The science and medicine of human immunology

Abstract

Although the development of effective vaccines has saved countless lives from infectious diseases, the basic workings of the human immune system are complex and have required the development of animal models, such as inbred mice, to define mechanisms of immunity. More recently, new strategies and technologies have been developed to directly explore the human immune system with unprecedented precision. We discuss how these approaches are advancing our mechanistic understanding of human immunology and are facilitating the development of vaccines and therapeutics for infection, autoimmune diseases, and cancer.

Fig. 1.. Systems biology approach to probing human immunity.

The human immune system can be perturbed by vaccination, infection, or allergens, or in autoimmunity. Blood samples or fine needle aspirate samples of lymph nodes or other human tissues (e.g., skin biopsies) can be isolated and the immune response analyzed at multiple levels of the hierarchy of biological organization, using a wide array of technologies including transcriptomics, epigenomics, mass cytometry, and metabolomics.

Fig. 2.. Variations in the immunological states of humans.

The immunological state of an individual can vary with time as a result of stochastic changes, environmental perturbations (e.g., vaccination, infection, exposure to allergens), or developmental changes. Alternatively, the immunological state of individuals in a given population, or individuals in different populations, may vary because of differences in host genetics, the environment, or individuals’ microbiomes. Such human variation can lead to different outcomes in responses to vaccination, therapies, or susceptibilities to infections and inflammatory disorders.

Fig. 3.. From bedside to bench to bedside: The iterative cycle of human immunology.

Historically, drugs and vaccines have been developed by the “bench-to-bedside” model, which is a linear process that starts with basic research in animal models and culminates in clinical trials. New advances in systems biology have revitalized human immunology and our capacity to profile human immunity with great precision. Thus, the discovery process can now begin with the human model, where systems-based approaches can be used to analyze the immune response (e.g., response to a vaccine or an infection). The ensuing high-throughput data can then be mined computationally to generate novel hypotheses about the underlying biological mechanisms, which can in turn be tested in animal models. The insights gained can then guide the design of new therapeutics and vaccines. This new framework represents an iterative cycle that seeks to bridge basic and applied science, as well as mouse and human immunology, in a continuum of scientific discovery and translational medicine.