anti-TNF agent was defined as a composite outcome combining steroid-free drug persistence with no use of new biologics or immunomodulators, hospital admission, surgery or endoscopic therapy during follow-up. RESULTS: Overall, 262 patients with Crohn's disease were included (53% male; median disease duration, 35 months, 15% active smokers), who received either infliximab (N = 141, 54%) or adalimumab (N = 121, 46%). The treatment was effective in 87% and 73% of patients after 6 and 12 months, respectively, and continued to be effective in 26% after a median follow-up of 40 months (IQR, 19-85). Nonetheless, 15% and 21% of individuals required surgery after 1 and 2 years, respectively, with an overall surgery rate of 32%. Postoperative complications were identified in 15% of patients, with surgical site infection as the most common. Starting anti-TNF therapy in the first 18 months after the diagnosis of Crohn's disease or the identification of stricturing complications was associated with a higher effectiveness (HR 1.62, 95% CI 1.18-2.22; and HR 1.55, 95% CI 1.1-2.23; respectively). Younger age, lower albumin levels, strictures located in the descending colon, concomitant aminosalicylates use or presence of lymphadenopathy were associated with lower effectiveness. CONCLUSIONS: Anti-TNF agents are effective in approximately a quarter of patients with Crohn's disease and symptomatic intestinal strictures, and 68% of patients are free of surgery after a median of 40 months of follow-up. Early treatment and some potential predictors of response were associated with treatment success in this setting.

IL-10 IS DOWN-REGULATED IN THE CARDIOVASCULAR DISEASES SUSPECTED PATIENTS, INDEPENDENT OF ANGIOGRAPHY. / RIVEN' IL-10 ZNYZhENYY̆ U PATsIIeNTIV IZ SERTsEVO-SUDYNNYMY ZAKhVORIuVANNIaMY, NEZALEZhNO VID PROVEDENNIa ANGIOGRAFIChNYKh DOSLIDZhEN'.

IL-10 and interferon-gamma (IFN-γ) are the important anti and pro-inflammatory cytokines, respectively, which may participate in the cardiovascular disease pathogenesis. Additionally, environmental factors, such as the X-ray, can modulate cytokine expression. Due to the fact that X-ray is used during angiography, hence, angiography may alter expression of the cytokines. OBJECTIVE: Accordingly, this project was aimed to assess IL-10 and IFN-γ serum levels within cardiovascular patients (with and without vessel stenosis) versus healthy controls and also the effects of angiography on the serum levels of the cytokines. MATERIAL AND METHODS: This study was performed on the 80 participants, including twenty cases in each group (healthy controls and cardiovascular patients without vessel stenosis, stenosis of 1 vessel and stenosis of more than 1 vessel) to evaluate IL-10 and IFN-γ serum levels using ELISA technique. The IL-10 and IFN-γ serum levels also compared within group 2, 3 and 4 before and after angiography to explore the effects of the technique on the IL-10 and IFN-γ serum levels. RESULTS: IL-10, but not IFN-γ, serum levels were higher in the healthy controls than all cardiovascular patients. IL-10 and IFN-γ serum levels were not altered after angiography and also were not differ in the smoker versus non- smoker and opium consuming versus non-opium consuming participants. CONCLUSION: Due to the results it may be concluded that IL-10 can be considered as a plausible inhibitor of cardio- vascular diseases independent of angiography duration and X-ray, however, IFN-γ has no effects in the Iranian patients suffering from cardiovascular diseases.

TPO-Ab plays a role in arterial remodeling in patients with intracranial stenosis.

BACKGROUND AND AIMS: Intracranial stenosis (ICS), the common cause of ischemic stroke worldwide, is associated with a high risk of recurrent stroke. We aimed to investigate the relationship between arterial remodeling and antithyroid peroxidase-antibody (TPO-Ab) level in ICS and the effect of TPO-Ab level on the migration of vascular smooth muscle cells (VSMCs). METHODS: We analyzed data of mild-to-severe ICS patients with normal thyroid function who underwent high-resolution magnetic resonance imaging in our center. Vessel area (VA), lumen area, wall area and plaque size were assessed at the most narrowed lumen (MNL) and reference site, respectively. The remodeling index (RI) was defined as VAMNL/VAreference. Negative remodeling (NR) or non-NR was defined as RI ≤ 0.95 or > 0.95. A scratch-wound healing assay was also designed to analyze the impact of TPO-Ab level on migration of VSMCs, which were isolated from thoracic aorta segments of Sprague Dawley rats. RESULTS: A total of 88 patients were included. Patients with elevated TPO-Ab had smaller VA, wall area, plaque size and RI than those with normal level (p < 0.05). Elevated TPO-Ab was significantly associated with NR after adjusting for demographic and vascular risks (odds ratio 10.629, 95% confidence interval, 1.842-61.327, p = 0.008). The rate of VSMCs migration was significantly increased after culture with TPO-Ab (TPO-Ab 1 µg/ml vs. Mock, 29.8% vs. 12.0%, p < 0.01). CONCLUSIONS: Elevated TPO-Ab in ICS patients was related to NR. TPO-Ab could promote VSMCs migration, which might be involved in the NR of intracranial artery.

