Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions

Abstract

Balancing the immune response after solid organ transplantation (SOT) and vascularized composite allotransplantation (VCA) remains an ongoing clinical challenge. While immunosuppressants can effectively reduce acute rejection rates following transplant surgery, some patients still experience recurrent acute rejection episodes, which in turn may progress to chronic rejection. Furthermore, these immunosuppressive regimens are associated with an increased risk of malignancies and metabolic disorders. Despite significant advancements in the field, these IS related side effects persist as clinical hurdles, emphasizing the need for innovative therapeutic strategies to improve transplant survival and longevity. Cellular therapy, a novel therapeutic approach, has emerged as a potential pathway to promote immune tolerance while minimizing systemic side-effects of standard IS regiments. Various cell types, including chimeric antigen receptor T cells (CAR-T), mesenchymal stromal cells (MSCs), regulatory myeloid cells (RMCs) and regulatory T cells (T_regs), offer unique immunomodulatory properties that may help achieve improved outcomes in transplant patients. This review aims to elucidate the role of cellular therapies, particularly MSCs, T cells, T_regs, RMCs, macrophages, and dendritic cells in SOT and VCA. We explore the immunological features of each cell type, their capacity for immune regulation, and the prospective advantages and obstacles linked to their application in transplant patients. An in-depth outline of the current state of the technology may help SOT and VCA providers refine their perioperative treatment strategies while laying the foundation for further trials that investigate cellular therapeutics in transplantation surgery.

Keywords: SOT; VCA; cellular therapies; solid organ transplantation; vascularized composite allotransplantation.

Figure 1

(A) Enhancing T_regs to promote tolerance in heart transplantation. This figure illustrates the sequential steps from the in vitro induction of T_regs using TGF-β and IL-12 cytokines to the maturation of Foxp3⁺CD4⁺CD25⁺ T_regs. Additionally, the diagram provides a schematic representation of a human heart transplant, indicating the flow of blood through major vessels and heart chambers. This enhancement process is expected to improve transplant tolerance, reduce rejection rates, and potentially lower the need for immunosuppressive drugs (66). (B) Development of CAR-T_regs for targeted immunosuppression in a mouse model. The process begins with the extraction of T_regs from the mouse bloodstream, followed by their engineering to express CARs recognizing specific HLA molecules on transplanted tissues. The diagram depicts the binding of modified T_regs (CAR-Tregs) to HLA-A2+ allografts, showcasing antigen-specific activation. The expanded CAR-T_regs are then reintroduced into the mouse’s circulatory system. This targeted approach aims to minimize drug dosages, extend allograft survival, and reduce the risk of off-target side effects (67, 68).

Figure 2

Mechanisms of MSC-mediated immune modulation in SOT. Infused MSCs interact with various immune cell populations, impacting Th17 and T_regs cell dynamics. The presence of MSCs further fosters the emergence of IL-17A⁺Foxp3⁺ cells and transitions IL-17-producing T cells to an IL-17A^-Foxp3⁺ phenotype. This MSC-induced alteration facilitates the direct conversion of pro-inflammatory Th17 cells to anti-inflammatory T_regs (92).

Figure 3

Interactions of MSCs with immune cells and their mediated cytokines. MSC illustrates the role in modulating various immune responses through cytokine secretion and direct interactions with multiple immune cell types. Dendritic cells (DC) and regulatory dendritic cells (RDC) and their differentiation modulated by cytokines such as 1L-6, HGF, TGF-β, and PGE2 (131). Macrophages (MI and M2) showcase the polarization of macrophages into Ml (pro-inflammatory) and M2 (anti-inflammatory) phenotypes in the presence of 1L-6 and other modulating factors. MSCs play a role in this differentiation through the release of cytokines like PGE-2, IDO, and 1L-6 (132). T Cells illustrates the various T cell subsets - Th1, Th2, Treg, and Th17, and their interactions with MSCs. Cytokines like HGF, TGF-β1, PGE-2, 1DO, and IL-10 play a role in modulating these T cell responses (133). MSCs impact B cells and natural killer (NK) cells through the secretion of mediators such as PGE-2, PD-1, VEGF for B cells and IDO, INF-γ, PGE-2, IL-2, IL-12, IL-18, and TNF-α for NK cells (134).