Dr. Donna Farber Research
Mapping the Human Immune Response
Translating immune therapies from animal models to patients for suppressing the immune response in autoimmune diseases and transplantation, and enhancing immunity to pathogens and tumors in vaccines, presents a number of biological, practical and conceptual challenges. Chief among them is the well-known fact that strategies that alter the immune response in mouse models which are the prevalent model for immunology studies, do not work when applied to humans. For example, autoimmune or Type I diabetes (T1DM) has been cured in mouse models through manipulating a plethora of immune-related molecules, genes, and pathways; yet there remains no cure for autoimmune diabetes. Conversely, tumor immunotherapy has been successfully applied to numerous mouse tumor models, yet immunotherapy as a cure for cancer remains elusive. In addition, vaccine strategies for eliciting protective immunity to pathogens exhibit selective efficacy and there are no vaccines developed nor on the horizon for endemic pathogens such as malaria, HIV, multiple intestinal and respiratory bacterial pathogens, and chronic virus infections. The reasons underlying the disparate immune responses of humans and animal models to diseases and immunotherapies remain largely unresolved—mostly because we still are lacking fundamental information on the human immune response in steady state conditions. The vast majority of our knowledge of innate and adaptive human immune responses derives from studies of immune cells in peripheral blood, although the majority of immune cells-- including T lymphocytes which orchestrate adaptive immune responses-- reside in lymphoid and peripheral tissues. However, the identity, composition, functional capacities and regulation of immune responses in lymphoid and non-lymphoid tissue sites remain largely unknown and unexplored. Elucidating this fundamental information on the immune response in the human body is essential for designing new strategies to treat infectious, inflammatory, autoimmune and neoplastic diseases through immunomodulation.
We are taking a novel “whole-body” approach to study human immunity and map the human immune responses throughout the body in both lymphoid, mucosal and non-lymphoid tissues. Through the support of an NIH challenge grant, we have set up a collaboration with CUMC surgeons and the New York Organ donor Network (NYODN) to obtain multiple lymphoid and non-lymphoid tissues from human organ donors. We have focused our initial studies on T lymphocytes which coordinate and regulate adaptive immune responses. In response to pathogen infection, naïve T cells in lymphoid tissue become activated and differentiate to effector cells to migrate to peripheral sites of infection to direct pathogen clearance. While most activated effector cells die after antigen is cleared, a subset persist as long-lived memory t cells in lymphoid and peripheral tissue sites, with large numbers in mucosal tissue such as lung and intestines. T cells in peripheral and mucosal sites can potentially mediate in situ responses to pathogen at their portal of entry, although little is known about peripheral T cell responses in humans. By obtaining tissues from organ donors, we have characterized the phenoptypic and functional properties of T cells derived from multiple lymphoid tissues (bone marrow, thymus, spleen, peripheral and tissue-draining lymph nodes) and mucosal tissue and organs (upper and lower lung, multiple regions of small and large intestine), as well as liver. Our analysis has generated a unique topological “map” of the human immune system, revealing a precise regional and tissue-specific compartmentalization of human naïve and memory T cells with blood T cells distinct from all lymphoid and non-lymphoid T cells in terms of composition, phenotype and function. Our results indicate that the human immune response mediated by naive and memory T cells is exquisitely compartmentalized, suggesting a new model for human T cell differentiation which links T cell fate and function directly to the anatomical site.