Temporal Frame of Immune Cell Infiltration during Heart Failure Establishment: Lessons from Animal Models.

Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.

Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II.

The activation of T helper cells requires antigens to be exposed on the surface of antigen presenting cells (APCs) via MHC class II (MHC-II) molecules. Expression of MHC-II is generally limited to professional APCs, but other cell types can express MHC-II under inflammatory conditions. However, the importance of these conditional APCs is unknown. We and others have previously shown that Schwann cells are potentially conditional APCs, but the functional relevance of MHC-II expression by Schwann cells has not been studied in vivo. Here, we conditionally deleted the MHC-II ß-chain from myelinating Schwann cells in mice and investigated how this influenced post-traumatic intraneural inflammation and neuropathic pain using the chronic constriction injury (CCI) model. We demonstrate that deletion of MHC-II in myelinating Schwann cells reduces thermal hyperalgesia and, to a lesser extent, also diminishes mechanical allodynia in CCI in female mice. This was accompanied by a reduction of intraneural CD4+ T cells and greater preservation of preferentially large-caliber axons. Activation of T helper cells by MHC-II on Schwann cells thus promotes post-traumatic axonal loss and neuropathic pain. Hence, we provide experimental evidence that Schwann cells gain antigen-presenting function in vivo and modulate local immune responses and diseases in the peripheral nerves.

Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure.

BACKGROUND: Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs), are key contributors to cardiac remodeling after myocardial infarction, their role in pressure-overload remodeling is unclear. We tested the hypothesis that these immune cells are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling. METHODS AND RESULTS: C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expansion of circulating LyC6hi monocytes and pro-inflammatory CD206- cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C+ monocytes and DCs in the spleen. Periodic systemic MP depletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter cardiac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naïve recipients did not induce immediate or long-term cardiac dysfunction in recipient mice. CONCLUSIONS: Mononuclear phagocytes populations expand in a phasic manner in the heart during pressure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized.

Stricturing Crohn's disease-like colitis in a patient treated with belatacept.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) modifying agents have been involved in the development of intestinal inflammation, especially therapeutic monoclonal antibodies directed against CTLA-4. Here we report the appearance of a severe stricturing Crohn's disease-like colitis in a patient with a kidney allograft who was treated with belatacept, a recombinant CTLA-4-Ig fusion protein.

Mechanisms, Management, and Treatment of Fibrosis in Patients With Inflammatory Bowel Diseases.

In the last 10 years, we have learned much about the pathogenesis, diagnosis, and management of intestinal fibrosis in patients with inflammatory bowel diseases. Just a decade ago, intestinal strictures were considered to be an inevitable consequence of long-term inflammation in patients who did not respond to anti-inflammatory therapies. Inflammatory bowel diseases-associated fibrosis was seen as an irreversible process that frequently led to intestinal obstructions requiring surgical intervention. This paradigm has changed rapidly, due to the antifibrotic approaches that may become available. We review the mechanisms and diagnosis of this serious complication of inflammatory bowel diseases, as well as factors that predict its progression and management strategies.

Serologic Anti-GP2 Antibodies Are Associated with Genetic Polymorphisms, Fibrostenosis, and Need for Surgical Resection in Crohn's Disease.

