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ABSTRACT Objective: Tofacitinib, an oral Janus kinase inhibitor, has been tested against a placebo in 289 patients with COVID-19 pneumonia. We analyzed the data from the tofacitinib- and placebo-treated patient cohorts to evaluate the laboratory profiles between baseline and day 7. Methods: We performed post hoc analyses on the following laboratory tests over time during the first 7 days after randomization: hemoglobin, leukocytes, neutrophils, lymphocytes, platelets, alanine aminotransferase, and aspartate aminotransferase. Results: Through the first 7 days after randomization, the levels of hemoglobin, white blood cells, neutrophils, and platelet counts were not significantly different between patients treated with tofacitinib or a placebo (all p>0.05). Non-significant differences were observed in aspartate aminotransferase levels over time between treatment groups, whereas alanine aminotransferase levels (U/L) were higher among tofacitinib-treated patients compared to placebo-treated patients (mean ratio, 1.30 [95% confidence interval (95%CI) = 1.14–1.48; p

Abstract Background Recent studies have presented inflammatory features on keratoconus (KC) and many inflammatory markers are described in the tears of patients with this disease. The KC pathogenesis is still unknown just like the correlation with inflammatory patterns. However, environmental and genetic issues may be part of the progress of KC. In addition, some systemic features, such as allergy and obesity, seem to be related to the progression of KC. Our purpose was to evaluate the neuropeptides vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), chemokines ligand 2 (CCL-2) and 5 (CCL-5), and interleukins 6 (IL-6) and 8 (IL-8) on corneal epithelial cells and blood of patients with KC and in healthy controls. In addition, the neutrophil-to-lymphocyte ratio (NLR) was evaluated to predict inflammation. Methods This including prospective observational study included 32 KC patients who underwent corneal crosslinking (CXL) and 32 control patients who underwent photorefractive keratectomy (PRK). Patients’ corneal epithelial cells were removed surgically, and blood (buffy coat) was analyzed. Samples in triplicate were evaluated on rt-PCR for neuropeptides (VIP e NPY), interleukins (IL-6 e IL-8), and chemokines (CCL-2 and CCL-5). Results Our study showed statistically higher CCL-5 and IL-8 on corneal epithelial cells in patients with KC. Blood cells were statistically higher in VIP and NPY in the KC group. Interleukin-8 on blood cells was statistically significant in KC’S group; for CCL-2 and CCL-5 they were statistically lower in patients with KC compared with controls. NLR showed no difference between the groups. Conclusions Our data support the findings of other studies that suggested altering KC status, such as inflammatory corneal disease. The presence of IL-8 in the cornea and blood samples of KC’s group suggested systemic disease with a possible local or repercussion action. Further studies are warranted to elucidate KC pathogenesis and its correlation to systemic disease.

Abstract Objectives: We assessed the effectiveness of heterologous vaccination strategy in immunocompromised individuals regarding COVID-19 outcomes, comparing it to homologous approaches. Design: Systematic literature review/meta-analysis. Methods: We searched PubMed, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from January 1, 2020 to September 29, 2023. We included studies that evaluated the heterologous vaccination strategy on immunocompromised individuals through outcomes related to COVID-19 (levels of anti-SARS-CoV-2 spike protein IgG, neutralizing antibodies, symptomatic COVID-19 infection, hospitalization, and death) in comparison to homologous schemes. We also used random-effect models to produce pooled odds ratio estimates. Heterogeneity was investigated with I2 estimation. Results: Eighteen studies met the inclusion criteria for this systematic review. Fourteen of them provided quantitative data for inclusion in the meta-analysis on vaccine response, being four of them also included in the vaccine effectiveness meta-analysis. The vaccination strategies (heterologous vs homologous) showed no difference in the odds of developing anti-SARS-CoV-2 spike protein IgG (odds ratio 1.12 [95% Cl: 0.73–1.72]). Heterologous schemes also showed no difference in the production of neutralizing antibodies (odds ratio 1.48 [95% Cl: 0.72–3.05]) nor vaccine effectiveness in comparison to homologous schemes (odds ratio 1.52 [95% CI: 0.66–3.53]). Conclusions: Alternative heterologous COVID-19 vaccinations have shown equivalent antibody response rates and vaccine effectiveness to homologous schemes, potentially aiding global disparity of vaccine distribution.

