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Introduction: Pro-resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor-biased agonist endowed with pro-resolving and anti-inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID-19., Methods: C57BL/6j mice were infected intranasally with MHV-A59 or hK18-ACE2 mice with SARS-CoV-2. AP1189 (10 mg·kg -1 , BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS-CoV-2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo-controlled, double-blind trial that enrolled 54 hospitalized COVID-19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO 2  ≥ 93% in ambient air., Results: Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV-A59 or SARS-CoV-2 and decreased the release of CXCL10, TNF-α and IL-1β by human PBMCs. Hospitalized COVID-19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (P = 0.017)., Conclusion: Treatment with AP1189 was associated with less disease caused by beta-coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro-resolving molecule in the context of severe infection in humans., (© 2024 British Pharmacological Society.)

Intrauterine life is a critical period for the development of body fat and metabolic risk. This study investigated associations between birth weight and total and truncal body fat in adults. To do so, we analyzed data on 10,011 adults participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) who self-reported birth weight as < 2.5kg, 2.5-4.0kg, or > 4.0kg at baseline (2008-2010) and underwent bioimpedance in the next follow-up visit (2012-2014). Greater mean total and truncal fat mass were seen in those with high birth weight compared with adequate birth weight (p < 0.001) in both sexes (total fat: 25.2 vs. 23.1kg in men and 31.4 vs. 27.7kg in women, and truncal fat: 13.5 vs. 12.4kg in men and 15.9 vs. 14.2kg in women). U-shaped patterns were observed in restricted cubic-spline analyses in the subset of 5,212 individuals reporting exact birth weights, although statistically significant only for those with high birth weight. In the whole sample, in comparing high to adequate birth weight, the latter predicted having a large (> 85 percentile) total and truncal fat mass, respectively: OR = 1.76, 95%CI: 1.37-2.25 (men) and OR = 1.86, 95%CI: 1.42-2.44 (women); OR = 1.68, 95% CI: 1.31-2.16 (men) and OR = 1.73, 95%CI: 1.31-2.28 (women). However, low birth weight predicted having a large (> 85 percentile) % truncal fat only in women (OR = 1.40, 95%CI: 1.03-1.91). In conclusion, in these men and women born in a period in which fetal malnutrition was prevalent, birth weight showed complex, frequently non-linear associations with adult body fat, highlighting the need for interventions to prevent low and high birth weight during pregnancy.

Acute exercise increases the amount of circulating inflammatory cells and cytokines to maintain physiological homeostasis. However, it remains unclear how physical training regulates exercise-induced inflammation and performance. Here, we demonstrate that acute high intensity exercise promotes an inflammatory profile characterized by increased blood IL-6 levels, neutrophil migratory capacity, and leukocyte recruitment to skeletal muscle vessels. Moreover, we found that physical training amplified leukocyte-endothelial cell interaction induced by acute exercise in skeletal muscle vessels and diminished exercise-induced inflammation in skeletal muscle tissue. Furthermore, we verified that disruption of the gp-91 subunit of NADPH-oxidase inhibited exercise-induced leukocyte recruitment on skeletal muscle after training with enhanced exercise time until fatigue. In conclusion, the training was related to physical improvement and immune adaptations. Moreover, reactive oxygen species (ROS) could be related to mechanisms to limit aerobic performance and its absence decreases the inflammatory response elicited by exercise after training., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Barcellos, Gonçalves, Esteves de Oliveira, Guimarães, Queiroz-Junior, Resende, Russo, Coimbra, Silva, Teixeira, Rezende and Pinho.)

The neutrophil is an important cell in host defense against infections, acting as the first line of microorganism control. However, this cell exhibits dysregulated activity in sepsis and may contribute to the pathogenesis of the disease. This systematic review aimed to highlight the major scientific findings regarding neutrophil activity in sepsis reported in clinical and experimental research published in the last 10 years. The search was conducted in the Virtual Health Library of PAHO-WHO (BVS) and PubMed databases, and articles published between January 2007 and May 2017 in Portuguese, English, and Spanish were eligible. Article selection was carried out independently by two reviewers (CB and IB). A total of 233 articles were found, of which 87 were identified on PubMed and 146 on BVS. Eighty-two articles were duplicates. Of the remaining 151 articles, 19 met the inclusion criteria after title, abstract, and full-text analysis. Overall, research in clinical samples and animal models of sepsis showed reduced capacity of neutrophils to migrate and delayed apoptosis, but there was no consensus on the phagocytic activity of neutrophils in sepsis. Molecules, such as pentraxin 3 (PTX3), have been analyzed as potential diagnostic markers in sepsis but the diversity of soluble molecules detected in blood samples of sepsis patients did not enable further understanding of the correlation of these circulating molecules with neutrophil activity during sepsis. Optimal understanding of the function of neutrophils in sepsis remains a challenge that, if overcome, would eventually allow targeted therapeutic interventions in patients affected by this severe syndrome.

