Treatment of Graft-versus-Host Disease with Naturally Occurring T Regulatory Cells

Abstract

A significant body of evidence suggests that treatment with naturally occurring CD4+CD25+ T regulatory cells (Tregs) is an appropriate therapy for graft-versus-host disease (GvHD). GvHD is a major complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of death after bone marrow transplantation. Tregs constitute a population responsible for dominant tolerance to self-tissues in the immune system. These cells prevent autoimmune and allergic reactions and decrease the risk of rejection of allotransplants. For these reasons, Tregs are considered as a cellular drug in GvHD. The results of the first clinical trials with these cells are already available. In this review we present important experimental facts which led to the clinical use of Tregs. We then critically evaluate specific requirements for Treg therapy in GvHD and therapies with Tregs currently under clinical investigation, including our experience and future perspectives on this kind of cellular treatment.

Phenotypic Complexity of the Human Regulatory T Cell Compartment Revealed by Mass Cytometry

“…In this procedure, Tregs are isolated from a patient, expanded in vitro, and then reinfused (9,11). Because its intranuclear location precludes the use of FOXP3 as a marker, isolation of Tregs for clinical use is achieved based on a surface phenotype of CD4 + CD25 high CD127 low (10).…”

“…The inclusion of increased numbers of subjects in future studies will support observation and establishment of potential disease-specific differences in the composition of the human Treg compartment. Similarly, the clinical application of in vitro-expanded Tregs is under intensive investigation in the context of a wide spectrum of human diseases including autoimmunity, transplantation, and graft-versus-host disease (9)(10)(11). The investigatory approaches we present in this study could be pivotal to completely profiling the Treg compartment and identifying the optimal population or combination of subpopulations that may be more efficacious within the context of a particular immune insult, provide a stratified approach with regards to Treg cell therapy, and, importantly, further our understanding of Tregs during both health and disease.…”

“…Intensive research has helped inform a consensus of the critical role Tregs play in both health and disease. The clinical manipulation of Tregs is currently under intense investigation in autoimmunity, transplantation, graft-versus-host disease, and anticancer therapy (9)(10)(11)(12)(13). However, it is not possible to isolate viable Tregs based on FOXP3 expression (given its intranuclear location).…”

“…However, it is not possible to isolate viable Tregs based on FOXP3 expression (given its intranuclear location). Current protocols rely on isolation of highly pure Tregs defined as CD4 + CD25 high CD127 low cells for in vitro studies focused on Treg biology and functionality (10) or as the starting material from which to expand Tregs for adoptive cell therapy, which involves the isolation and expansion of Tregs from an individual followed by reinfusion (9,11,13). However, it is now clear that in humans, Tregs are in fact a heterogeneous mixture of cellular subphenotypes reflecting different states of maturation, differentiation, and activation (reviewed in Refs.…”

Stellate Cells in Hepatic Immunological Tolerance

“…It is worth mentioning that LPS pretreatment of HSCs increased their ability to expand Tregs, but did not affect their immunosuppressive function beyond that by unstimulated HSCs [56]. The impressive ability of HSCs to modulate Tregs may have significant potential for Treg therapy, which is being tested clinically to treat graftversus-host disease, autoimmune diseases, and inflammatory diseases [135][136][137]. Even though KCs are also shown to expand Tregs, they are inferior to freshly isolated cells in their immunosuppressive potential and LPS treatment of KCs actually reverses the suppressive activity of KC-expanded Tregs [138].…”