Abstract Objective: We performed a systematic literature review and meta-analysis on the effectiveness of coronavirus disease 2019 (COVID-19) vaccination against post-COVID conditions (long COVID) in the pediatric population. Design: Systematic literature review/meta-analysis. Methods: We searched PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 1, 2019, to August 14, 2023, for studies evaluating the COVID-19 vaccine effectiveness against post-COVID conditions among vaccinated individuals < 21 years old who received at least 1 dose of COVID-19 vaccine. A post-COVID condition was defined as any symptom that was present 4 or more weeks after COVID-19 infection. We calculated the pooled diagnostic odds ratio (DOR) (95% CI) for post-COVID conditions between vaccinated and unvaccinated individuals. Results: Eight studies with 23,995 individuals evaluated the effect of vaccination on post-COVID conditions, of which 5 observational studies were included in the meta-analysis. The prevalence of children who did not receive COVID-19 vaccines ranged from 65% to 97%. The pooled prevalence of post-COVID conditions was 21.3% among those unvaccinated and 20.3% among those vaccinated at least once. The pooled DOR for post-COVID conditions among individuals vaccinated with at least 1 dose and those vaccinated with 2 doses were 1.07 (95% CI, 0.77–1.49) and 0.82 (95% CI, 0.63–1.08), respectively. Conclusions: A significant proportion of children and adolescents were unvaccinated, and the prevalence of post-COVID conditions was higher than reported in adults. While vaccination did not appear protective, conclusions were limited by the lack of randomized trials and selection bias inherent in observational studies.

ABSTRACT The Scientists of Tomorrow/ Cientistas do Amanhã project is an immersive science training program developed by the Program of Post-Graduation in Health Sciences at Hospital Israelita Albert Einstein. This program was conducted in partnership with Volunteering and Escola Municipal de Ensino Fundamental Professor Paulo Freire in Paraisópolis, São Paulo, Brazil. The Scientists of Tomorrow Program comprised a short training period conducted in May 2022 involving 37 students, and a long training period from August to December 2022, which included 15 students. It aimed to popularize science through practical activities; transfer knowledge to young students; sensitize and guide them to pursue academic-scientific careers; reduce stereotypes about scientific work and scientists; and help students understand the social, political, and ethical roles of science within society. All activities were led by postgraduate students and professors from our postgraduate program, physicians, nurses, physiotherapists, biomedicals, and veterinarians from Hospital Israelita Albert Einstein, as well as medical students from Faculdade Israelita de Ciências da Saúde Albert Einstein . Activities in the short training included lectures on cinema and science, strategies to combat fake news, non-violent communication, innovation, design-thinking framework, and developing a scientific project. During the long training period, discussions were focused on nanotechnology, animal research, big data, bioinformatics, meditation, blood and bone marrow donation, telemedicine, sex and sexually-transmitted infections, rehabilitation, career opportunities, and scientific integrity. In addition, practical activities were further expanded using optical and confocal microscopy, cytometry, and basic concepts regarding the structure and function of living cells. The program also included the launching of the open-air outreach Education E-natureza activity, which turned students into ambassadors of nature. In conclusion, the Scientists of Tomorrow Program was innovative and enabled young students to learn that science is a collective activity that can enhance public health.

Abstract Objective: We performed a systematic literature review and meta-analysis on the effectiveness of coronavirus disease 2019 (COVID-19) vaccination against post-COVID conditions (long COVID) among fully vaccinated individuals. Design: Systematic literature review/meta-analysis. Methods: We searched PubMed, Cumulative Index to Nursing and Allied Health, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 1, 2019, to June 2, 2023, for studies evaluating the COVID-19 vaccine effectiveness (VE) against post-COVID conditions among fully vaccinated individuals who received two doses of COVID-19 vaccine. A post-COVID condition was defined as any symptom that was present four or more weeks after COVID-19 infection. We calculated the pooled diagnostic odds ratio (DOR) (95% confidence interval) for post-COVID conditions between fully vaccinated and unvaccinated individuals. Vaccine effectiveness was estimated as 100% x (1-DOR). Results: Thirty-two studies with 775,931 individuals evaluated the effect of vaccination on post-COVID conditions, of which, twenty-four studies were included in the meta-analysis. The pooled DOR for post-COVID conditions among fully vaccinated individuals was 0.680 (95% CI: 0.523–0.885) with an estimated VE of 32.0% (11.5%–47.7%). Vaccine effectiveness was 36.9% (23.1%–48.2%) among those who received two doses of COVID-19 vaccine before COVID-19 infection and 68.7% (64.7%–72.2%) among those who received three doses before COVID-19 infection. The stratified analysis demonstrated no protection against post-COVID conditions among those who received COVID-19 vaccination after COVID-19 infection. Conclusions: Receiving a complete COVID-19 vaccination prior to contracting the virus resulted in a significant reduction in post-COVID conditions throughout the study period, including during the Omicron era. Vaccine effectiveness demonstrated an increase when supplementary doses were administered.

