Papers by Thiago J Borges
Frontiers in Immunology, May 6, 2022
This mini review describes the role of gut and lung microbiota during respiratory viral infection... more This mini review describes the role of gut and lung microbiota during respiratory viral infection and discusses the implication of the microbiota composition on the immune responses generated by the vaccines designed to protect against these pathogens. This is a growing field and recent evidence supports that the composition and function of the microbiota can modulate the immune response of vaccination against respiratory viruses such as influenza and SARS-CoV-2. Recent studies have highlighted that molecules derived from the microbiome can have systemic effects, acting in distant organs. These molecules are recognized by the immune cells from the host and can trigger or modulate different responses, interfering with vaccination protection. Modulating the microbiota composition has been suggested as an approach to achieving more efficient protective immune responses. Studies in humans have reported associations between a better vaccine response and specific bacterial taxa. These associations vary among different vaccine strategies and are likely to be context-dependent. The use of prebiotics and probiotics in conjunction with vaccination demonstrated that bacterial components could act as adjuvants. Future microbiota-based interventions may potentially improve and optimize the responses of respiratory virus vaccines.
Nature Communications, 2021
COVID-19 manifests as a milder disease in children than adults, but the underlying mechanisms are... more COVID-19 manifests as a milder disease in children than adults, but the underlying mechanisms are not fully characterized. Here we assess the difference in cellular or humoral immune responses of pediatric and adult COVID-19 patients to see if these factors contribute to the severity dichotomy. Children’s non-specific immune profile is dominated by naive lymphocytes and HLA-DRhighCX3CR1low dendritic cells; meanwhile, children show strong specific antibody and T cell responses for viral structural proteins, with their T cell responses differing from adults by having weaker CD8+TNF+ T cells responses to S peptide pool but stronger responses to N and M peptide pools. Finally, viral mRNA is more abundant in pediatric patients. Our data thus support a scenario in which SARS-CoV-2 infected children contribute to transmission yet are less susceptible to COVID-19 symptoms due to strong and differential responses to the virus.
Frontiers in Immunology, 2021
An author name was incorrectly spelled as "Cravedil". The correct spelling is "Cravedi".
Frontiers in Immunology, 2021
An author name was incorrectly spelled as "Cravedil". The correct spelling is "Cravedi".
European Journal of Pharmacology, 2021
Esophageal cancer is a prominent worldwide illness that is divided into two main subtypes: esopha... more Esophageal cancer is a prominent worldwide illness that is divided into two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Mortality rates are alarming, and the understanding of the mechanisms involved in esophageal cancer development, becomes essential. Purinergic signaling is related to many diseases and among these various types of tumors. Here we studied the effects of the P2Y2 receptor activation in different types of esophageal cancer. Esophageal tissue samples of healthy controls were used for P2Y2R expression quantification. Two human esophageal cancer cell lines Kyse-450 (squamous cell carcinoma) and OE-33 (adenocarcinoma) were used to perform in vitro analysis of cell proliferation, migration, adhesion, and the signaling pathways involved in P2Y2R activation. Data showed that P2Y2R was expressed in biopsies of patients with ESCC and adenocarcinoma, as well as in the two human esophageal cancer cell lines studied. The RT-qPCR analysis demonstrated that OE-33 cells have higher P2RY2 expression than Kyse-450 squamous cell line. Results showed that P2Y2R activation, induced by ATP or UTP, promoted esophageal cancer cells proliferation and colony formation. P2Y2R blockage with the selective antagonist, AR-C 118925XX, led to decreased proliferation, colony formation and adhesion. Treatments with ATP or UTP activated ERK 1/2 pathway in ESCC and ECA cells. The P2Y2R antagonism did not alter the migration of esophageal cancer cells. Interestingly, the esophageal cancer cell lines presented a distinct profile of nucleotide hydrolysis activity. The modulation of P2Y2 receptors may be a promising target for esophageal cancer treatment.
Scientific Reports, 2020
Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current ... more Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2Kb, I-Ab) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2Kd, I-Ad) or third-party (C3H, H2Kk, I-Ak) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regula...
Immunology & Cell Biology, 2020
Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in chi... more Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV-specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL)-21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL-21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL-21/interleukin-21 receptor (IL-21R) in Tfh cells and upregulated programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and B cells. PD-L1 blockade during infection recovered IL-21R expression in Tfh cells and increased the secretion of IL-21 in a DC-dependent manner. IL-21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti-RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL-21treated RSV-infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD-L1 expression on antigen-presenting cells, highlighting the importance of an IL-21-PD-L1 axis for the generation of protective responses to RSV infection.
