PEPITEM Treatment Ameliorates EAE in Mice by Reducing CNS Inflammation, Leukocyte Infiltration, Demyelination, and Proinflammatory Cytokine Production.

To investigate the effect of the therapeutic treatment of the immunopeptide, peptide inhibitor of trans-endothelial migration (PEPITEM) on the severity of disease in a mouse model of experimental autoimmune encephalomyelitis (EAE) as a model for human multiple sclerosis (MS), a series of experiments were conducted. Using C57BL/6 female mice, we dosed the PEPITEM in the EAE model via IP after observing the first sign of inflammation. The disease was induced using MOG35-55 and complete Freund's adjuvants augmented with pertussis toxin. The EAE score was recorded daily until the end of the experiment (21 days). The histological and immunohistochemistry analysis was conducted on the spinal cord sections. A Western blot analysis was performed to measure the protein concentration of MBP, MAP-2, and N-Cadherin, and ELISA kits were used to measure IL-17 and FOXP3 in the serum and spinal cord lysate. The therapeutic treatment with PEPITEM reduced the CNS infiltration of T cells, and decreased levels of the protein concertations of MBP, MAP-2, and N-Cadherin were observed, in addition to reduced concertations of IL-17 and FOXP3. Using PEPITEM alleviated the severity of the symptoms in the EAE model. Our study revealed the potential of PEPITEM to control inflammation in MS patients and to reduce the harmful effects of synthetic drugs.

Origin-Specific Adhesive Interactions of Mesenchymal Stem Cells with Platelets Influence Their Behavior After Infusion.

We investigated the adhesive behavior of mesenchymal stem cells (MSC) in blood, which might influence their fate when infused as therapy. Isolated human bone marrow MSC (BMMSC) or umbilical cord MSC (UCMSC) adhered efficiently from flow to the matrix proteins, collagen, or fibronectin, but did not adhere to endothelial selectins. However, when suspended in blood, BMMSC no longer adhered to collagen, while UCMSC adhered along with many aggregated platelets. Neither MSC adhered to fibronectin from flowing blood, although the fibronectin surface did become coated with a platelet monolayer. UCMSC induced platelet aggregation in platelet rich plasma, and caused a marked drop in platelet count when mixed with whole human or mouse blood in vitro, or when infused into mice. In contrast, BMMSC did not activate platelets or induce changes in platelet count. Interestingly, isolated UCMSC and BMMSC both adhered to predeposited platelets. The differences in behavior in blood were attributable to expression of podoplanin (an activating ligand for the platelet receptor CLEC-2), which was detected on UCMSC, but not BMMSC. Thus, platelets were activated when bound to UCMSC, but not BMMSC. Platelet aggregation by UCMSC was inhibited by recombinant soluble CLEC-2, and UCMSC did not cause a reduction in platelet count when mixed with blood from mice deficient in CLEC-2. We predict that both MSC would carry platelets in the blood, but their interaction with vascular endothelium would depend on podoplanin-induced activation of the bound platelets. Such interactions with platelets might target MSC to damaged tissue, but could also be thrombotic. Stem Cells 2018;36:1062-1074.

Melatonin Improves Memory Deficits in Rats with Cerebral Hypoperfusion, Possibly, Through Decreasing the Expression of Small-Conductance Ca2+-Activated K+ Channels.