Abstract Objective: To compare the long-term vaccine effectiveness between those receiving viral vector [Oxford-AstraZeneca (ChAdOx1)] or inactivated viral (CoronaVac) primary series (2 doses) and those who received an mRNA booster (Pfizer/BioNTech) (the third dose) among healthcare workers (HCWs). Methods: We conducted a retrospective cohort study among HCWs (aged ≥18 years) in Brazil from January 2021 to July 2022. To assess the variation in the effectiveness of booster dose over time, we estimated the effectiveness rate by taking the log risk ratio as a function of time. Results: Of 14,532 HCWs, coronavirus disease 2019 (COVID-19) was confirmed in 56.3% of HCWs receiving 2 doses of CoronaVac vaccine versus 23.2% of HCWs receiving 2 doses of CoronaVac vaccine with mRNA booster (P < .001), and 37.1% of HCWs receiving 2 doses of ChAdOx1 vaccine versus 22.7% among HCWs receiving 2 doses of ChAdOx1 vaccine with mRNA booster (P < .001). The highest vaccine effectiveness with mRNA booster was observed 30 days after vaccination: 91% for the CoronaVac vaccine group and 97% for the ChAdOx1 vaccine group. Vacine effectiveness declined to 55% and 67%, respectively, at 180 days. Of 430 samples screened for mutations, 49.5% were SARS-CoV-2 delta variants and 34.2% were SARS-CoV-2 omicron variants. Conclusions: Heterologous COVID-19 vaccines were effective for up to 180 days in preventing COVID-19 in the SARS-CoV-2 delta and omicron variant eras, which suggests the need for a second booster.

Background: Telemedicine provides accurate diagnoses for skin disorders and has gained emphasis. It may be used for the triage and management of common skin diseases in primary care, improving patients’ access and reducing time to treatment. Objective: To evaluate the proportion of atopic dermatitis patients who could be managed with the support of telemedicine and its accuracy. Second, we aimed to assess the frequency of atopic dermatitis, demographics, clinical features, and therapies dispensed in relation to the disease. Methods: Retrospective study in a population of 30,976 individuals, assisted by telemedicine. We assessed patients with the diagnosis of atopic dermatitis and evaluated the proportion of cases referred to biopsy, in-person dermatologists, or to be managed by primary care; the treatments suggested; and telemedicine accuracy to diagnose atopic dermatitis. Results: Atopic dermatitis was diagnosed in 1648 patients (5.3%), the sixth most common dermatosis, with 2058 lesions (3.7%) analyzed. Primary care physicians were able to manage 72% of the atopic dermatitis patients, whereas 28% of them were referred to in-person dermatologists. Accuracy for atopic dermatitis diagnosis was 84.4%. Conclusion: Telemedicine was an accurate method and helped primary care physicians to treat 72% of the atopic dermatitis lesions, thereby optimizing the availability of in-person appointments with dermatologists for more severe cases.

Abstract Background: Although multiple studies revealed high vaccine effectiveness of coronavirus disease 2019 (COVID-19) vaccines within 3 months after the completion of vaccines, long-term vaccine effectiveness has not been well established, especially after the δ (delta) variant became prominent. We performed a systematic literature review and meta-analysis of long-term vaccine effectiveness. Methods: We searched PubMed, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 2019 to November 15, 2021, for studies evaluating the long-term vaccine effectiveness against laboratory-confirmed COVID-19 or COVID-19 hospitalization among individuals who received 2 doses of Pfizer/BioNTech, Moderna, or AstraZeneca vaccines, or 1 dose of the Janssen vaccine. Long-term was defined as >5 months after the last dose. We calculated the pooled diagnostic odds ratio (DOR) with 95% confidence interval for COVID-19 between vaccinated and unvaccinated individuals. Vaccine effectiveness was estimated as 100% × (1 − DOR). Results: In total, 16 studies including 17,939,172 individuals evaluated long-term vaccine effectiveness and were included in the meta-analysis. The pooled DOR for COVID-19 was 0.158 (95% CI: 0.157-0.160) with an estimated vaccine effectiveness of 84.2% (95% CI, 84.0- 84.3%). Estimated vaccine effectiveness against COVID-19 hospitalization was 88.7% (95% CI, 55.8%–97.1%). Vaccine effectiveness against COVID-19 during the δ variant period was 61.2% (95% CI, 59.0%–63.3%). Conclusions: COVID-19 vaccines are effective in preventing COVID-19 and COVID-19 hospitalization across a long-term period for the circulating variants during the study period. More observational studies are needed to evaluate the vaccine effectiveness of third dose of a COVID-19 vaccine, the vaccine effectiveness of mixing COVID-19 vaccines, COVID-19 breakthrough infection, and vaccine effectiveness against newly emerging variants.

