Myeloid and Mesenchymal Stem Cell Therapies for Solid Organ Transplant Tolerance

Abstract

TRANSPLANT TOLERANCE AND TOLEROGENIC CELL TYPESImmunological tolerance is the "holy grail" of transplantation and describes nonreactivity of the recipient's immune system to the nonself, immunogenic donor Review Abstract. Transplantation is now performed globally as a routine procedure. However, the increased demand for donor organs and consequent expansion of donor criteria has created an imperative to maximize the quality of these gains. The goal is to balance preservation of allograft function against patient quality-of-life, despite exposure to long-term immunosuppression. Elimination of immunosuppressive therapy to avoid drug toxicity, with concurrent acceptance of the allograft-so-called operational tolerance-has proven elusive. The lack of recent advances in immunomodulatory drug development, together with advances in immunotherapy in oncology, has prompted interest in cell-based therapies to control the alloimmune response. Extensive experimental work in animals has characterized regulatory immune cell populations that can induce and maintain tolerance, demonstrating that their adoptive transfer can promote donor-specific tolerance. An extension of this large body of work has resulted in protocols for manufacture, as well as early-phase safety and feasibility trials for many regulatory cell types. Despite the excitement generated by early clinical trials in autoimmune diseases and organ transplantation, there is as yet no clinically validated, approved regulatory cell therapy for transplantation. In this review, we summarize recent advances in this field, with a focus on myeloid and mesenchymal cell therapies, including current understanding of the mechanisms of action of regulatory immune cells, and clinical trials in organ transplantation using these cells as therapeutics. (Transplantation 2021;105: e303-e321).

Lymph Node Fibroblastic Reticular Cells Attenuate Immune Responses Through Induction of Tolerogenic Macrophages at Early Stage of Transplantation

“…Despite several studies reporting that macrophages accelerate aGVHD, they can be therapeutic depending on the number, properties, and utilization pattern. 46,47 However, it is still unclear how macrophages in SLOs especially in LNs are generated. Recently, Valencia et al have found that FRCs in LNs secrete several factors related to macrophage expansion.…”

Transcriptomic Analysis Identifies A Tolerogenic Dendritic Cell Signature

“…This paper further highlights the need for further -omic studies to identify a consensus gene expression profile, including distinct signaling pathways, that can confirm tolDC function and stability in vivo . Despite the reported safety of tolDC in early-phase human trials ( 17 ), and known efficacy in large animal models ( 76 ), potential variability in clinical grade tolDC preparations remains a concern for translational purposes. The advent of standardized tolDC manufacturing through Focus and Accelerate Cell-based Tolerance-inducing Therapies ( 77 ) aims to minimize variations in approach and is a key step towards a standardized tolDC production for pre-clinical studies and clinical trials.…”

“…Although expression appears relatively conserved between species, tissues and disease models ( 2 ), the same standardized characteristics are not yet available for tolDC. Indeed, tolDC used in recent clinical studies did not have uniform methods for generation, phenotype or functional measurements ( 17 ). To date, there is no consensus for “gold-standard” validation of tolerogenic properties, and current methods range from analysis of cell-surface markers to allogeneic T cell stimulation ( 10 ).…”

miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2

“…Bone marrow mesenchymal stem cells (BMMSCs) have the characteristics of easy access, a high proliferation rate, and low immunogenicity. They play an important role in organ injury repair and transplantation immune regulation [ 4 – 6 ]. However, the complex pathophysiological environment in the lesion, such as oxidative stress, seriously limits the survival of BMMSCs and reduces the efficacy of BMMSCs transplantation.…”