Various prophylactic modalities are available today to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). All have demonstrated moderate success in preventing severe GVHD, but they have associated toxicity. Newer biologic-based therapies are emerging that may be safer and less toxic. A review published in Frontiers in Immunology discussed the current literature and concepts surrounding these biologics.
The 3 therapies discussed are T regulatory cells (Tregs), myeloid-derived-suppressor-cells (MDSCs), and mesenchymal stromal cell (MSC) exosomes. “Each specific modality is unique in its mechanism of action, but [they] also share a common theme in their ability to preferentially activate and expand Treg populations in vivo,” the authors explained.
There are 2 types of Tregs, and both have “non-overlapping roles in controlling immune responses.” Thymus-derived Tregs (tTregs) recognize germline self-antigens and induced-Tregs (iTregs) recognize microbiota-derived antigens. Despite differences in the antigens they recognize, when both types are elevated in the graft, they are predictive of survival and correlated with lower rates of GVHD.
Myeloid-derived-suppressor-cells are characterized into 3 main groups: immature-MDSCs (i-MDSC), granulocytic-MDSCs (G-MDSC), and monocytic-MDSCs (M-MDSCs). According to the review authors, “While specific markers of the MDSC populations are still being resolved, the gold standard in defining MDSC populations is their functional ability to restructure T cell responses, suppressing classical T cell activation and promoting Treg development.” Studies show that cord blood is high in MDSC, which may be why rates of GVHD are lower with cord-blood transplants.
Mesenchymal stromal cell exosomes represent yet another rung in the ladder toward GVHD prevention. Similar to how MDSCs promote Treg development, MSC exosomes play a role in inducing MDSC development. In addition, the mechanism of development is poorly understood. “With exosomes often loaded with a multitude of miRNAs and miRNAs able to influence both transcription and post-transcriptional protein expression,” wrote the authors, “studying MDSC development represents an arduous endeavor that is nevertheless essential to fully understand MDSC development.”
These biologic-based treatments aren’t yet standard due to difficulty producing them for mass use, but they represent an exciting approach to improving the quality of life for patients undergoing allogeneic HSCT. The most promising of the 3 appears to be MSC exosomes, as they are the most mass-producible of the approaches and lead to the development of Tregs. “Their eventual use in the clinic will ultimately be decided by their ease of use and long-term efficacy compared to direct cellular therapies which boast strong short term activity but are limited to a single infusion and long-term activity,” the authors concluded.
Exosomes, MDSCs and Tregs: A new frontier for GVHD prevention and treatment