This study investigated the expression pattern, regulation of expression, and the role of hippocampal small-conductance Ca2+-activated K+ (SK) channels in memory deficits after cerebral hypoperfusion (CHP) with or without melatonin treatment, in rats. Adults male Wistar rats (n = 20/group) were divided into (1) a sham (2) a sham + melatonin (3) a two-vessel occlusion (2-VO) model, and (4) a 2-VO + melatonin. Melatonin was administered (i.p.) to all rats at a daily dose of 10 mg kg-1 for 7 days starting at the time of 2-VO-induction. In contrast to 2-VO rats, melatonin increased the latency of the passive avoidance learning test and decreased time to find the hidden platform in Water Morris Test in all tested rats. In addition, it concomitantly downregulated SK1, SK2, and SK3 channels, downregulated mRNA levels of TNFα and IL-1ß, enhanced BDNF levels and activity of PKA levels, and restored the levels of cholinergic markers in the hippocampi of the treated-rats. Mechanistically, melatonin significantly prevented CHP-induced activation of ERK1/2, JNK, and P38 MAPK at least by inhibiting ROS generation and enhancing the total antioxidant potential. In cultured hypoxic hippocampal neurons, individual blockage of MAPK signaling by the MEK1/2 inhibitor (U0126), but not by the P38 inhibitor (SB203580) or JNK inhibitor (SP600125), completely prevented the upregulation of all three kinds of SK channels. These data clearly confirm that upregulation of SK channels plays a role in CHP-induced memory loss and indicate that melatonin reverses memory deficits after CHP in rats, at least by, downregulation of SK1, SK2, and SK3 channels in their hippocampi.

Chronic consumption of a high-fat diet rich in corn oil activates intrinsic cell death pathway and induces several ultrastructural changes in the atria of healthy and type 1 diabetic rat.

This study investigates the effect of chronic consumption of a high-fat diet rich in corn oil (CO-HFD) on atrial cells ultrastructure, antioxidant levels and markers of intrinsic cell death of both control and type 1 diabetes mellitus (T1DM)-induced rats. Adult male rats (10 rats/group) were divided into four groups: control fed standard diet (STD) (3.82 kcal/g, 9.4% fat), CO-HFD (5.4 kcal/g, 40% fat), T1DM fed STD, and T1DM + CO-HFD. CO-HFD and T1DM alone or in combination impaired systolic and diastolic functions of rats and significantly reduced levels of GSH and the activity of SOD, enhanced lipid peroxidation, increased protein levels of P53, Bax, cleaved caspase-3, and ANF and decreased levels of Bcl-2 in their atria. Concomitantly, atrial cells exhibited fragmentation of the myofibrils, disorganized mitochondria, decreased number of atrionatriuretic factor (ANF) granules, and loss of gap junctions accompanied by changes in capillary walls. Among all treatments, the severity of all these findings was more severe in T1DM and most profound in the atria of T1DM + CO-HFD. In conclusion, chronic consumption of CO-HFD by T1DM-induced rats elicits significant biochemical and ultrastructural damage to rat atrial cells accompanied by elevated oxidative stress and mitochondria-mediated cell death.

Crataegus Aronia protects and reverses vascular inflammation in a high fat diet rat model by an antioxidant mechanism and modulating serum levels of oxidized low-density lipoprotein.

CONTEXT: Crataegus aronia (Willd.) Bosc (Rosaceae) (syn. Azarolus L) is traditionally used to treat cardiovascular disorders. OBJECTIVES: To investigate C. aronia protection against a high-fat diet (HFD)-induced vascular inflammation in rats. MATERIALS AND METHODS: Wistar Male rats (180-220 g) were divided (n = 10/group) as control fed a standard diet (STD), STD + C. aronia (200 mg/kg, orally), HFD, HFD + C. aronia and HFD post-treated with C. aronia. Simvastatin (20 mg/kg) was co- or post-administered as a positive control drug. HFD was given for 8 weeks, and all other treatments were administered for 4 weeks. RESULTS: Most significantly, co-administration of C. aronia to HFD-fed rats reduced the thickness of aorta tunica media (90 ± 5 vs. 160 ± 11.3 µm) and adventitia (54.3 ± 3.8 vs. 93.6 ± 9.4 µm). It also lowered protein levels of TNF-α (0.51 ± 0.15 and 0.15 ± 0.16 vs. 0.1 ± 0.09%) and IL-6 (0.52 ± 0.19 vs. 1.0 ± 0.2%) in their aorta or serum (5.9 ± 0.91 vs. 12.98 ± 1.3 ng/mL and 78.1 ± 6.7 vs. 439 ± 78 pg/mL, respectively). It also lowered all serum lipids and increased aorta levels of GSH levels (70.4 ± 4.0 vs. 40.7 µM) and activity of SOD (5.7 ± 0.7 vs. 2.9 ± 0.6 U/mg) and decreased serum levels of ox-LDL-c (566.7 ± 46 vs. 1817 ± 147 ng/mL). Such effects were more profound than all other treatments. CONCLUSIONS: C. aronia inhibits the HFD-induced vascular inflammation and its use in clinical trials is recommended.

