Tolerizing Strategies for the Treatment of Autoimmune Diseases: From ex vivo to in vivo Strategies

Abstract

Autoimmune diseases such as multiple sclerosis (MS), type I diabetes (T1D), inflammatory bowel diseases (IBD), and rheumatoid arthritis (RA) are chronic, incurable, incapacitating and at times even lethal conditions. Worldwide, millions of people are affected, predominantly women, and their number is steadily increasing. Currently, autoimmune patients require lifelong immunosuppressive therapy, often accompanied by severe adverse side effects and risks. Targeting the fundamental cause of autoimmunity, which is the loss of tolerance to self-or innocuous antigens, may be achieved via various mechanisms. Recently, tolerance-inducing cellular therapies, such as tolerogenic dendritic cells (tolDCs) and regulatory T cells (Tregs), have gained considerable interest. Their safety has already been evaluated in patients with MS, arthritis, T1D, and Crohn's disease, and clinical trials are underway to confirm their safety and therapeutic potential. Cell-based therapies are inevitably expensive and time-consuming, requiring laborious ex vivo manufacturing. Therefore, direct in vivo targeting of tolerogenic cell types offers an attractive alternative, and several strategies are being explored. Type I IFN was the first disease-modifying therapy approved for MS patients, and approaches to endogenously induce IFN in autoimmune diseases are being pursued vigorously. We here review and discuss tolerogenic cellular therapies and targeted in vivo tolerance approaches and propose a novel strategy for cell-specific delivery of type I IFN signaling to a cell type of choice.

Allergoid–mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring

“…19,20,[30][31][32] Some of them, such as dexamethasone, minocycline, ethyl pyruvate, or vitamin D 3 , also induce tolerogenic DCs in mice in vivo. 20,33 Here, we demonstrate that allergoid-mannan conjugates can also drive monocyte differentiation into tolerogenic DCs in both nonatopic and allergic subjects. The generated mannan-tolDCs significantly increase the expression of classical tolerogenic molecules and polarize functional FOXP3 1 Treg cells.…”

Immune regulation in renal inflammation

“…Besides Treg-based therapy, application of tolerogenic DCs is currently being tested in clinical trials for the treatment of allograft rejection and autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis since these cells not only induce anergy and apoptosis in effector T cells but also mediate iTreg induction in vivo (Obregon et al 2017 ; Cauwels et al 2020 ). In kidney disease, the protective potential of donor-derived tolerogenic DCs and also Mregs is being explored in renal transplant patients (Obregon et al 2017 ; Amodio et al 2019 ; Cauwels et al 2020 ). Hence, experience gained in this clinical setup might encourage trials using cell-based immunosuppressive therapy as a treatment option for renal autoimmune diseases.…”

Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance

“…Unfortunately, even though these therapies appear to be safe and well-tolerated, much needs to be done to increase therapeutic efficacy. One putative explanation for this observation is that ex vivo cultured DCs are largely monocyte-derived that differ from the naturally occurring DCs in vivo ( 19 ). In addition, ex vivo DC therapy is costly and cumbersome, as cells have to be processed in a controlled, sterile lab environment.…”