Abstract
Chronic graft rejection remains a significant barrier to solid organ transplantation as a treatment for end-organ failure. Patients receiving organ transplants typically require systemic immunosuppression in the form of pharmacological immunosuppressants for the duration of their lives, leaving these patients vulnerable to opportunistic infections, malignancies, and other use-restricting side-effects. In recent years, a substantial amount of research has focused on the use of cell-based therapies for the induction of graft tolerance. Inducing or adoptively transferring regulatory cell types, including regulatory T cells, myeloid-derived suppressor cells, and IL-10 secreting B cells, has the potential to produce graft-specific tolerance in transplant recipients. Significant progress has been made in the optimization of these cell-based therapeutic strategies as our understanding of their underlying mechanisms increases and new immunoengineering technologies become more widely available. Still, many questions remain to be answered regarding optimal cell types to use, appropriate dosage and timing, and adjuvant therapies. In this review, we summarize what is known about the cellular mechanisms that underly the current cell-based therapies being developed for the prevention of allograft rejection, the different strategies being explored to optimize these therapies, and all of the completed and ongoing clinical trials involving these therapies.
Highlights
At present, solid organ transplantation remains the only curative treatment for patients with end-stage organ disease
We summarize what is known about the cellular mechanisms that underly the current cell-based therapies being developed for the prevention of allograft rejection, the different strategies being explored to optimize these therapies, and all of the completed and ongoing clinical trials involving these therapies
The vast majority of animal model studies and all of the clinical trials have utilized the adoptive transfer of only a single cell type
Summary
Solid organ transplantation remains the only curative treatment for patients with end-stage organ disease. Using chimeric antigen receptor (CAR) technology, multiple groups have developed Tregs expressing HLA-A2-specific CARs that have more potent immunosuppressive capabilities compared to polyclonal Tregs in the setting of humanized mouse models with HLA-A2+ skin xenografts, resulting in prevention of skin graft rejection [6, 129,130,131]. MDSCs can be generated ex vivo by co-culturing bone marrow precursor cells with GM-CSF, dendritic cells, and hepatic stellate cells [100] These MDSCs can be adoptively transferred to promote islet cell allograft survival in a manner that is dependent on iNOS expression and results in the expansion and accumulation of antigenspecific Tregs in lymphoid organs close to the grafts when MDSCs are co-transplanted [100, 108]. Several ongoing studies are utilizing donor alloantigenspecific Tregs in the setting of liver transplantation, including the LITTMUS trial (NCT03577431 and NCT03654040), the ARTEMIS
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