Abstract Background: Although multiple studies have revealed that coronavirus disease 2019 (COVID-19) vaccines can reduce COVID-19–related outcomes, little is known about their impact on post–COVID-19 conditions. We performed a systematic literature review and meta-analysis on the effectiveness of COVID-19 vaccination against post–COVID-19 conditions (ie, long COVID). Methods: We searched PubMed, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 1, 2019, to April 27, 2022, for studies evaluating COVID-19 vaccine effectiveness against post–COVID-19 conditions among individuals who received at least 1 dose of Pfizer/BioNTech, Moderna, AstraZeneca, or Janssen vaccine. A post–COVID-19 condition was defined as any symptom that was present 3 or more weeks after having COVID-19. Editorials, commentaries, reviews, study protocols, and studies in the pediatric population were excluded. We calculated the pooled diagnostic odds ratios (DORs) for post–COVID-19 conditions between vaccinated and unvaccinated individuals. Vaccine effectiveness was estimated as 100% × (1 − DOR). Results: In total, 10 studies with 1,600,830 individuals evaluated the effect of vaccination on post–COVID-19 conditions, of which 6 studies were included in the meta-analysis. The pooled DOR for post–COVID-19 conditions among individuals vaccinated with at least 1 dose was 0.708 (95% confidence interval (CI), 0.692–0.725) with an estimated vaccine effectiveness of 29.2% (95% CI, 27.5%–30.8%). The vaccine effectiveness was 35.3% (95% CI, 32.3%–38.1%) among those who received the COVID-19 vaccine before having COVID-19, and 27.4% (95% CI, 25.4%–29.3%) among those who received it after having COVID-19. Conclusions: COVID-19 vaccination both before and after having COVID-19 significantly decreased post–COVID-19 conditions for the circulating variants during the study period although vaccine effectiveness was low.

Crohn’s disease (CD) is a chronic inflammatory disease with a complex interface of broad factors. There are two main treatments for Chron’s disease: biological therapy and nonbiological therapy. Biological agent therapy (e.g., anti-TNF) is the most frequently prescribed treatment; however, it is not universally accessible. In fact, in Brazil, many patients are only given the option of receiving nonbiological therapy. This approach prolongs the subsequent clinical relapse; however, this procedure could be implicated in the immune response and enhance disease severity. Our purpose was to assess the effects of different treatments on CD4+ T cells in a cohort of patients with Crohn’s disease compared with healthy individuals. To examine the immune status in a Brazilian cohort, we analyzed CD4+ T cells, activation status, cytokine production, and Treg cells in blood of Crohn’s patients. Patients that underwent biological therapy can recover the percentage of CD4+CD73+ T cells, decrease the CD4+ T cell activation/effector functions, and maintain the peripheral percentage of regulatory T cells. These results show that anti-TNF agents can improve CD4+ T cell subsets, thereby inducing Crohn’s patients to relapse and remission rates.

ABSTRACT Follicular helper T lymphocytes are a subpopulation of CD4+ T lymphocytes initially identified in germinal centers of follicles found in secondary lymphoid organs. The primary function of follicular helper T lymphocytes is to help B lymphocytes’ antibody production. Changing of antibody class and affinity, B cell differentiation and memory generation depend on cooperation between follicular helper T lymphocytes and B cells. In blood, follicular helper T lymphocytes are called circulating follicular helper T lymphocytes. They are considered to have specificities similar to those developed in the secondary lymphoid organs. The phenotype of human follicular helper T lymphocytes is given by simultaneous expression of the markers CXCR5, Bcl-6, CD40L, PD-1, and ICOS. In germinal centers, follicular helper T lymphocytes synthesize interleukin 21 as predominant cytokine. In blood, subpopulations of circulating follicular helper T lymphocytes can be recognized, with different expressions of the classical follicular helper T lymphocytes markers and, in addition, can express other markers such as CXCR3 and CCR6. Presently, there is great interest in follicular helper T lymphocytes and circulating follicular helper T lymphocytes in vaccination studies as indicators of immunization efficacy. In addition, follicular helper T lymphocytes are investigated as possible markers of activity in many diseases and potential therapeutic intervention. This short review describes aspects of immunobiology and quantification of follicular helper T lymphocytes and circulating follicular helper T lymphocytes, and presents a few examples of related findings in systemic lupus erythematosus, rheumatoid arthritis, HIV infection and vaccination.