Graft-versus-host disease (GVHD) is the most serious complication limiting the clinical utility of allogeneic hematopoietic stem cell transplantation (HSCT), in which lymphocytes of donors (graft) are activated in response to the host antigen. This disease is associated with increased inflammatory response through the release of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species (ROS). In this study, we have evaluated the role of ROS in GVHD pathogenesis by treatment of recipient mice with apocynin (apo), an inhibitor of intracellular translocation of cytosolic components of NADPH oxidase complex. The pharmacological blockade of NADPH oxidase resulted in prolonged survival and reduced GVHD clinical score. This reduction in GVHD was associated with reduced levels of ROS and TBARS in target organs of GVHD in apocynin-treated mice at the onset of the mortality phase. These results correlated with reduced intestinal and liver injuries and decreased levels of proinflammatory cytokines and chemokines. Mechanistically, pharmacological blockade of the NADPH oxidase was associated with inhibition of recruitment and accumulation of leukocytes in the target organs. Additionally, the chimerism remained unaffected after treatment with apocynin. Our study demonstrates that ROS plays an important role in mediating GVHD, suggesting that strategies aimed at blocking ROS production may be useful as an adjuvant therapy in patients subjected to bone marrow transplantation., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Barbara Maximino Rezende et al.)

Objective: To evaluate the accuracy of IL-3 to predict the outcome of septic patients., Methods: Prospective cohort study with adult patients in an intensive care unit with sepsis or septic shock diagnosed within the previous 48 hours. Circulating IL-3 levels were measured upon inclusion (day 1) and on days 3 and 7. The primary outcome was hospital mortality., Results: One hundred and twenty patients were included. Serum levels of IL-3 on day 1 were significantly higher among patients who died than among patients who survived the hospital stay (91.2pg/mL versus 36pg/mL, p = 0.024). In a Cox survival model considering the IL-3 levels at inclusion, age and sequential SOFA, IL-3 values remained independently associated with mortality (HR 1.032; 95%CI 1.010 - 1.055; p = 0.005). An receiver operating characteristic curve was built to further investigate the accuracy of IL-3, with an area under the curve of 0.62 (95%CI 0.51 - 0.73; p = 0.024) for hospital mortality. A cutoff initial IL-3 value above 127.5pg/mL was associated with hospital mortality (OR 2.97; 95%CI: 1.27 - 6.97; p = 0.0019) but with a low performance (82% for specificity, 39% for sensibility, 53% for the positive predictive value, 72% for the negative predictive value, 0.73 for the negative likelihood and 2.16 for the positive likelihood ratio)., Conclusion: Higher levels of IL-3 are shown to be independently associated with hospital mortality in septic patients but with poor clinical performance.

Leukotriene B 4 (LTB 4 ), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the participation of the 5-LO/LTB 4 axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO-deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB 4 inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD. Mice receiving 5-LO-deficient cell transplant or zileuton treatment had prolonged survival, reduced GVHD clinical scores, reduced intestinal and liver injury, and decreased levels of serum and hepatic LTB 4 These results were associated with inhibition of leukocyte recruitment and decreased production of cytokines and chemokines. Treatment with CP-105,696 achieved similar effects. The chimerism or the beneficial graft-versus-leukemia response remained unaffected. Our data provide evidence that the 5-LO/LTB 4 axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment., (© 2017 Rezende et al.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Conflict of Interest: None.

Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2-4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2-4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