Acylated ghrelin protects aorta damage post-MI via activation of eNOS and inhibition of angiotensin-converting enzyme induced activation of NAD(P)H-dependent oxidase.

NAD(P)H dependent oxidase derived-reactive oxygen species (ROS) due to activation of the renin-angiotensin-aldosterone system (RAAS) in blood vessels postmyocardial infarction MI or during the HF leads to endothelium dysfunction and enhanced apoptosis. Acylated ghrelin (AG) is a well-reported cardioprotective and antiapoptotic agent for the heart. AG receptors are widely distributed in most of blood vessels, suggesting a role in the regulation of endothelial function and survival. This study investigated if AG can protect aorta of rats' postmyocardial infarction (MI)-induced damage and endothelial dysfunction. Adult male rats were divided into four groups of (1) Sham, (2) Sham + AG, (3) MI, and (4) MI + AG. Vehicle (normal saline) or AG (100 µ/kg) was administered to rats for 21 consecutive days, after which, numerous biochemical markers were detected by blot. Both histological and electron microscope studies were carried on aortic samples from MI-induced rats. AG increased protein levels of both total and phosphorylated forms of endothelial nitric oxide synthase (eNOS and p-eNOS, respectively). Only in MI-treated rats, AG prevented the decreases in the levels of reduced glutathione (GSH) and superoxide dismutase (SOD) and lowered levels of malondialdehyde (MDA) and glutathione disulfide (GSSG). Concomitantly, it lowered the increased protein levels of angiotensin-converting enzyme (ACE), p22phox and cleaved caspase-3 and prevented the aorta histological and ultrustructural abnormalities induced by MI.

Correction: Men's knowledge, attitude, and barriers towards emergency contraception: A facility based cross-sectional study at King Saud University Medical City.

[This corrects the article DOI: 10.1371/journal.pone.0249292.].

Corrigendum: BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

[This corrects the article DOI: 10.3389/fphar.2023.1265230.].

Subtractive panning for the isolation of monoclonal PEPITEM peptide antibody by phage display.

Antibody phage display is a key tool for the development of monoclonal antibodies against various targets. However, the development of anti-peptide antibodies is a challenging process due to the small size of peptides for binding. This makes anchoring of peptides a preferred approach for panning experiments. A common approach is by using streptavidin as the anchor protein to present biotinylated peptides for panning. Here, we propose the use of recombinant expression of the target peptide and an immunogenic protein as a fusion for panning. The peptide inhibitor of trans-endothelial migration (PEPITEM) peptide sequence was fused to the Mycobacterium tuberculosis (Mtb) α-crystalline (AC) as an anchor protein. The panning process was carried out by subtractive selection of the antibody library against the AC protein first, followed by binding to the library to PEPITEM fused AC (PEPI-AC). A unique monoclonal scFv antibodies with good specificity were identified. In conclusion, the use of an alternative anchor protein to present the peptide sequence coupled with subtractive panning allows for the identification of unique monoclonal antibodies against a peptide target.

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

Melatonin attenuates cerebral hypoperfusion-induced hippocampal damage and memory deficits in rats by suppressing TRPM7 channels.