Abstract Objective: Healthcare workers (HCWs) are at risk of COVID-19 due to high levels of SARS-CoV-2 exposure. Thus, effective vaccines are needed. We performed a systematic literature review and meta-analysis on COVID-19 short-term vaccine effectiveness among HCWs. Methods: We searched PubMed, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 2019 to June 11, 2021, for studies evaluating vaccine effectiveness against symptomatic COVID-19 among HCWs. To meta-analyze the extracted data, we calculated the pooled diagnostic odds ratio (DOR) for COVID-19 between vaccinated and unvaccinated HCWs. Vaccine effectiveness was estimated as 100% × (1 − DOR). We also performed a stratified analysis for vaccine effectiveness by vaccination status: 1 dose and 2 doses of the vaccine. Results: We included 13 studies, including 173,742 HCWs evaluated for vaccine effectiveness in the meta-analysis. The vast majority (99.9%) of HCWs were vaccinated with the Pfizer/BioNTech COVID-19 mRNA vaccine. The pooled DOR for symptomatic COVID-19 among vaccinated HCWs was 0.072 (95% confidence interval [CI], 0.028–0.184) with an estimated vaccine effectiveness of 92.8% (95% CI, 81.6%–97.2%). In stratified analyses, the estimated vaccine effectiveness against symptomatic COVID-19 among HCWs who had received 1 dose of vaccine was 82.1% (95% CI, 46.1%–94.1%) and the vaccine effectiveness among HCWs who had received 2 doses was 93.5% (95% CI, 82.5%–97.6%). Conclusions: The COVID-19 mRNA vaccines are highly effective against symptomatic COVID-19, even with 1 dose. More observational studies are needed to evaluate the vaccine effectiveness of other COVID-19 vaccines, COVID-19 breakthrough after vaccination, and vaccine efficacy against new variants.

ABSTRACT Objective This study describes epidemiological and clinical features of patients with confirmed infection by SARS-CoV-2 diagnosed and treated at Hospital Israelita Albert Einstein , which admitted the first patients with this condition in Brazil. Methods In this retrospective, single-center study, we included all laboratory confirmed COVID-19 cases at Hospital Israelita Albert Einstein , São Paulo, Brazil, from February until March 2020. Demographic, clinical, laboratory and radiological data were analyzed. Results A total of 510 patients with a confirmed diagnosis of COVID-19 were included in this study. Most patients were male (56.9%) with a mean age of 40 years. A history of a close contact with a positive/suspected case was reported by 61.1% of patients and 34.4% had a history of recent international travel. The most common symptoms upon presentation were fever (67.5%), nasal congestion (42.4%), cough (41.6%) and myalgia/arthralgia (36.3%). Chest computed tomography was performed in 78 (15.3%) patients, and 93.6% of those showed abnormal results. Hospitalization was required for 72 (14%) patients and 20 (27.8%) were admitted to the Intensive Care Unit. Regarding clinical treatment, the most often used medicines were intravenous antibiotics (84.7%), chloroquine (45.8%) and oseltamivir (31.9%). Invasive mechanical ventilation was required by 65% of Intensive Care Unit patients. The mean length of stay was 9 days for all patients (22 and 7 days for patients requiring or not intensive care, respectively). Only one patient (1.38%) died during follow-up. Conclusion These results may be relevant for Brazil and other countries with similar characteristics, which are starting to deal with this pandemic.

Infection with the protozoan Trypanosoma cruzi causes Chagas disease and consequently leads to severe inflammatory heart condition; however, the mechanisms driving this inflammatory response have not been completely elucidated. Nitric oxide (NO) is a key mediator of parasite killing in T. cruzi-infected mice, and previous studies have suggested that leukotrienes (LTs) essentially regulate the NO activity in the heart. We used infected 5-lipoxygenase-deficient mice (5-LO−/−) to explore the participation of nitric oxide synthase isoforms, inducible (iNOS) and constitutive (cNOS), in heart injury, cytokine profile, and oxidative stress during the early stage of T. cruzi infection. Our evidence suggests that the cNOS of the host is involved in the resistance of 5-LO−/− mice during T. cruzi infection. iNOS inhibition generated a remarkable increase in T. cruzi infection in the blood and heart of mice, whereas cNOS inhibition reduced cardiac parasitism (amastigote nests). Furthermore, this inhibition associates with a higher IFN-γ production and lower lipid peroxidation status. These data provide a better understanding about the influence of NO-interfering therapies for the inflammatory response toward T. cruzi infection.

