Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice

Abstract

Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.

Keywords: Crohn’s disease; human immune system; humanized mice; inflammatory bowels disease; regulatory T cells; ulcerative colitis.

Figure 1

Regulation of the intestinal homeostasis in healthy and IBD inflamed gut. A healthy intestinal epithelial barrier (IEB) in presence of TGF-β, retinoic acid (RA) and IL-2 promote dendritic cells (DCs) and macrophages (mφ) to stimulate the generation of inducible Trges (iTregs). TGF-β and IL-10 are markers that contribute to the generation of iTregs, and establish and maintain the tolerogenic environment in a healthy gut. On the contrary, IBD induced inflammation induces intestinal epithelial barriers and secrete TGF-β, IL-6 and IL-8, stimulating DCs and mφ to produce the inflammatory Th-17 (IL-17A, IL-22, IL-21), Th-1 (IFN-γ, TNF-α, IL-6) and Th-2 type cells (IL-5, IL-6, IL-13) creating an inflammation focus and diseased intestine.

Figure 2

Role of natural and inducible regulatory T cells (iTregs) involved in the pathogenesis of IBD. Inflammation (IL-6) dependent interconversion of regulatory and effector T cell phenotype and role in dol 2, 3 dioxygenases (IDO) in the generation of inducible Tregs (iTregs). Inflammatory (IL-17A, IL-21, IL-22) and immunosuppressive (TGF-β, IL-10) conditions following antigenic stimulation were seen during the conversion of Th17 to iTreg phenotype. This interconversion plays a crucial role in maintaining tolerance towards IBD.

Figure 3

The different types of animal model used to study IBD pathogenesis. In genetically engineered type, different genes are targeting and according to it they are mainly divided into 9 different groups (the detailed information is reviewd in [162]) (adapted and modified from [157,162]).

Figure 4

Schematic presentation of the development of the human immune system (HIS)-repopulated mice by the transplantation of CD34+ human hematopoietic stem cells (HSCs) in NOD.PrkdcscidIl2rg−/− (NSG) immunodeficient mice and the induction of experimental colitis by TNBS to assess the pathology and immunopathogenesis of colitis.