BACKGROUND: The presentation of Crohn's disease (CD) is heterogeneous and often leads to serious complications and need for surgery. We tested serum anti-zymogen granule glycoprotein 2 (GP2) antibodies, including its novel isoform alpha, for association with genetic variants, diagnosis, disease stratification, and prediction of CD courses in a combined cross-sectional and cohort study. METHODS: Serum samples of 303 CD, 108 ulcerative colitis, 72 other inflammatory gastrointestinal diseases, and 206 controls without predominant gastrointestinal diseases controls (HC) were tested for the presence of Anti-GP2 and Anti-Saccharomyces cervisiae (ASCA) by enzyme-linked immunosorbent assay. Genetic analysis was performed using the Illumina Immunochip. RESULTS: GP2 IgA and IgG had the highest discriminatory capability for CD versus ulcerative colitis and CD versus inflammatory gastrointestinal diseases. We identified an association of GP2 IgA and IgG each with 5 distinct single-nucleotide polymorphisms. Levels of anti-GP2 IgG were moderately associated with ileal disease location. Interestingly, both, anti-GP2 IgA and IgG were exclusively associated with the occurrence of stenosis and need for surgery, independently of disease location, but not with fistulizing CD, early disease onset or disease activity. ASCA IgG and IgA were qualitatively and quantitatively linked to CD, CD complications, and need for surgery. Increased levels of ASCA IgG and IgA and positivity for ASCA IgG, but neither levels nor positivity for GP2 IgG or IgA were predictive of the earlier occurrence of complications or surgery. CONCLUSIONS: Anti-GP2 antibodies may aid as a tool for diagnosis and differentiation of CD and could indicate a more complicated CD course.

Omega-3 fatty acid supplement prevents development of intracranial atherosclerosis.

OBJECTIVES: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We adapted a rat model of atherosclerosis to study brain intracranial atherosclerosis, and further investigated the effect of omega-3 fatty acids (O3FA) in attenuating development of ICAS. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into control normal-cholesterol or high-cholesterol diet groups with or without O3FA for up to 6weeks. During the first 2weeks, NG-nitro-l-arginine methyl ester (l-NAME, 3mg/mL) was added to the drinking water of the high-cholesterol groups. The rats received supplementation with O3FA (5mg/kg/day) by gavages. Blood lipids including low density lipoprotein (LDL), cholesterol (CHO), triglycerides (TG) and high density lipoprotein (HDL) were measured at 3 and 6weeks. The lumen of middle cerebral artery (MCA) and the thickness of the vessel wall were assessed. Inflammatory molecular markers were assessed by Western blot. RESULTS: A high-cholesterol diet exhibited a significant increase in the classic blood markers (LDL, CHO, and TG) for atherosclerosis, as well as a decrease in HDL. These markers were found to be progressively more severe with time. Lumen stenosis and intimal thickening were increased in MCA. O3FA showed attenuation of blood lipids with an absence of morphological changes. O3FA significantly reduced the inflammatory marker CD68 in MCA and prevented monocyte chemotactic protein (MCP-1) and interferon-γ (IFN-γ) expression in the brain. O3FA similarly decreased inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6), markers affiliated with monocyte activity in atherosclerosis. Furthermore, O3FA significantly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial activation. Lastly, O3FA increased ATP-binding cassette transporter A1 (ABCA1) protein expression via silent information regulator 1 (SIRT1) activation, thus increasing cholesterol efflux from macrophages to HDL. CONCLUSIONS: Long-term O3FA dietary supplementation prevents the development of intracranial atherosclerosis. This O3FA effect appears to be mediated by its prevention of macrophage infiltration into the vessel wall, therefore reducing inflammation and intimal thickening. While similar effects in humans need to be determined, O3FA dietary supplement shows promising results in the prevention of ICAS.

IgG4-related cholangitis: Case report and literature review.

CASE PRESENTATION: We describe a case of a patient who presents with jaundice, elevated cholestatic liver enzymes, an extreme weight loss and a midcholedochal stricture very suspect for a cholangiocarcinoma. In the conviction of malignancy, although the absence of anatomopathological prove, the patient underwent a choledochal resection. The anatomopathological specimen revealed no malignancy. In the year following resection, the patient keeps presenting with bile duct strictures and further weight loss. Ultimately the diagnosis of Ig G4-related cholangitis is withheld. Therapy with corticosteroids is initiated with a spectacular clinical, biochemical and radiographical result. DISCUSSION: IgG4-related cholangitis is the biliary presentation of IgG4-related disease, a recently discovered entity of fibroinflammatory masses which can affect virtually every organ in the body. It is characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis and a presence of > 30 IgG4-positive plasma cells per high power field. Main differential diagnosis contains cholangiocarcinoma and primary sclerosing cholangitis. Corticoids are cornerstone of therapy, with azathioprine frequently used as a maintenance in case of relapse. CONCLUSIONS: With this case we want to draw the attention to a rather uncommon cause of biliary obstruction, easily mistaken for a cholangiocarcinoma.