The FEBS Journal, 2020
The use of model organisms for recombinant protein production results in the addition of modelspe... more The use of model organisms for recombinant protein production results in the addition of modelspecific post-translational modifications (PTMs) that can affect the structure, charge, and function of the protein. The 70-kDa heat shock proteins (Hsp70) were originally described as intracellular chaperones, with ATPase and foldase activity. More recently, new extracellular activities of Hsp70 proteins (e.g., as immunomodulators) have been identified. While some studies indicate an inflammatory potential for extracellular Hsp70 proteins, others suggest an immunosuppressive activity. We hypothesized that the production of recombinant Hsp70 in different expression systems would result in the addition of different PTMs, perhaps explaining at least some of these
Respiratory syncytial virus (RSV) is the major cause of hospitalization for children under two ye... more Respiratory syncytial virus (RSV) is the major cause of hospitalization for children under two years of age. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain, fail to develop protective memory responses. Follicular helper T (TFH) cells specialize in providing B cell help to antibody production and affinity maturation, mainly via IL-21 secretion. Although RSV-specific antibodies can be detected upon infection, how they are generated and their relevance against disease protection has not been fully examined. Here, we observed that RSV expands a functionally impaired murine TFH cell population in vitro and vivo, with downregulated IL-21R expression and IL-21 production. IL-21 treatment of RSV-infected mice, however, increased TFH cells frequency, enhanced the germinal center reaction and improved protective humoral immune responses by increasing viral protein F specific antibody avidity and neutralization capacity. In vi...
Frontiers in Immunology, 2019
Background: There is unmet need for non-invasive immunomonitoring to improve diagnosis and treatm... more Background: There is unmet need for non-invasive immunomonitoring to improve diagnosis and treatment of acute rejection in vascularized composite allotransplantation (VCA). Circulating matrix metalloproteinase 3 (MMP3) was described as a candidate non-invasive biomarker to predict treatment response to acute rejection in clinical VCA. However, larger validation studies are yet to be reported to allow for more definitive conclusions. Methods: We retrospectively measured MMP3 levels using ELISA in a total of 140 longitudinal serum samples from six internal and three external face transplant recipients, as well as three internal and seven external upper extremity transplant recipients. The control groups comprised serum samples from 36 kidney transplant recipients, 14 healthy controls, and 38 patients with autoimmune skin disease. A linear mixed model was used to study the effect of rejection state (pre-transplant, no-rejection, non-severe rejection (NSR), and severe rejection) on MMP3 levels. Results: In VCA, MMP3 levels increased significantly (p < 0.001) between pre-and post-transplant no-rejection states. A further increase occurred during severe rejection (p < 0.001), while there was no difference in MMP3 levels between non-severe and no-rejection episodes. A threshold of 5-fold increase from pre-transplant levels could discriminate severe from NSR with 76% sensitivity and 81% specificity (AUC = 0.79, 95% CI = 0.65-0.92, p < 0.001). In kidney transplantation, the MMP3 levels were significantly (p < 0.001) elevated during antibody-mediated rejection but not during T-cell mediated rejection (TCMR) (p = 0.547). MMP3 levels in healthy controls and autoimmune skin disease patients were comparable with either pre-transplant or no-rejection/NSR episodes of VCA patients. Kollar et al. MMP3 Biomarker Validation in VCA Conclusion: The results of this study suggest that serum MMP3 protein is a promising marker for stratifying patients according to severity of rejection, complementary to biopsy findings.