Objective: Bleeding of esophageal varices is the main cause of morbidity and mortality in children with portal hypertension. It is important to understand the factors related with a bleeding episode to evaluate more effective primary prophylaxis. The present study aims to describe the endoscopic and laboratory findings associated with upper gastrointestinal bleeding (UGIB) secondary to esophageal varices., Method: A cross-sectional study with 103 children and adolescents with cirrhosis, divided into a group that had experienced an episode of upper UGIB (35 patients) and a group without a history of UGIB (68 patients), was carried out. The esophageal and gastric varices were classified, and the portal hypertensive gastropathy, laboratory findings, and Child-Pugh classification were measured., Results: Factors observed in univariate analysis to be associated with UGIB were the presence of esophageal varices of medium caliber or larger, portal hypertensive gastropathy, presence of red spots on esophageal varices, Child-Pugh class B or C, and hypoalbuminemia (P < 0.05). After multivariate logistic regression analysis, the significant factors were the presence of red spots on esophageal varices and the presence of gastric varices. When separated the autoimmune hepatitis, nonbiliary atresia patients (all patients except the patients with biliary atresia), and biliary atresia groups the findings in the univariate analysis were the presence of esophageal varices of medium or larger caliber, presence of red spots on varices, and presence of gastric varices in the autoimmune hepatitis patients and nonbiliary atresia patients and presence of red spots on esophageal varices, presence of gastric varices, and Child-Pugh classification B or C in biliary atresia group (P < 0.05). After multivariate logistic regression analysis, no statistical significance was found for any factor analyzed in any groups., Conclusions: The presence of gastric varices and red spots on esophageal varices were related to episodes of UGIB secondary to rupture of esophageal varices. When these findings are observed, indications for endoscopic primary prophylaxis should be evaluated. More studies are, however, necessary to better understand this problem.

Background: The efficacy of nonselective β-blocker and endoscopic procedures, such as endoscopic variceal ligation, as primary prophylaxis of variceal hemorrhage in cirrhotic adults was demonstrated by numerous controlled trials, but in pediatric population, few are the number of studies., Objective: The objective of this study is to evaluate the primary prophylaxis with β-blocker in cirrhotic children and adolescents with portal hypertension., Methods: This is a cohort study encompassing 26 cirrhotic patients. β-blocker prophylaxis was performed with propranolol. When contraindicated the use of β-blocker, or if side effects presents, the patients were referred to endoscopic therapy with band ligation. Patients were evaluated by endoscopy, and those who had varicose veins of medium and large caliber or reddish spots, regardless of the caliber of varices, received primary prophylaxis., Results: Of the 26 patients evaluated, 9 (34.6%) had contraindications to the use of propranolol and were referred for endoscopic prophylaxis. Six (35.3%) of the 17 patients who received β-blocker (propranolol), had bled after a median follow-up time of 1.9 years. β-blockage dosage varied from 1 mg/kg/day to 3.1 mg/kg/day and seven (41.2%) patients had the propranolol suspended due to fail of the β-blockage or adverse effects, such as drowsiness, bronchospasm and hypotension. Patients who received endoscopic prophylaxis (elastic bandage) had no bleeding during the follow-up period., Conclusion: All of the patients that had upper gastroinstestinal bleeding in this study were under propranolol prophylaxis. The use of propranolol showed a high number of contraindications and side effects, requiring referral to endoscopic prophylaxis. The endoscopic prophylaxis was effective in reducing episodes of bleeding.

Objective: To analyze the correlation between quality of life, symptoms, and cognition assessed by the interview-based Schizophrenia Cognition Rating Scale (SCoRS)., Methods: Seventy-nine outpatients diagnosed with schizophrenia were evaluated with the Quality of Life Scale - Brazilian version (QLS-BR), the SCoRS, and symptoms scales (Positive and Negative Syndrome Scale [PANSS]). After determining the potential explanatory variables using Spearman's correlation and Student's t test results, we ran simple, multivariate, and decision-tree regression analyses to assess the impact of SCoRS and PANSS ratings on mean overall quality of life., Results: Cognitive deficits and negative symptoms were the best predictors of quality of life. A low degree of negative symptoms (PANSS negative < 11) was a strong predictor of better quality of life (QLS ∼ 75), regardless of SCoRS rating. Among participants with more severe negative symptoms, elevated cognitive impairment (interviewer SCoRS ∼ 44) was a predictor of worse quality of life (QLS ∼ 44)., Conclusions: Cognitive impairment determined by interview-based assessment seems to be a strong predictor of quality of life in subjects with severe negative symptoms. These results support the usefulness of SCoRS for cognitive assessment that is relevant to the everyday life of patients with schizophrenia.

