New Approaches to Human Immunology

For many decades, the immunology research community has focused on the study of inbred mice and creating models of disease in that organism. While this has taught us a great deal about the basic workings of the immune system, the record has been much more spotty in understanding and treating human diseases. The spectacular success of checkpoint inhibitors in cancer therapy for example, should be balanced against the much more numerous failures in previous cancer treatments and the fact that we have cured no one of autoimmunity despite having done this in models hundreds of time. Nor has there been progress in developing even basic metrics of immunological health, such as we have had for many years in cardiovascular health, despite the booming market in "Immune Booster" products. This has led my group and others to try to devise new approaches and methodologies to directly measure immune function in human beings. Here there has been a good start and much promise for the future. First and foremost is to have a good strategy that can be built on over decades, much as the mouse system has been-and what it makes it so powerful today. Since many of the manipulations done in mice are not possible or permissible in human beings, it has been necessary to develop a new strategy that could both inform us about the immune system in humans and especially to take advantage of the many immune interventions that are being done with patients every day to discover new relationships between immune system components and disease. The strategy that I have advocated (Davis,M.M. Immunity 2008;29:835-838.) has been a "systems immunology" approach, where we collect as much information as technically possible in a blood sample on the key components of immunity, namely the varied cell types and the cytokines they use to communicate with each other and mediate functions. Here the broad availability of blood samples that can be stored for years in almost any patient cohort is tremendous resource for immunological studies. Similarly there are a number of high throughput low cost assays that can analyze many of the immune components quickly, together with analytical methods to understand the data. To do many of these efficiently, at Stanford we have established a Human Immune Monitoring Center to standardize and carry out these assays, freeing academic labs from this task, and allowing them to focus on designing the studies and interpreting the results. This has enabled many studies by my group and others, and addressed such important questions as the role of genetics in immune variation, predicting response to flu vaccination, and connections between pathways of immune inflammation and cardiovascular diseases. New methodologies and approaches have also shed light on basic immunology such as the relative importance of clonal deletion in T cell tolerance and the recognition targets of T cells infiltrating and proliferating in human cancer.