Human immunology studies using organ donors: Impact of clinical variations on immune parameters in tissues and circulation

Abstract

Organ donors are sources of physiologically healthy organs and tissues for life-saving transplantation, and have been recently used for human immunology studies which are typically confined to the sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here a coordinate analysis of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain-dead organ donors (2 months-93 years; n = 291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro-inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL-8, IL-6, and MCP-1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donors maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology.

Integration of Omics Data Sources to Inform Mechanistic Modeling of Immune‐Oncology Therapies: A Tutorial for Clinical Pharmacologists

“…We note that the purpose of our study is to demonstrate how omics data can be used to calibrate a QSP model, rather than to qualify a model for application in drug development. Figure 3 shows the constraints on state variables in the minimal CIC model based on data from "Immune Landscape of Cancer" (Figure 1a,b), high-throughput flow cytometry of human donor tissues, [13][14][15] T-cell repertoire sequencing, 16 and the established literature of basic cellular composition of the immune system. State variables describing cell populations in most QSP models in IOincluding the minimal model presented here-are expressed as absolute cell numbers rather than relative amounts.…”

“…In a series of recent studies, Farber's group applied high-throughput flow cytometry to organ donor tissues to quantitatively describe the state of the immune system in healthy individuals. [13][14][15] These unique data provide insight into relative distributions of multiple T-cell types and dendritic cells among different tissues, including lymph nodes. Thome et al 13 studied tissues from 56 donors and determined the distribution of CD4 and CD8 T-cells in peripheral blood, spleen, inguinal lymph node (draining the peripheral skin and muscle), lung-draining lymph node, lungs, mesenteric lymph node (draining the intestines), small intestine (jejunum and ileum), and colon.…”

A single-cell reference map for human blood and tissue T cell activation reveals functional states in health and disease

“…These findings suggest that localization of T cells in tissues likely involves structural changes in the cell that facilitate interactions with tissue matrix. 9 We compared the single-cell distribution of average expression of tissue signature genes in the blood and three tissues ( Fig. 3d).…”

“…In humans, most of our knowledge of T cell activation and function derives from the sampling of peripheral blood. Recent studies in human tissues have revealed that the majority of human T cells are localized in lymphoid mucosal and barrier tissues 8 and that T cell subset composition is a function of the specific tissue site 9,10 . Human TRM cells can be defined based on their phenotypic homology to mouse TRM and are distinguished from circulating T cells in blood and tissues by a core transcriptional and protein signature [10][11][12][13] .…”

“…This approach has been applied to analyze human T cells in diseased tissues 25,26 and in response to immunotherapies in cancer 27 ; however, the baseline functional profiles of human T cells in healthy blood and tissues have not been defined. We have established a tissue resource where we obtain multiple lymphoid, mucosal, and other peripheral tissue sites from human organ donors [9][10][11]13,28,29 , enabling study of T cells across different anatomical spaces. Here, we used scRNA-seq of over 50,000 resting and activated T cells from lung (LG), lymph nodes (LN), bone marrow (BM) and blood, along with innovative computational analysis to define cellular states of homeostasis and activation of human blood and tissue-derived T cells.…”