Introduction: The Sino-Nasal Outcome Test 22 (SNOT-22) is an important tool in assessing the quality of life (QoL) of patients with chronic rhinosinusitis with a validated version in Brazil. The eosinophilic nasal polyposis (ENP) represents most of the cases of nasal polyposis (85-90%) and belongs to the group of chronic rhinosinusitis. It is a chronic inflammatory disease that impacts the QoL of patients, not only causing localized symptoms, but also resulting in a general malaise. The standard treatments (corticosteroids and nasal endoscopic surgery) lead to partial control of symptoms, but relapses are frequent. Macrolide acting as an immunomodulator is a promising tool for more effective control of this disease. Studies are still lacking to assess the real impact on the QoL in patients treated with macrolides., Objective: To evaluate the improvement of QL, evaluated using SNOT-22, in patients with PNSE treated with immunomodulatory dose azithromycin., Methods: This is a paired experimental study in patients with ENP. Comparison of pre-treatment and post-treatment with azithromycin was performed. Patients completed the SNOT-22 questionnaire before the start of treatment and returned for evaluation after eight weeks of treatment. Azithromycin was prescribed at a dose of 500 mg, orally, three times a week, for 8 weeks., Results: SNOT-22 score decreased 20.3 points on average. There was a significant decrease in the SNOT-22 (difference greater than 14 points) in 19 patients (57.6%). There was no significant difference in improvement in SNOT in subgroups with or without asthma/aspirin intolerance., Conclusion: Azithromycin resulted in significant improvement of QoL, assessed by SNOT-22, in the studied population., (Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: Auditory screening in newborns allows for detection of hearing problems early in life. However, middle ear diseases can make the diagnosis more difficult., Objective: To evaluate the power reflectance test as an indicator of the middle ear disease and to compare it to tympanometry., Methods: Case study evaluating 105 newborns and infants who participated in the audiology screening in 2013. The following exams were performed: transient otoacoustic emissions, power reflectance, and tympanometry., Results: In the optoacoustic emission evaluation, approximately 95% of the subjects passed the test. The specificity of power reflectance in all frequencies studied ranged from 75.3% to 95.9%, and that of tympanometry at 1000Hz ranged from 83% to 87.2%; there was agreement among these exams., Conclusion: The outcome of power reflectance tests at 2000Hz and 3000Hz showed a correlation with tympanometry and otoacoustic emissions, and these were the most appropriate frequencies to determine middle ear disease through power reflectance measurement. It was also observed that values of power reflectance above reference levels suggested the presence of fluid in the middle ear, and thus a conductive hearing loss., (Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Graft versus host disease (GVHD) is an immunological disorder triggered by bone marrow transplantation that affects several organs, including the gastrointestinal tract and liver. Fullerenes and their soluble forms, fullerols, are nanocomposites with a closed symmetrical structure with anti-inflammatory and anti-oxidant properties. The present study evaluated the effects of treatment with the fullerol (C60(OH)18-20) in the development and pathogenesis of GVHD in a murine model. Mice with experimental GVHD that were treated with the fullerol showed reduced clinical signs of disease and mortality compared with untreated mice. Treatment with the fullerol decreased the hepatic damage associated with reduced hepatic levels of reactive oxygen species, pro-inflammatory cytokines and chemokines (IFN-γ TNF-α, CCL2, CCL3 and CCL5) and reduced leukocyte accumulation. The amelioration of GVHD after treatment with the fullerol was also associated with reduced intestinal lesions and consequent bacterial translocation to the blood, liver and peritoneal cavity. Moreover, the fullerol treatment alleviated the GVHD while preserving effects of the graft against a leukemia cell line (GFP+P815). In summary, the fullerol was effective in reducing the GVHD inflammatory response in mice and may suggest novel ways to treat this disease.

Objective: To assess the validity and reliability of the Brazilian Portuguese version of the Brief Assessment of Cognition in Schizophrenia by examining its temporal stability, internal consistency, and discriminant and convergent validity., Methods: The Brief Assessment of Cognition in Schizophrenia was administered to 116 stable patients with schizophrenia and 58 matched control subjects. To assess concurrent validity, a subset of patients underwent a traditional neuropsychological assessment., Results: The patients with schizophrenia performed significantly worse than the controls (p<0.001) on all subtests of the Brief Assessment of Cognition in Schizophrenia and on the total score, which attests to the discriminant validity of the test. The global score of the Brief Assessment of Cognition in Schizophrenia was significantly correlated with all of the subtests and with the global score for the standard battery. The Brief Assessment of Cognition in Schizophrenia also had good test-retest reliability (rho>0.8). The internal consistency of the Brief Assessment of Cognition in Schizophrenia was high (Cronbach's α  ϝ 0.874)., Conclusion: The Brazilian Portuguese version of the Brief Assessment of Cognition in Schizophrenia exhibits good reliability and discriminant and concurrent validity and is a promising tool for easily assessing cognitive impairment in schizophrenia and for comparing the performance of Brazilian patients with that of patients from other countries.

