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Our Work

Our lab focuses in the following areas:

01

Immune Responses in Infection and Vaccination

The immune response to viral infections is inherently different from the one generated by vaccines. Viruses continuously try to evade the immune system; vaccines are designed to minimize evasion mechanisms and activate immunity. Our research aims to elucidate the mechanisms underlying the body's ability to recognize and eliminate viral infections, with the ultimate goal of developing novel strategies for the prevention (vaccination)  and treatment of viral diseases.

We employ a variety of cutting-edge techniques, including multi-parametric flow cytometry, cell sorting, high-throughput sequencing, single-cell analysis, and functional assays, to investigate the complex interactions between the immune system and viral pathogens. Our multidisciplinary approach allows us to gain a comprehensive understanding of the immune response against viruses at both the molecular and cellular levels.

Image by Fusion Medical Animation
Image by ANIRUDH
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02

Development of Monoclonal Antibodies

Monoclonal antibodies are laboratory-produced biomolecules that mimic the natural antibodies produced by the human immune system to fight infections and abnormal cells.

Why develop monoclonal antibodies?

A new monoclonal antibody is a new structure to be patented; they constitute the backbone of a highly resourceful pharmaceutical platform. Because they are virtually identical to antibodies naturally found in the human body, they present low toxicity. Additionally, they can be designed to specifically target certain pathogens or cancer cells for destruction by the immune system, to enhance or prevent cell interactions, or to deliver drugs to certain cells, minimizing systemic side effects.

Developing a monoclonal also includes testing its activity in different assays; and exploring its design to minimize toxicity and enhance function. This is done with a combination of artificial intelligence, molecular biology, and immune assays.  

Desenvolvimento de imunoterápicos oncológicos seus testes preditivos de resposta para o SUS

Agency: Ministério da Saúde

Associated grants:

Implantação da estrutura para o desenvolvimento de Imunoterápicos para câncer e infecções virais

Agency: FAPERGS

03

Genetic Testing for Oncology

Tumors are characterized by a high mutational load. Tumor mutations are usually characterized as one of two types: driver mutations; and passenger mutations. Detecting driver mutations in certain types of tumors is now essential to significantly increase treatment responsiveness. A whole plethora of drugs that target specific mutations can now be used to adapt pharmacotherapy to the most appropriate treatment for each patient. The development of next-generation sequencing systems has made it possible to detect these mutations on a large scale.

However, these tests are currently not only expensive but also have a long turnaround time, and they are not covered by Brazil's Universal Healthcare System (SUS). As a result, access to these tests is limited to those who can afford them, which reduces treatment efficacy due to long waits. Therefore, developing a quick and affordable test that is tailored for Brazil's SUS system is critical,  and an important goal of our 2019 PRONON project.

DNA

Associated grants:

Desenvolvimento de imunoterápicos oncológicos seus testes preditivos de resposta para o SUS

Agency: Ministério da Saúde

Implantação da estrutura para o desenvolvimento de Imunoterápicos para câncer e infecções virais

Agency: FAPERGS

Image by Markus Spiske
Screenshot from 2023-04-27 11-35-02.png

04

Single-Cell and Spatial Transcriptomics

Systems biology is a specially powerful approach to studying complex biological systems, such as cancer. By analyzing the interactions between different biological components, such as genes, proteins, and metabolites, systems biology studies can lead to the development of new genetic tests for early detection, diagnosis, and personalized treatment of cancer.

Moreover, systems biology can provide insights into the complex mechanisms underlying cancer development and progression, including immune evasion and drug resistance. By identifying key molecular players involved in these processes, new immunotherapeutic strategies can be developed to improve patient outcomes. We study the cell composition and interactions in the tumor microenvironment and lymphoid organs, using the single-cell transcriptomics approach, validating the findings after deconvolution in tissue sections. 

Associated grants:

Desenvolvimento de imunoterápicos oncológicos seus testes preditivos de resposta para o SUS

Agency: Ministério da Saúde

Implantação da estrutura para o desenvolvimento de Imunoterápicos para câncer e infecções virais

Agency: FAPERGS

Read about some of our projects

Role of the ubiquitinase March1 in the immune response against cancer – Funding: CNPq Universal 2018

This project derives from one of our previous findings - described in 2018 (Borges et al., Nat. Comm. ) - on modulation of MHC class II levels in dendritic cells as a strategy to ameliorate transplant rejection. We found that graft treatment with DnaK from M. tuberculosis upregulated MARCH1 in migratory dendritic cells, leading to less antigen presentation and less rejection. We next hypothesized that inhibition of MARCH1 in dendritic cells could lead to tumor rejection.​ This study project is a collaboration with Dr. Thiago Borges, now an investigator at the Massachusetts General Hospital (MGH), and Dr. Leo Riella, Head of Surgery at MGH, Harvard, Boston. It has also been awarded a CAPES PDSE fellowship for one of our graduate students to work at the MGH to complete some experiments. Our preliminary results indicate that both routes of antigen presentation - MHC class II and MHC class I - are impacted when MARCH1 is knocked out in different cells. We are mapping molecular routes that mediate these effects.

Pediatric immunity generated during SARS-COV-2 infection - Funding: PROADI 2020

This project is a partnership with pediatricians from Hospital Moinhos de Vento (Drs. Renato Stein and Marcelo Scotta). During the SARS-CoV-2 pandemic, we were able to repurpose a grant previously destined to study tuberculosis in children. The goal of the project was to characterize the immune response generated by children with COVID-19. The results were published in Lima et al., 2022. We showed that children did get infected and presented high viral titers, but did not evolve to severe disease. The immune response in pediatric COVID was characterized by early anti-N CD8+T cells and antibodies. While antibodies to S protein decreased over time, anti-N titers were maintained. Neutralizing antibody titers, measured in collaboration with UNICAMP (Drs. José Luiz Modena and Rafael Elias) were lost over 3 months after infection. Memory CD8+ TNF+ T cells that are specific for N peptides were induced early and maintained over time. Our results indicate that immunization in children against COVID-19 might benefit from vaccines that include N peptides.