Scientific Reports, 2018
Face transplantation is a viable treatment option for carefully selected patients with devastatin... more Face transplantation is a viable treatment option for carefully selected patients with devastating injuries to the face. However, acute rejection episodes occur in more than 80% of recipients in the first postoperative year. Unfortunately, neither a correlation between histological grades of rejection and anti-rejection treatment nor systemic surrogate markers of rejection in face transplantation are established in clinical routine. Therefore, we utilized next generation aptamer-based SOMAscan proteomics platform for non-invasive rejection biomarker discovery. Longitudinal serum samples from face transplant recipients with long-term follow-up were included in this study. From the 1,310 proteins analyzed by SOMAscan, a 5-protein signature (MMP3, ACY1, IL1R2, SERPINA4, CPB2) was able to discriminate severe rejection from both no-rejection and nonsevere rejection samples. Technical validation on ELISA platform showed high correlation with the SOMAscan data for the MMP3 protein (r s = 0.99). Additionally, MMP3 levels were significantly increased during severe rejection as compared to no-rejection (p = 0.0009) and nonsevere rejection (p = 0.0173) episodes. Pathway analyses revealed significant activation of the metallopeptidase activity during severe face transplant rejection. This pilot study demonstrates the feasibility of SOMAscan to identify non-invasive candidate biomarkers of rejection in face transplantation. Further validation in a larger independent patient cohort is needed. Face transplantation is a viable reconstructive option for carefully selected patients with severe facial disfigurement 1,2. Since 2005, 40 such procedures have been performed worldwide 3. Face transplantation, similar to hand transplantation, belongs to a field called vascularized composite allotransplantation (VCA), which is characterized by the presence of tissues of different function and immunogenicity in the allograft, such as skin, fat, muscle, tendon, bone, bone marrow, nerves and vessels 4. From these tissues, skin is believed to be the most immunogenic and susceptible for acute rejection 5,6. In contrast to solid organ transplantation (SOT) in which rejection occurs in about 10-20% of transplant recipients, the incidence of acute rejection in VCA is more than 80% in the first year after transplantation 7-9. The VCA allografts are available for direct inspection, which is a unique feature compared to SOT. In face transplantation, sentinel flaps may complement the rejection diagnosis and the experience from our center showed good correlation of histological findings between the face allografts and sentinel flaps, so far 10. However, apart from clinical presentation and biopsy, there are no other assays to diagnose acute rejection in VCA 4. Therefore, biomarkers to diagnose, monitor or even prevent rejection are of great interest for the field of VCA. The gold standard to diagnose acute rejection in VCA is the skin biopsy assessed by the Banff classification of skin-containing composite tissues 11. However, skin biopsy is associated with morbidity to the patient, including scarring, bleeding or infection, hence it is not favorable for frequent monitoring. Furthermore, the Banff grading of skin rejection is semiquantitative, might be prone to intra-and interobserver variability, and lacks a correlation
American Journal of Transplantation, 2018
Successful allotransplantion of complex composite tissues such as a face has dramatically transfo... more Successful allotransplantion of complex composite tissues such as a face has dramatically transformed restorative options for severely disfigured patients. 1 Ongoing development and adaptation of iatrogenic immunosuppressive regimens have significantly reduced the risks of acute rejection (AR) episodes. Chronic changes in allografts, known as chronic rejection (CR), are responsible for long-term allograft deterioration and the potential for graft loss in solid organ transplant (SOT). In both SOT and vascularized composite allograft transplantation (VCA), CR has been associated with graft vasculopathy involving vascular narrowing due to intimal hyperplasia and fibrosis. 2-4 Initially, antibody-mediated graft injury was implicated in
Nature communications, Aug 28, 2018
In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by dir... more In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103 DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103 do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD1...
Molecular oncology, Jan 8, 2018
We describe a cell damage-induced phenotype in mammary carcinoma cells involving acquisition of e... more We describe a cell damage-induced phenotype in mammary carcinoma cells involving acquisition of enhanced migratory and metastatic properties. Induction of this state by radiation required increased activity of the Ptgs2 gene product cyclooxygenase 2 (Cox2), secretion of its bioactive lipid product prostaglandin E2 (PGE2), and the activity of the PGE2 receptor EP4. Although largely transient, decaying to low levels in a few days to a week, this phenotype was cumulative with damage and levels of cell markers Sca-1 and ALDH1 increased with treatment dose. The Sca-1 , metastatic phenotype was inhibited by both Cox2 inhibitors and PGE2 receptor antagonists, suggesting novel approaches to radiosensitization.
Molecular oncology, Jan 8, 2018
We describe a cell damage-induced phenotype in mammary carcinoma cells involving acquisition of e... more We describe a cell damage-induced phenotype in mammary carcinoma cells involving acquisition of enhanced migratory and metastatic properties. Induction of this state by radiation required increased activity of the Ptgs2 gene product cyclooxygenase 2 (Cox2), secretion of its bioactive lipid product prostaglandin E2 (PGE2), and the activity of the PGE2 receptor EP4. Although largely transient, decaying to low levels in a few days to a week, this phenotype was cumulative with damage and levels of cell markers Sca-1 and ALDH1 increased with treatment dose. The Sca-1 , metastatic phenotype was inhibited by both Cox2 inhibitors and PGE2 receptor antagonists, suggesting novel approaches to radiosensitization.