We found significantly higher incidence of Toxoplasma gondii DNA in eye bank specimens from Joinville in southern Brazil (13/15, 87%) than in São Paulo (3/42, 7%; p = 2.1 × 10E–8). PCR DNA sequence analysis was more sensitive at locus NTS2 than at locus B1; a high frequency of mixed co-infections was detected.

Autoimmune Uveitis is an important chronic inflammatory disease and a leading cause of impaired vision and blindness. This ocular autoimmune disorder is mainly mediated by T CD4+ lymphocytes poising a TH1 phenotype. Costimulatory molecules are known to play an important role on T cell activation and therefore represent interesting therapeutical targets for autoimmune disorders. CD28 is the prototypical costimulatory molecule for T lymphocytes, and plays a crucial role in the initiation, and maintenance of immune responses. However, previous attempts to use this molecule in clinical practice achieved no success. Thus, we evaluated the efficacy of mPEG PV1-Fab' (PV1), a novel selective CD28 antagonist monovalent Fab fragment in the treatment of Experimental Autoimmune Uveitis (EAU). Here, we showed that PV1 treatment decreases both average disease score and incidence of EAU. A decrease in the activation profile of both T CD4+ and T CD8+ eye-infiltrating lymphocytes was evidenced. In the periphery, T CD4+ cells from PV1-treated mice also showed a decrease in their activation status, with reduced expression of CD69, CD25, and PD-1 molecules. This suppression was not dependent on Treg cells, as both their frequency and absolute number were lower in PV1-treated mice. In addition, frequency of CD4+IFN-γ+ T cells was significantly lower in PV1-treated group, but not of IL-17-producing T cells. Moreover, after specific restimulation, PV1 blockade selectively blocked IFN-γ production by CD4+ lymphocytes Taken together, our data suggest that mPEG PV1-Fab' acts mainly on IFN-γ-producing CD4+ T cells and emphasize that this specific CD28 blockade strategy is a potential specific and alternative tool for the treatment of autoimmune disorders in the eye.

OBJECTIVES: FTY720 modulates CD4+T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment. METHODS: F1 mice (C57BL/6xBALB/c) and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry), gene expression (real-time PCR) and cytokine (Bio-Plex) analysis. RESULTS: The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4+ graft-infiltrating cells. The cytokine analysis (splenocytes) showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft. CONCLUSIONS: Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.

ABSTRACT Experimental autoimmune uveitis is an organ-specific T-cell mediated autoimmune disease characterized by inflammation and consequent destruction of the neural retina and adjacent tissues. Inflammation in experimental autoimmune uveitis may be induced in rodents by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein. We present a review of experimental studies that correlate primary immunobiological functions with this chronic disease and the possible use of molecules for the treatment of autoimmune uveitis.

Introduction: The occurrence of foreign bodies in otorhinolaryngology is a cause of frequent consultations in the urgency service. Objective: The objective of this work is to describe a number of patients with foreign bodies, as well as to evaluate the clinical picture and the treatment of these cases. Method: We carried out a prospective study of 128 patients with diagnosis of nose, ear and oropharynx foreign body, attended in the emergency room of the Hospital Paulista de Otorrinolaringologia, São Paulo, in the period from August 2005 through august 2007. Results: They were 67.18% of cases of foreign body in the ear; 18.75% cases in the nasal cavity and 14.07% in the oropharynx. Out of these patients 55.47% were men and 44.53% were women. The mean age was of 17 years. The evolution time average was of 12.2 days, and 57.03% of the cases were attended with less than 24 hours of evolution. From the total of patients, 64.85% received initial service in the Emergency Room of the Hospital and 35.15% had been sent from another service after some previous removal attempt. The most common symptom of the cases of foreign body in the oropharynx was odinophagia, which was present in 88.88% of the cases; of foreign body in the nose, unilateral rhinorrhea, present in 37.5% of the cases and cacosmia in 25% of the cases; and in the foreign body in the ear, 39.53% evolved with hypacusis. Conclusion: Most of the cases with prior manipulation for removal of the foreign bodies by non-skilled professional or laymen evolved with complications.

