New perspectives on the biology of acute GVHD

Abstract

The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as: (1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

Figure 1

Pathways of antigen presentation in GVHD. The direct and cross-presentation pathways of antigen presentation. Endogenous antigens released by autophagy can be presented to CD4⁺ T cells through a novel MHC class II pathway.

Figure 2

GVHD sensors, (APC)-mediators and (T cell) interactions. The critical interaction for induction of GVHD is the activation of its primary mediators, donor T cells by the primary sensors, the professional APCs. This interaction is enhanced or negatively regulated by a plethora of other immune cell subsets, cytokines and chemokines.

Figure 3

GVHD effectors and amplifiers. Target organ apoptosis is induced both by (a) cellular effectors such as CD4⁺ and CD8⁺ effector T cells that induce epithelial cell apoptosis through the perforin/granzyme pathway or by the Fas/FasL pathway and (b) by inflammatory effectors such as IFN-γ, TNF-α, IL-1 cytokines and nitric oxide (NO) secreted not only by the effector T cells but also by a variety of other cells such as activated macrophages.

Figure 4

Network of immune cell interactions in GVHD. Complex interactions exist between the various factors that contribute to the pathophysiology of GVHD. The lines between the nodes represent interactions and the node size is proportional to the number of factors interacting with the node. The network was created using Cytoscape version 2.6.3.