This study was conducted to examine if modulating transporters like transient receptor potential cation channels, subfamily M, member 7 (TRPM7) underlies the hippocampal neuroprotection afforded by melatonin (Mel) in rats exposed to cerebral hypoperfusion (CHP). Experimental groups included control, Mel-treated (1.87 g/kg), CHP, and CHP + Mel (1.87 g/kg)-treated rats. CHP was induced by the permanent bilateral occlusion of the common carotid arteries (2VO) method and treatments were conducted for 7 days, orally. Mel prevented the damage of the dental gyrus and memory loss in CHP rats and inhibited the hippocampal reactive oxygen species (ROS), lipid peroxidation levels of tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6), interleukine-1 beta (IL-1ß), and prostaglandin E2 (PGE2). It also reduced the hippocampal transcription of the TRPM7 channels and lowered levels of calcium (Ca2+) and zinc (Zn2+). Mel Also enhanced the levels of total glutathione (GSH) and superoxide dismutase (SOD) in the hippocampus of the control and CHP-treated rats. In conclusion, downregulation of TRPM7 seems to be one mechanism underlying the neuroprotective effect of Mel against global ischemia and is triggered by its antioxidant potential.

Application of phage display for T-cell receptor discovery.

The immune system is tasked to keep our body unharmed and healthy. In the immune system, B- and T-lymphocytes are the two main components working together to stop and eliminate invading threats like virus particles, bacteria, fungi and parasite from attacking our healthy cells. The function of antibodies is relatively more direct in target recognition as compared to T-cell receptors (TCR) which recognizes antigenic peptides being presented on the major histocompatibility complex (MHC). Although phage display has been widely applied for antibody presentation, this is the opposite in the case of TCR. The cell surface TCR is a relatively large and complex molecule, making presentation on phage surfaces challenging. Even so, recombinant versions and modifications have been introduced to allow the growing development of TCR in phage display. In addition, the increasing application of TCR for immunotherapy has made it an important binding motif to be developed by phage display. This review will emphasize on the application of phage display for TCR discovery as well as the engineering aspect of TCR for improved characteristics.

The Prevalence of Depression and Anxiety in Post-bariatric Surgery Patients at King Khalid University Hospital, Riyadh.

Background Obesity negatively impacts mental and physical health and is a leading cause of disease worldwide. Obesity affects 33% of Saudi adults, with 10% being morbidly obese (body mass index, BMI >40 kg/m2). This study explored the association between bariatric surgery (BS) and a predisposition or exacerbation of depressive and anxiety symptoms. Material and methods A cross-sectional study of patients who underwent bariatric surgery at the King Khalid University Hospital in Riyadh, Saudi Arabia, was conducted between February 2016 and December 2021. The patients were contacted by phone to complete a self-administered questionnaire on demographic information, chronic medical diseases, psychiatric diseases, body mass index, and type of bariatric surgery. In addition, they completed the patient health questionnaire-9 (PHQ-9) and general anxiety disorder-7 (GAD-7) questionnaire to screen for patients' depression and anxiety symptoms. Results The findings of the 367 BS patients showed that 20.7% of the patients were considered to have mild anxiety, 11.2% had moderate anxiety, and 8.7% had high anxiety levels. However, regarding depression, 46.9% had extremely low levels of depression, followed by mild depression in 29.4% and moderate depression in 11.2%. Furthermore, another 8.2% of BS patients had moderately high depression levels, and 4.4% had severe depression. The anxiety and depression levels of the patients in this study did not show any statistically significant changes postoperatively in the short, medium, or long term. On the other hand, almost all of the patients 97% who underwent bariatric surgery were satisfied with the outcome of their surgery. Conclusion Few BS patients had high symptoms of depression and anxiety. We recommend pre- and postoperative psychiatric assessment for all bariatric surgery patients as surgical protocol.

Men's knowledge, attitude, and barriers towards emergency contraception: A facility based cross-sectional study at King Saud University Medical City.