Production of a monoclonal antibody against SARS-COV-2 / Development of a test for neutralizing antibodies by flow cytometry - Funding: CAPES Fármacos e Imunologia 2020

Our university is the only one in Brazil exclusively dedicated to Health Sciences. During the SARS-COV-2 pandemic, when applications were open for projects that could provide national solutions for the technical challenges imposed by the pandemic, we proposed to generate a neutralizing, anti-S protein, monoclonal antibody for the virus. We also developed a neutralization assay based on flow cytometry, as an alternative to the PRNT or FRNT assays that required NB3 facilities. We collaborated with Dr. Andre Valle, from UFRJ, and generated a fully human, neutralizing antibody using public sequences for the binding sequences. We also collaborated with Drs. José Luiz Modena and Rafael Elias to validate the FACS-based neutralization assay by PRNT. These results are being submitted for publication. Funding is necessary to further develop these products - contact us, if you wish to invest.

Immunity generated by the tetravalent live, attenuated dengue vaccine – Vacina NIH-Butantan-MSD - Funding: Ministry of Health; Butantan Institute

Immunity generated by infection is inherently different from immunity generated by vaccination. Viruses evolve strategies to infect the host involving escape mechanisms that elude the immune system; thus, immune memory generated by infection is highly variable and may not be effective in protecting against another challenge. Vaccine design involves preventing the escape strategies presented by the virus, focusing the immune responses on the molecules that are essential for infection. In Dengue disease, four viral serotypes can take turns in infecting humans, leading to repeated episodes of infection throughout the host's life. In some cases, antibodies produced in response to infection by one serotype can worsen the disease upon infection by a different serotype. This vaccine was developed by researchers Steve Whitehead and Anna Durbin, who deleted virulence sequences in each serotype's genome (Dengue 1, 2 3, and 4), creating a live attenuated dengue vaccine aiming to protect from disease caused by any of the serotypes. A live attenuated vaccine employs the same cellular and molecular routes as the wild-type virus; however, it provides enough time for the immune system to generate an adequate response. A Phase III clinical study is being conducted nationally, in 19 centers, by a partnership between Butantan Institute and MSD Pharma. Our lab has been involved in the clinical study from the start, and preserved serial samples of individuals vaccinated in Porto Alegre - a region where most individuals have never been infected by the virus - a collaboration with Dr. Fabiano Ramos, at Hospital São Lucas (PUCRS). Our goal is to characterize the kinetics and phenotype of memory T cells generated in naive individuals by this vaccine and compare that with the clinical data, looking for an immune signature that correlates with protection.

Development of oncology immunotherapeutic drugs and predictive tests for the Sistema Único de Saúde (SUS)  Funding:  Pronon 2019, DECIT/Ministry of Health
Partners:  Santa Casa de Misericórdia de Porto Alegre

Cancer therapy has been revolutionized by immunotherapy. The use of monoclonal antibodies against cancer was initially conceived as targeting tumor cells and their antigens. Antibodies against the HER-2 molecule are an example. However, the great game-changer was the development of antibodies that target checkpoints in immune cells, enabling them to recover their anti-tumor functions. Antibodies to immune checkpoints today represent a large segment of the biotechnology and health markets because they are the first therapy able to revert metastasis in patients with advanced forms of cancer. However, not all patients respond equally to these drugs. Finally, these drugs are extremely expensive, are all imported, and are not available to patients through our Unified Health System (SUS). We are developing a national alternative to these monoclonal antibodies, so they can benefit SUS patients. Another important type of cancer therapy are drugs that target specific driver mutations in certain tumors. They can be identified using molecular biology tests - specifically, Next Generation Sequencing (NGS). These tests are also expensive and are not available to SUS patients. The best available cancer treatment thus currently depends on the genetic and immunological characterization of the tumor. We are developing an inexpensive alternative to the tests which help predict the success of the most suitable therapy. The genetic and immunological characterization of the tumors of SUS patients will create a rich dataset of information that is extremely relevant and necessary to devise new mechanisms by which tumors can evade the immune system, immune checkpoint immunotherapy, or targeted drugs. A system biology approach is used to investigate these phenomena, generating a pipeline for discovery.

Development of Immunotherapeutic Drugs  in Rio Grande do Sul  Funding: FAPERGS RITES 2022

Science has a gigantic impact on our lives. Nevertheless, most people are unaware of such influence. Science is the base of technological societies, which are nowadays the richest and most prosperous in the world. The RITES program was designed by FAPERGS to fuel the development of scientific networks in the State of Rio Grande do Sul, aiming the transference of technology to the community. This technology transfer can take many forms. Science education and communication can help qualify professionals from different areas, from both public and private sectors. Entrepreneurial initiatives can be taught to science professionals, but support is needed to help transform scientific discoveries into products with economic value. Our group proposed to develop the infrastructure to discover and develop new monoclonal antibodies that can be used as therapeutic drugs for cancer and viral infections. Together with different partners, such as UNISC, PUCRS, UFRGS, UCSD, USP, UFRJ and many others, we will not only develop this pipeline, but also educate and train young science professionals to be entrepreneurs. At the same time, we are working with the state’s Health Department to help qualify public servants in scientific related themes, such as vaccination, cancer, and viral infection. Finally, we have established a partnership with private donors to build a junior science initiation program for students from public schools.

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