Mesenchymal stromal cells in transplantation rejection and tolerance

Abstract

Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cell-based immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.

Figure 1.

Influence of ischemia reperfusion injury on MSC function. Ischemia reperfusion injury (associated with organ retrieval) leads to the production of DAMPs including HMGB-1 and HSPs among others. Signaling through PRRs including TLRs, NOD receptors, and RAGE results in the activation of the complement system, recruitment of innate immune cells (neutrophils and macrophages), and the production of reactive oxygen species (ROS). Depending on the timing, dose, and route of administration, MSC given to patients in the context of SOT may encounter an ischemia reperfusion microenvironment. MSCs express a number of PRRs including NOD, RAGE, and TLRs, and activation of these receptors through DAMPs like HMGB-1 and HSPs may determine MSC function. Signaling through RAGE, NOD-like receptors, or TLR4 on MSC may lead to the promotion of a proinflammatory environment leading to the production of the proinflammatory cytokines IL-6, IL-8, and TNF-α, neutrophil recruitment, and complement deposition resulting in elevated serum creatinine and accelerated graft rejection. Alternatively, activation of TLR3 on MSC may induce an anti-inflammatory milieu, reducing the production of proinflammatory cytokines (IL-1β, TNF-α, and IFN-γ), decreasing ROS and apoptosis, and generating tolerogenic dendritic cells and Treg facilitating graft acceptance.