BACKGROUND: Male partners have a considerable role in influencing women's contraceptive decision making to reduce the chance of unintended pregnancy. Most studies are focused on women's knowledge and barriers for emergency contraception (EC) use. There is limited research on this topic from the male perspective. This study aimed to gather baseline data on men's knowledge, attitudes and barriers about EC. METHODS: Descriptive analytic cross-sectional study was conducted from Dec 2019 -May 2020 at the King Khalid University Hospital (KKUH); a teaching facility with general and subspecialty medical services in King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia. Data were collected using a structured pretested questionnaire and analyzed using SPSS version 23.0. Descriptive statistics and Chi square tests were used. Multivariate logistic regression analysis was used to find significant predictors for EC awareness and use. A p value < 0.05 was considered statistically significant. RESULTS: A total of 461 participants completed the questionnaire (response rate 86%). The majority (82%) of the participants were unaware of EC; with only 18% having some knowledge. Knowledgeable men had positive attitudes (73.5%) about EC as compared to non- knowledgeable ones (55.0%). Factors found to be associated with less knowledge of EC were cultural [0.46, 95%CI 0.22. 0.96] and religious unacceptability [OR 0.51, 95%CI 0.29, 0.89)]. Higher level of education [OR 1.83, 95%CI 0.94, 3.53] was associated with more knowledge regarding EC. The study showed that correct information about using contraceptives within 3 days of unprotected sex [OR 4.96, 95%CI 1.81, 13.60]; availability without prescription [OR 5.06, 95%CI 1.68, 15.30], EC advertisement [OR 4.84, 95%CI 0.96, 24.27] and receipt of information from family/friends [OR 18.50, 95%CI 5.19, 65.93] were factors that contributed to men using EC. CONCLUSION: The current knowledge of EC among men is limited. Social determinants affect these levels of knowledge, as well as the usage of EC. Factors that were associated with the use of ECPs were correct knowledge, advertisement, availability and receipt of information from family/friends. The findings highlight the need to educate men on this important topic to avoid unintended pregnancy, keeping in view cultural and social values. Future qualitative studies are needed to understand the male perspective.

Exposure to cell phones reduces heart rate variability in both normal-weight and obese normotensive medical students.

BACKGROUND: We investigated and compared the effect of the radiofrequency electromagnetic field (RF-EM) emitted by a cell phone on the electrocardiogram and heart rate variability (HRV) of normotensive normal-weight and obese medical students. METHOD: Twenty medical student volunteers, normal weight (age = 23 ± 2, BMI = 23.05 ± 1.72) or obese (age = 24 ± 2, BMI = 32.39 ± 4.78), were exposed to a cell phone (1) close to the heart in silent mode, no ringing or vibrating; (2) close to the heart in ring and vibration mode; (3) next to the ear (brain) while listening; and (4) next to the ear while listening and speaking. RESULTS: The average basal HR of obese students significantly increased, while the PR interval; time domains, including standard deviation (SD) of all normal R-R intervals (SDNN), mean of the SD of all normal R-R intervals (SDNNi), SD of the average of normal R-R intervals (SDANN), and percentage of R-R intervals at least 50 ms different from the previous interval (pNN50); and high-power frequency (HF) decreased. The LF/HF ratio also significantly increased. The SDNN, SDNNi, SDANN, pNN50, and HF levels significantly decreased and the LF/HF significantly increased in normal-weight and obese individuals only when the phone was near the apex of the heart in ring and vibration mode. All changes were more profound in obese students. CONCLUSION: Keeping the phone in a chest pocket reduced the HRV of normal-weight and obese medical students and exaggerated the effect of obesity on sympathetic activation.

Comparative adhesive and migratory properties of mesenchymal stem cells from different tissues.