Ocular toxoplasmosis is the most common cause of posterior uveitis worldwide. The infection can be acquired congenitally or postnatally and ocular lesions may present during or years after the acute infection occur. Current treatment controls ocular infection and inflammation, but does not prevent recurrences. We present a review and update on ocular toxoplasmosis and address misconceptions still found in the current medical literature.

Leprosy control is achieved through a fine-tuning of TH1 and TH2 immune response pattern balance. Given the increasing epidemiological overlay of HIV and M. leprae infections, immune response in co-infected patients consists in an important contemporary issue. Here we describe for the first time the innate lymphoid cells compartment in peripheral blood of leprosy and HIV/M. leprae co-infected patients, and show that co-infection increases group 2 innate lymphoid whilst decreasing group 1 innate lymphoid cells frequencies and function.

The major complications after bone marrow transplant are related to opportunistic infections or to graft-versus-host disease. Today, there is a wealth of information associated with bone marrow transplantation and new treatment approaches have been proposed to overcome these complications. Behind these new therapies, such as adoptive transfer of T cells or mesenchymal stem cell infusions, there is significant basic research to support these clinical advances. Most of this knowledge has derived from the development of animal models and intense laboratory work to test and confirm hypotheses. There is no doubt that basic research is still necessary to better understand the basis for clinical outcome improvements.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized by immunopathology driven by IFN-γ secreting Th1-like T cells. T. cruzi has a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described that T. cruzi or its products—like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins)—are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-γ primed murine macrophages. However, little is known about whether T. cruzi or GPI-mucins exert a similar action in human cells. We therefore decided to further investigate the in vitro cytokine production profile from human mononuclear cells from uninfected donors exposed to T. cruzi as well as tGPI-mucins. We observed that both living T. cruzi trypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood monocytes and this effect depends on CD40-CD40L interaction and IFN-γ. Our findings suggest that the polarized T1-type cytokine profile seen in T. cruzi infected patients might be a long-term effect of IL-12 production induced by lifelong exposure to T. cruzi tGPI-mucins.

The intracellular protozoan parasite Trypanosoma cruzi causes Chagas disease, a serious disorder that affects millions of people in Latin America. Cell invasion by T. cruzi and its intracellular replication are essential to the parasite’s life cycle and for the development of Chagas disease. Here, we present evidence suggesting the involvement of the host’s cyclooxygenase (COX) enzyme during T. cruzi invasion. Pharmacological antagonist for COX-1, aspirin (ASA), caused marked inhibition of T. cruzi infection when peritoneal macrophages were pretreated with ASA for 30 min at 37°C before inoculation. This inhibition was associated with increased production of IL-1β and nitric oxide (NO∙) by macrophages. The treatment of macrophages with either NOS inhibitors or prostaglandin E2 (PGE2) restored the invasive action of T. cruzi in macrophages previously treated with ASA. Lipoxin ALX-receptor antagonist Boc2 reversed the inhibitory effect of ASA on trypomastigote invasion. Our results indicate that PGE2, NO∙, and lipoxins are involved in the regulation of anti-T. cruzi activity by macrophages, providing a better understanding of the role of prostaglandins in innate inflammatory response to T. cruzi infection as well as adding a new perspective to specific immune interventions.

Since 2004, when a case report describing the use of human mesenchymal stem cells (hMSCs) infusion as a therapy for GVHD after bone marrow transplantation, a new perspective in MSC function emerged. Since then hMSCs immunomodulatory potential became the target of several studies. Although great progress has been made in our understanding of hMSCs, their effect on T cell remains obscure. Our study has confirmed the already described effect of hMSCs on lymphocytes proliferation and survival. We also show that the impairment of lymphocyte proliferation and apoptosis is contact-independent and occurs in a prostaglandin-independent manner. A potential correlation between IL-7 and hMSCs effect is suggested, as we observed an increase in IL-7 receptors (CD127) on lymphocyte membrane in MSC presence. Additionally, blocking IL-7 in hMSCs-lymphocytes co-cultures increased lymphocytes apoptosis and we also have demonstrated that hMSCs are able to produce this interleukin. Moreover, we found that during Th1/Th17 differentiation in vitro, hMSCs presence leads to Th1/Th17 cells with reduced capacity of INF-y and IL-17 secretion respectively, regardless of having several pro-inflammatory cytokines in culture. We did not confirm an increment of Treg in these cultures, but a reduced percentage of INF-y/IL-17 secreting cells was observed, suggesting that the ratio between anti and pro-inflammatory cells changed. This changed ratio is very important to GvHD therapy and links hMSCs to an anti-inflammatory role. Taken together, our findings provide important preliminary results on the lymphocyte pathway modulated by MSCs and may contribute for developing novel treatments and therapeutic targets for GvHD and others autoimmune diseases.