Lithothamnion muelleri (Hapalidiaceae) is a marine red alga, which is a member of a group of algae with anti-inflammatory, antitumor, and immunomodulatory properties. The present study evaluated the effects of treatment with Lithothamnion muelleri extract (LM) in a model of acute graft-versus-host disease (GVHD), using a model of adoptive splenocyte transfer from C57BL/6 donors into B6D2F1 recipient mice. Mice treated with LM showed reduced clinical signs of disease and mortality when compared with untreated mice. LM-treated mice had reduced tissue injury, less bacterial translocation, and decreased levels of proinflammatory cytokines and chemokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5)). The polysaccharide-rich fraction derived from LM could inhibit leukocyte rolling and adhesion in intestinal venules, as assessed by intravital microscopy. LM treatment did not impair the beneficial effects of graft-versus-leukaemia (GVL). Altogether, our studies suggest that treatment with Lithothamnion muelleri has a potential therapeutic application in GVHD treatment.

Introduction: Interview-based scales can be used as coprimary measures to complement the assessment of cognitive impairment in schizophrenia. One major question that arises from the use of such tools is how specific they are in relation to other psychopathological domains. We analyse the specificity of the Positive and Negative Syndrome Scale (PANSS) negative subscale and the Schizophrenia Cognition Rating Scale (SCoRS)., Methods: We performed a principal component analysis (PCA) of PANSS negative subscale, rated by the interviewer, and SCoRS ratings from three different sources (patient, informant, and interviewer) in 101 patients with schizophrenia. Additionally, we correlated mean SCoRS ratings to PANSS negative subscale items to determine whether any PANSS item is particularly related to cognition., Results: The PCA showed that the two first components, which explained approximately 40% of the total variance of the scales, represent the SCoRS ratings and the PANSS negative subscale ratings, respectively. The mean interviewer SCoRS was significantly correlated with the PANSS negative Item 5 (difficulty in abstract thinking) and with the mean PANSS negative subscale. The latter correlation was no longer significant when "difficulty in abstract thinking" was eliminated from PANSS negative subscale., Conclusions: In general, SCoRS and PANSS negative subscale scores address different constructs; however, the PANSS negative item "difficulty in abstract thinking" seems to address a cognitive dimension.

PAF is a potent lipid mediator involved in several manifestations of acute inflammation, including leukocyte influx, leukocyte interaction with endothelium, and production of inflammatory cytokines. The present study evaluated the relevance of PAFR for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PAFR(-/-) C57BL/6J to B6D2F1 mice. Mice, which received PAFR(-/-) splenocytes or treatment with the PAFR antagonist, showed reduced clinical signs of disease and no mortality. In GVHD mice receiving PAFR(-/-) splenocytes, there was deceased bacterial translocation and tissue injury. Furthermore, production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and accumulation of CD8(+) cells in intestine and liver were reduced in mice transplanted with the PAFR(-/-) splenocyte. Mechanistically, an absence or pharmacological blockade of PAFR was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PAFR(-/-) leukocytes were transferred into WT mice. In conclusion, PAFR on donor leukocytes plays a critical role in GVHD by mediating leukocyte influx and cytokine production in target tissues. PAFR antagonist may potentially be useful in the treatment of GVHD in bone marrow-transplanted patients.

CCL3 is a protein of the CC chemokine family known to be important for T cell recruitment in inflammatory diseases. The aim of the current study was to evaluate the effects and putative mechanism of action of evasin-1, a novel CCL3-binding protein, in the pathogenesis of acute graft-versus-host disease (GVHD). GVHD was induced by the transplantation of splenocytes from C57BL/6J to B6D2F1 mice. Treatment of recipient mice with evasin-1 prevented mortality associated with GVHD. This was correlated with reduced weight loss and clinical disease severity. Analysis of the small intestine showed that evasin-1 treatment reduced the histopathological score and decreased levels of IFN-gamma and CCL5. Mechanistically, evasin-1 treatment reduced the number of CD4(+) and CD8(+) T cells infiltrating the small intestine, as assessed by immunohistochemistry, and the adhesion of leukocytes to intestinal venules of recipient mice, as assessed by intravital microscopy. Evasin-1 was also able to decrease liver damage, as seen by reduction of inflammatory infiltrate and IFN-gamma levels. Treatment with evasin-1 did not interfere with graft-versus-leukemia. Altogether, our studies demonstrate that CCL3 plays a major role in mediating GVHD, but not graft-versus-leukemia in mice and suggest that blockade of CCL3 with evasin-1 has potential therapeutic application in patients undergoing bone marrow transplantation.