Antiviral research, Jan 7, 2018
Respiratory syncytial virus (RSV) is the most common etiologic agent in severe infections of the ... more Respiratory syncytial virus (RSV) is the most common etiologic agent in severe infections of the lower respiratory tract in children with a high mortality rate. However, there are still no licensed vaccines for RSV. In this study, we investigated a putative vaccine based on M peptide. Mice vaccinated with M peptide expanded M-specific effector CD4 T cells upon infection. Vaccination resulted in increased numbers of regulatory T cells (Treg) and Th1 cells, and decreased numbers of Th2 cells. In addition, vaccination with M peptide, protected mice from infection and prevented lung inflammation, leading to increase in IL-10 and IFN-γ production by lung CD4 T cells. Treg depletion with anti-CTLA4 antibodies abrogated protection induced by peptide vaccination. Our results support vaccination with M peptide as an important strategy to generate protection, both systemic and local, by memory RSV-specific CD4 T cells in mice. Contrarily to inactivated RSV particles, M peptide vaccination is ...
JCI insight, Jan 2, 2017
Tregs hold great promise as a cellular therapy for multiple immunologically mediated diseases, gi... more Tregs hold great promise as a cellular therapy for multiple immunologically mediated diseases, given their ability to control immune responses. The success of such strategies depends on the expansion of healthy, suppressive Tregs ex vivo and in vivo following the transfer. In clinical studies, levels of transferred Tregs decline sharply in the blood within a few days of the transfer. Tregs have a high rate of apoptosis. Here, we describe a new mechanism of Treg self-inflicted damage. We show that granzymes A and -B (GrA and GrB), which are highly upregulated in human Tregs upon stimulation, leak out of cytotoxic granules to induce cleavage of cytoplasmic and nuclear substrates, precipitating apoptosis in target cells. GrA and GrB substrates were protected from cleavage by inhibiting granzyme activity in vitro. Additionally, we show - by using cytometry by time of flight (CYTOF) - an increase in GrB-expressing Tregs in the peripheral blood and renal allografts of transplant recipient...
JCI insight, Jan 6, 2017
Rejection affects greater than 80% of face transplants, yet no diagnostic criteria for antibody-m... more Rejection affects greater than 80% of face transplants, yet no diagnostic criteria for antibody-mediated rejection (AMR) following face transplantation have been established. Given that different treatment strategies are required to address AMR and T cell-mediated rejection (TCMR), there is a critical need to delineate the features that can differentiate these two alloimmune responses. Here, we report the longitudinal immunological examination of what we believe to be the first and only highly sensitized recipient of a crossmatch-positive face transplant up to 4 years following transplantation. We conducted gene expression profiling on allograft biopsies collected during suspected AMR and TCMR episodes as well as during 5 nonrejection time points. Our data suggest that there are distinctive molecular features in AMR, characterized by overexpression of endothelial-associated genes, including ICAM1, VCAM1, and SELE. Although our findings are limited to a single patient, these findings...
Frontiers in Immunology, 2016
Current Opinion in Nephrology and Hypertension, 2016
Purpose of review-The present review aims to highlight the major recent advances in transplantati... more Purpose of review-The present review aims to highlight the major recent advances in transplantation with regards to basic, translational and clinical research. Recent findings-We describe new concepts in understanding allorecognition and allospecificity of T cells, and discuss current challenges in targeting memory T cells, including the limitation of rodent disease models. From a clinical perspective, we highlight the advances in molecular biopsy characterization, which have expanded our knowledge of potential drivers of injury and may provide better parameters for patient risk stratification. We also highlight the dual role of innate immunity in both stimulating and regulating adaptive immunity as well as novel insights into environmental exposures that may affect immune regulation, such as high-salt diet. Lastly, we discuss advances in understanding humoral response and novel technologies such as chimeric antigen receptors (CAR) engineered T cells, microparticle-based drug delivery and CRISPR/Cas9 gene editing that may provide intriguing and promising approaches to restrain alloimmunity. Summary-Current advances in our understanding of the basic mechanisms of alloimmunity and their potential translation to clinical applications will permit the development of novel diagnostic and therapeutic strategies to improve long-term graft survival.
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Papers by Thiago J Borges