Cell Therapy in Organ Transplantation: Our Experience on the Clinical Translation of Regulatory T Cells

Abstract

Solid organ transplantation is the treatment of choice for patients with end-stage organ dysfunction. Despite improvements in short-term outcome, long-term outcome is suboptimal due to the increased morbidity and mortality associated with the toxicity of immunosuppressive regimens and chronic rejection (1–5). As such, the attention of the transplant community has focused on the development of novel therapeutic strategies to achieve allograft tolerance, a state whereby the immune system of the recipient can be re-educated to accept the allograft, averting the need for long-term immunosuppression. Indeed, reports of “operational” tolerance, whereby the recipient is off all immunosuppressive drugs and maintaining good graft function, is well documented in the literature for both liver and kidney transplantations (6–8). However, this phenomenon is rare and in the setting of liver transplantation has been shown to occur late after transplantation, with the majority of patients maintained on life-long immunosupression to prevent allograft rejection (9). As such, significant research has focused on immune regulation in the context of organ transplantation with regulatory T cells (Tregs) identified as cells holding considerable promise in this endeavor. This review will provide a brief introduction to human Tregs, their phenotypic and functional characterization and focuses on our experience to date at the clinical translation of Treg immunotherapy in the setting of solid organ transplantation.

Adoptive Treg Cell Therapy in a Patient With Systemic Lupus Erythematosus

“…Findings from recent studies suggest that it may be possible to harness the immunoregulatory potential of these cells to treat autoimmune disease, prevent allograft rejection, and attenuate graft‐versus‐host disease . These studies used either low‐dose interleukin‐2 (IL‐2) as a means of pharmacologically augmenting Treg cells or ex vivo expansion and subsequent infusion of autologous Treg cells . While prior studies have demonstrated augmentation of Treg cell numbers and function in peripheral blood, little is known about how these cells affect peripheral tissues.…”

Lymphangiogenesis in a mouse model of renal transplant rejection extends life span of the recipients

“…1 To prevent this and the coincident toxicity of immunosuppression, considerable efforts are being made to develop effective therapeutic strategies for inducing functional immune tolerance, for example by manipulating the leukocytes responsible for rejection, which include allograftspecific T and B cells and the myeloid cells that present alloantigen to them and are effectors of graft injury. [2][3][4][5] Trafficking of the cells responsible for rejection into and out of the graft is an essential part of the allograft response. This occurs via the bloodstream and presumptively by newly formed lymphatic vessels, which develop within days of transplantation and connect rapidly with host lymphatics.…”

A Comparison of Automated Perfusion- and Manual Diffusion-Based Human Regulatory T Cell Expansion and Functionality Using a Soluble Activator Complex

“…It is also well accepted that the pool of human FoxP3 + Tregs is heterogeneous and is dependent on different development conditions, anatomical locations, cytokine microenvironment, levels of transcription factors, mechanisms of suppression, surface biomarkers, and age of the individual 35 – 38 . Harvested Tregs from both flasks and Quantum systems maintained a CD4 + CD25 + FoxP3 + Treg phenotype and memory CD4 + CD25 + FoxP3 + CD45RO + Treg phenotype considered important for maintenance of immune homeostasis 39 – 42 with very high frequencies of these phenotypes at harvest. However, there was a trend toward higher mature Treg and activated Treg frequencies in Quantum system culture versus flask culture.…”