It is well established that female sex hormones have a pivotal role in inflammation. For instance, our group has previously reported that estradiol has proinflammatory actions during allergic lung response in animal models. Based on these findings, we have decided to further investigate whether T regulatory cells are affected by female sex hormones absence after ovariectomy. We evaluated by flow cytometry the frequencies of CD4(+)Foxp3(+) T regulatory cells (Tregs) in central and peripheral lymphoid organs, such as the thymus, spleen and lymph nodes. Moreover, we have also used the murine model of allergic lung inflammation a to evaluate how female sex hormones would affect the immune response in vivo. To address that, ovariectomized or sham operated female Balb/c mice were sensitized or not with ovalbumin 7 and 14 days later and subsequently challenged twice by aerosolized ovalbumin on day 21. Besides the frequency of CD4(+)Foxp3(+) T regulatory cells, we also measured the cytokines IL-4, IL-5, IL-10, IL-13 and IL-17 in the bronchoalveolar lavage from lungs of ovalbumine challenged groups. Our results demonstrate that the absence of female sex hormones after ovariectomy is able to increase the frequency of Tregs in the periphery. As we did not observe differences in the thymus-derived natural occurring Tregs, our data may indicate expansion or conversion of peripheral adaptive Tregs. In accordance with Treg suppressive activity, ovariectomized and ovalbumine-sensitized and challenged animals had significantly reduced lung inflammation. This was observed after cytokine analysis of lung explants showing significant reduction of pro-inflammatory cytokines, such as IL-4, IL-5, IL-13 and IL-17, associated to increased amount of IL-10. In summary, our data clearly demonstrates that OVA sensitization 7 days after ovariectomy culminates in reduced lung inflammation, which may be directly correlated with the expansion of Tregs in the periphery and further higher IL-10 secretion in the lungs.

Experimental autoimmune uveitis (EAU) is a well established model for immune-mediated organ-specific disease. Our group has recently shown that the M. leprae Hsp65 aggravated the uveitis in mice; in the present study, we evaluated the action of M. leprae K409A mutant protein and the synthetic peptides Leader pep and K409A pep (covering amino acids residues 352–371 of WT and K409A proteins of M. leprae Hsp65, resp.) on the pathogenesis of EAU. Mice received the 161–180 IRBP peptide and B. pertussis toxin followed by the intraperitoneal inoculation of K409A protein or the Leader pep or K409A pep. The Leader pep aggravated the disease, but mice receiving the K409A pep did not develop the disease and presented an increase in IL-10 levels by spleen cells and a decrease in the percentage of CD4+ IFN-γ+ T cells. Moreover, animals receiving the Leader pep presented the highest scores of the disease associated with increase percentage of CD4+ IFN-γ+ T cells. These results would contribute to understanding of the pathogenesis of EAU and support the concept that immune responses to Hsp are of potential importance in exacerbating, perpetuating, or even controlling organ-restricted autoimmune diseases, and it is discussed the irreversibility of autoimmune syndromes.

Hsp60 is an abundant and highly conserved family of intracellular molecules. Increased levels of this family of proteins have been observed in the extracellular compartment in chronic inflammation. Administration of M. leprae Hsp65 [WT] in [NZBxNZW]F(1) mice accelerates the Systemic Lupus Erythematosus [SLE] progression whereas the point mutated K(409)A Hsp65 protein delays the disease. Here, the biological effects of M. leprae Hsp65 Leader pep and K(409)A pep synthetic peptides, which cover residues 352-371, are presented. Peptides had immunomodulatory effects similar to that observed with their respective proteins on survival and the combined administration of K(409)A+Leader pep or K(409)A pep+WT showed that the mutant forms were able to inhibit the deleterious effect of WT on mortality, indicating the neutralizing potential of the mutant molecules in SLE progression. Molecular modeling showed that replacing Lysine by Alanine affects the electrostatic potential of the 352-371 region. The number of interactions observed for WT is much higher than for Hsp65 K(409)A and mouse Hsp60. The immunomodulatory effects of the point-mutated protein and peptide occurred regardless of the catalytic activity. These findings may be related to the lack of effect on survival when F(1) mice were inoculated with Hsp60 or K(409)A pep. Our findings indicate the use of point-mutated Hsp65 molecules, such as the K(409)A protein and its corresponding peptide, that may minimize or delay the onset of SLE, representing a new approach to the treatment of autoimmune diseases.