Atorvastatin prevents neuroinflammation in chronic constriction injury rats through nuclear NFκB downregulation in the dorsal root ganglion and spinal cord.

Atorvastatin, traditionally used to treat hyperlipidemia, belongs to a class of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors. This study investigated the antineuroinflammatory and antihyperalgesic effects of atorvastatin in dorsal root ganglia (DRG) and spinal cord for chronic constriction injury (CCI) neuropathic pain in rats. Fifty-four Sprague-Dawley rats were divided into three groups including sham, CCI, and CCI+atorvastatin. Rats were orally administered atorvastatin (10 mg/kg/day) once daily for 2 weeks after surgery and sacrificed at days 3, 7, and 14. All animals were assessed for mechanical allodynia and thermal hyperalgesia in both hindpaws. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to detect inflammatory proteins and proinflammatory cytokines at day 7 after surgery. Pain behaviors were significantly reduced in the CCI+atorvastatin group compared to the CCI group. Atorvastatin attenuated CCI-induced inflammatory mediators (pAkt/Akt, COX-2, iNOS, EP1, and EP4) and reduced proinflammatory cytokines TNF-α and IL-1ß levels in DRG and spinal cord. Atorvastatin also inhibited nuclear pNFκB activation. Double immunofluorescent staining further demonstrated that pNFκB proteins were decreased by atorvastatin in DRG satellite cells and spinal microglia. Atorvastatin may primarily inhibit the nuclear translocation of pNFκB to prevent CCI-induced peripheral neuropathic pain. Atorvastatin exhibits antineuroinflammatory and antinociceptive properties in the central and peripheral nerve systems.

The innate immune system contributes to tissue-engineered vascular graft performance.

The first clinical trial of tissue-engineered vascular grafts (TEVGs) identified stenosis as the primary cause of graft failure. In this study, we aimed to elucidate the role of the host immune response in the development of stenosis using a murine model of TEVG implantation. We found that the C.B-17 wild-type (WT) mouse (control) undergoes a dramatic stenotic response, which is nearly completely abolished in the immunodeficient SCID/beige (bg) variant. SCID mice, which lack an adaptive immune system due to the absence of T and B lymphocytes, experienced rates of stenosis comparable to WT controls (average luminal diameter, WT: 0.071 ± 0.035 mm, SCID: 0.137 ± 0.032 mm, SCID/bg: 0.804 ± 0.039 mm; P < 0.001). The bg mutation is characterized by NK cell and platelet dysfunction, and systemic treatment of WT mice with either NK cell-neutralizing (anti-NK 1.1 antibody) or antiplatelet (aspirin/Plavix [clopidogrel bisulfate]; Asp/Pla) therapy achieved nearly half the patency observed in the SCID/bg mouse (NK Ab: 0.356 ± 0.151 mm, Asp/Pla: 0.452 ± 0.130 mm). Scaffold implantation elicited a blunted immune response in SCID/bg mice, as demonstrated by macrophage number and mRNA expression of proinflammatory cytokines in TEVG explants. Implicating the initial innate immune response as a critical factor in graft stenosis may provide a strategy for prognosis and therapy of second-generation TEVGs.

Influences of cerebral stent implantation on CD4+ CD25+ FOXP3+ Treg, Th1 and Th17 cells.

Stent implantation is primarily used for the treatment of artery stenosis. However, the application and use of stent struts induces local and systemic inflammation, leading to intractable neointimal hyperplasia. CD4(+) T cells are involved in artery stenosis diseases, but little is known about the influence of the CD4(+) T cells on the inflammation reaction after stent implantation. In this study, we analyzed the frequency of signature transcription factors and proinflammatory cytokine expression from each subtype of CD4(+) T cells in 50 patients receiving intracranial or cervical stent implantations from December 2011 to June 2012. The results showed that the frequency of signature transcription factor/cytokine production in Treg cells was reduced in the first week and returned to control levels at 3 months after stent implantation. However, we observed opposite trends for Th17 cells, showing increased signature transcription factor/cytokine production during the acute phase, which returned to control levels after 3 months. No significant difference in the frequency of signature transcription factor/cytokine expression was observed in Th1 cells from patients before and after stent implantation. We speculate that the maintenance of the frequency and function of Tregs controls the inflammatory response, which otherwise induces acute inflammation after stent implantation.