Tissue tolerance: a distinct concept to control acute GVHD severity

Abstract

Target tissue damage occurs as a consequence of pathological immune responses following allogeneic stem cell transplantation resulting in acute graft-versus-host disease (GVHD). Among those who study infections in plants, it is well recognized that tissues play a distinct role from the immune system in mediating disease severity. Recently, this has also been appreciated in mammals. However, the severity of immunopathology in the context of alloimmune diseases such as acute GVHD has been mainly understood and managed by direct targeting of immune cells to generate immune tolerance. The role of tissue-intrinsic factors that might contribute to regulation of acute GVHD severity has been largely overlooked. Here, we introduce the concept of "tissue tolerance" to discuss the tissue-specific programs that contribute to target tissue resilience, repair, and regeneration, and mitigate severity of acute GVHD without altering the load or function of alloreactive immune cells.

© 2017 by The American Society of Hematology.

Figures

Figure 1.

Modeling the relationship between immune elicitor, health, and tolerance. (A) Disease tolerance is measured by plotting host health over changing pathogen burden. (B) Tissue tolerance is determined by plotting host health over changing immune stimuli. Adapted from Ayres and Schneider, Medzhitov et al, and Schneider and Ayres with permission.

Figure 2.

Tissue tolerance interacts with immune tolerance to mediate immunopathology.

Figure 3.

Differential organ tissue-specific responses to allogeneic immune attack.

Figure 4.

Tissue tolerance is context dependent. (Line a) A linear relationship by health and immune burden regulated by tissue tolerance. (Line b) Another linear relationship, but one where tissue tolerance may appear to be greater or less than (line a) depending on measurement conditions. (Line c) A nonlinear mode of tissue tolerance–mediated regulation of health where tissue tolerance may appear relatively high or low depending on measurement conditions. Adapted from Little et al with permission.