BACKGROUND: Mesenchymal stem cells (MSC) are used in therapy, often by injection into the blood. OBJECTIVE: We aimed to compare the adhesive and migratory properties of MSC from umbilical cords (UCMSC), bone marrow (BMMSC) or trabecular bone (TBMSC), which might influence delivery to injured tissue. METHODS: MSC were perfused through glass capillaries coated with matrix proteins, collagen or fibronectin, or albumin. Adherent cells were counted microscopically and their spreading analysed over time. MSC migration through 8 µm pore filters coated with the same proteins was analysed. RESULTS: The number of MSC adhering to collagen was greater than fibronectin, decreased as wall shear rate increased from 17 to 70 s-1, and was in the order UCMSC>BMMSC>TBMSC. Conversely, spreading was more effective on fibronectin and was in the order BMMSC>TBMSC≥UCMSC. Migration was promoted by coating the lower surface of filters with either matrix protein, with UCMSC migrating more efficiently than BMMSC. CONCLUSIONS: MSC show origin-dependent variations in their efficiency of capture from flow and subsequent spreading or ability to migrate on matrix proteins. UCMSC showed most efficient capture from flow, which was followed by less spreading, but more rapid migration. These responses might be associated with more effective delivery from the circulation into damaged tissue.

A high-fat diet rich in corn oil induces cardiac fibrosis in rats by activating JAK2/STAT3 and subsequent activation of ANG II/TGF-1ß/Smad3 pathway: The role of ROS and IL-6 trans-signaling.

This study compared the effect of low-fat diet (LFD) and high-fat diet rich in corn oil (HFD-CO) on left ventricular (LV) fibrosis in rats and examined their effect of angiotensin II (ANG II), JAK/STAT, and TGF-1ß/smad3 pathways. As compared to LFD which didn't affect any of the measured parameters, HFD-CO-induced type 2 diabetes phenotype and increased LV collagen synthesis. Mechanistically, it increased LV levels of ROS, ANG II, ACE, IL-6, s-IL-6Rα, TGF-ß1, Smad-3, and activities of JAK1/2 and STAT1/3. AG490, a JAK2 inhibitor, partially ameliorated these effect while Losartan, an AT1 inhibitor completely abolished collagen synthesis. However, with both treatments, levels of ANG II, IL-6, and s-IL-6Rα, and activity of JAK1/STAT3 remained high, all of which were normalized by co-administration of NAC or IL-6 neutralizing antibody. In conclusion: HFD-CO enhances LV collage synthesis by activation of JAK1/STAT3/ANG II/TGF-1ß/smad3 pathway. PRACTICAL APPLICATIONS: We report that chronic consumption of a high-fat diet rich in corn oil (HFD-CO) induces diabetes mellitus phenotype 2 associated with left ventricular (LV) cardiac fibrosis in rats. The findings of this study show that HFD-CO, and through the increasing generation of ROS and IL-6 levels and shedding, could activate LV JAK1/2-STAT1/3  and  renin-angiotensin system (RAS) signaling pathways, thus creating a positive feedback between the two which ultimately leads to activation of TGF-1ß/Smad3 fibrotic pathway. Herein, we also report a beneficial effect of the antioxidant, NAC, or IL-6 neutralizing antibody in preventing such adverse effects of such HFD-CO. However, this presents a warning message to the current sudden increase in idiopathic cardiac disorders, especially with the big shift in our diets toward n-6 PUFA.

Mycotic aortic aneurysm due to brucellosis.

Brucellosis is a multisystem zoonotic disease. Mycotic aneurysm due to Brucella is rare and has no clear management approach. Here, we present two cases of mycotic aortic aneurysm due to Brucella. The first patient was treated with surgical resection of a symptomatic infrarenal abdominal aortic aneurysm combined with lifelong doxycycline and rifampicin. The second patient improved with conservative treatment including a 6-month course of antibiotics and regular clinical and radiologic monitoring. Through these cases, we hope to draw attention to this serious adverse effect of Brucella and the importance of management of its local arterial complications, especially in endemic areas.

Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease.

During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.