Petter Brodin

The Systemic environmental effects on neonatal Immune Development (SeenID) study is a highly innovative, ambitious, large-scale study to tackle a major global health concern: Neonatal immune system priming by the environment, predisposing to infections and immunopathologies later in life. After birth, the neonatal immune system must instantly cope with microbial colonization and environmental triggers and, at the same time, must provide immediate defense against invasive infections. While genetic variations cause specific immunodeficiencies and influence immune-related health and diseases later in life, it is mostly the environment that shapes the development and function of the human immune system early in extra-uterine life during a limited window of opportunity. Among the environmental factors contributing to the maturation of the immune system are the microbiome and exposure to potential pathogens, nutrition, which modulates the microbiome and immune reactions, as well as exposures to noxious agents, drugs, and standard-of-life environment. Episodes of immunological emergencies such as invasive infections are also influential. Here, we propose an approach based on a high-resolution, longitudinal analysis of >1000 neonates from highly distinctive, yet well-characterized environments over a two-year observational period. In the framework of two large intervention studies in rural Uganda and Kenya, we closely follow cohorts of neonates including assessment of health-associated data and sequential sampling of blood and stool. Recruitment is already successfully ongoing. The samples are locally stabilized and frozen, then shipped to Stockholm where they are analyzed side-by-side with age-matched samples from a Swedish cohort. This enables us to dissect specific environmental influences on the developing immune system. This study will provide a mechanistic understanding of factors involved in early immune programming and thus of early determinants contributing to infections and immunopathologies later in life.

Purpose and aimImmune mediated diseases originate early in life, are linked with perturbed immune-microbe interactions and are increasingly prevalent. Our hypothesis is that environmental exposures at birth, and during the first months of life exert imprinting effects on developing immune cells, which determine an individual’s trajectory towards immunological health or disease. MethodsIn a birth cohort in Stockholm with 309 children, monitored for up to four years, we are analyzing longitudinal blood and stool samples, comparing children born at term or preterm, by vaginal or cesarean delivery and fed breastmilk or formula, whilst keeping track of many environmental factors such as the evolving gut microbiome, vaccines, and nutrients. We assess in vivo developmental outcomes

atopy and serological responses to vaccines and compare children with different outcomes with respect to immunological features, metagenomes, and microbial metabolites. Furthermore, we aim to perform more in-depth in vitro experiments to investigate microbial metabolites for receptor binding, and functional modulation of epithelial cells and developing immune cells and the functional consequences thereof. ImportanceThese studies hold important potential by guiding future interventions in the form of pre/probiotics, metabolites, and nutritional supplements that hopefully can provide all children with a healthier start in life and promote immune-microbe mutualism and reduced risks of disease long term.

The immune system has an impressive power to fight cancer cells and in recent years many new treatments have been added that help the immune system in its fight against cancer. Very few of these treatments are used on children, and children's immune systems are significantly different from adults. Research concerning the immune system in children with cancer is a neglected area, and in order to move forward with new treatment strategies, more information is now required on how current treatment affects the immune system and its function in children, and when and how a child's immune system is activated against cancer. The human immune system consists of a multitude of interacting white blood cells that regulate each other in a complex network. Therefore, despite good knowledge of individual cell types, we cannot predict the behavior of the immune system as a whole. New technology now allows us to study the immune system as a whole with all its white blood cells. This can be done with repeated blood tests. Here we use such new methods in children with solid tumors, including brain tumors and lymphoma. However, leukemias are not included. We study how the immune system is affected by current treatments and try to predict which children will suffer complications and which will not. We hope that this new knowledge about the immune system in children with cancer will lead to more children being able to be helped by immunotherapy and to be cured, that we will be able to better tailor our treatment, not only according to the characteristics of the tumor but also according to the child's immune system, so that this may work in repelling cancer cells. We also hope that we will get better at finding the children with the greatest risk of complications due to reduced immune function such as infections and that we will be able to predict such risks earlier.

Survival for children affected by cancer has improved significantly but cancer is still one of the most common causes of death in children in Sweden. Medications aimed at improving the immune system's own ability to kill tumor cells have made great progress in recent years and show great potential but such treatments have not been used for children with solid tumors. The immune system of children and adult patients differs and an important first step towards the introduction of new immunological treatments in children is to increase our knowledge of how tumors and prevailing treatment protocols affect children's immune systems. The human immune system consists of many interacting cell types that regulate each other in a complicated network. Despite good knowledge of individual cell types, we cannot therefore predict the function of the immune system as a whole today. New technology offers new opportunities for extensive analysis of all the cells and proteins that make up human immune system and its function. We now want to use such methods to study the immune system in children with cancer, how its composition and function are affected by the disease and the treatment they are undergoing. If we are successful, we hope to see how the immune systems of children with cancer respond to different tumors and compare such responses in patients who survive to those who do not, something that would open to new treatments where the immune system's function is directed towards better attacking cancer cells in all children. We also believe that such analyzes can help us understand how and why some children suffer from side effects to their treatment, side effects that often involve the immune system.

Today, stem cell transplantation is an effective treatment for patients with leukemia but too many still suffer from severe complications such as infections, graft-versus host reaction and recurrence of leukemia. We do not know today what is required for the new immune system when it grows out of donated stem cells in order for the patient to be cured. With the help of the latest method for cell analysis, mass cytometry, we now want to study the immune systems of these patients to try to understand what distinguishes patients who are cured without complications from those who do not. Our hypothesis is that complications in patients can be explained by the fact that the immune system develops with an imbalance between different cell populations after transplantation. Thus, some cell populations can dominate the system and its function as a whole is weakened. We now want to investigate this idea If our idea of imbalance between cell types as an explanation for poor immunological function is correct, this opens up for both new possibilities for detecting threatening complications and earlier treatment of these. Thus, we hope to improve survival for patients with leukemia who undergo stem cell transplantation

Today, stem cell transplantation is an effective treatment for patients with leukemia but too many still suffer from severe complications such as infections, graft-versus host reaction and recurrence of leukemia. We do not know today what is required for the new immune system when it grows out of donated stem cells in order for the patient to be cured. With the help of the latest method for cell analysis, mass cytometry, we now want to study the immune systems of these patients to try to understand what distinguishes patients who are cured without complications from those who do not. Our hypothesis is that complications in patients can be explained by the fact that the immune system develops with an imbalance between different cell populations after transplantation. Thus, some cell populations can dominate the system and its function as a whole is weakened. We now want to investigate this idea If our idea of imbalance between cell types as an explanation for poor immunological function is correct, this opens up for both new possibilities for detecting threatening complications and earlier treatment of these. Thus, we hope to improve survival for patients with leukemia who undergo stem cell transplantation

Today, stem cell transplantation is an effective treatment for patients with leukemia but too many still suffer from severe complications such as infections, graft-versus host reaction and recurrence of leukemia. We do not know today what is required for the new immune system when it grows out of donated stem cells in order for the patient to be cured. With the help of the latest method for cell analysis, mass cytometry, we now want to study the immune systems of these patients to try to understand what distinguishes patients who are cured without complications from those who do not. Our hypothesis is that complications in patients can be explained by the fact that the immune system develops with an imbalance between different cell populations after transplantation. Thus, some cell populations can dominate the system and its function as a whole is weakened. We now want to investigate this idea If our idea of imbalance between cell types as an explanation for poor immunological function is correct, this opens up for both new possibilities for detecting threatening complications and earlier treatment of these. Thus, we hope to improve survival for patients with leukemia who undergo stem cell transplantation