Advancing Animal Models of Human Type 1 Diabetes by Engraftment of Functional Human Tissues in Immunodeficient Mice

Abstract

Despite decades of studying rodent models of type 1 diabetes (T1D), no therapy capable of preventing or curing T1D has successfully been translated from rodents to humans. This inability to translate otherwise promising therapies to clinical settings likely resides, to a major degree, from significant species-specific differences between rodent and human immune systems as well as species-related variances in islets in terms of their cellular composition, function, and gene expression. Indeed, taken collectively, these differences underscore the need to define interactions between the human immune system with human b cells. Immunodeficient mice engrafted with human immune systems and human b cells represent an interesting and promising opportunity to study these components in vivo. To meet this need, years of effort have been extended to develop mice depleted of undesirable components while at the same time, allowing the introduction of constituents necessary to recapitulate physiological settings as near as possible to human T1D. With this, these so-called "humanized mice" are currently being used as a preclinical bridge to facilitate identification and translation of novel discoveries to clinical settings. O ur understanding of TID has been influenced greatly by studies performed using rodent models. The two rodent models studied most extensively are the nonobese diabetic (NOD) mouse and the biobreeding (BB) rat (Greiner et al. 2001). These two rodent models have helped define the autoimmune response that leads to the destruction of b cells and to provide clues into the pathogenesis of T1D. These models have noted that T1D is characterized by a T-cell-mediated immune response against islet autoantigens, that it can be transferred with autoreactive lymphocytes (i.e., T cells), and that the autoimmunity persists long after the loss of

Does the microbiota play a role in the pathogenesis of autoimmune diseases?

“…Several animal models of T1D exist 31. Of these, the non-obese diabetic (NOD) mouse and the biobreeding diabetes-prone rodent model exhibit similar genetic predisposition and pathological disease progression to human T1D and have been used to explore the relationship between the gut microbiome and T1D.…”

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

“…A variety of different rat and mouse models of T1D have been used over the past several decades to investigate the immuno-pathogenesis and treatment of this autoimmune disease. Because a T1D-like disease was found to spontaneously develop in NOD mice without the need for addition of toxic chemicals or infectious agents, it became and continues to be the most popular animal model for T1D preclinical studies (19;167;168). Despite the wealth of information that has been generated related to the immuno-pathogenesis and treatment of T1D using this mouse model, no therapy has been shown to prevent or cure patients with T1D.…”

“…Despite the wealth of information that has been generated related to the immuno-pathogenesis and treatment of T1D using this mouse model, no therapy has been shown to prevent or cure patients with T1D. The differences between mouse and human immune systems as well as differences in islet cell composition and function may be major contributors to this lack of bench to bedside transition (19;168). The development of humanized mouse models based upon the different immuno-deficient IL2rγ −/− stocks provides investigators with immunologically more relevant animal models for investigating immuno-pathogenesis and treatment of T1D.…”

“…The diabetes/hyperglycemia that develops in these mice (called Ins2 Akita mice) are not associated with obesity or insulitis. Backcrossing Ins2 Akita mice with NRG mice produced immuno-deficient offspring that develop spontaneous hyperglycemia by 3–6 weeks of age (19;157;171). Investigators demonstrated that normoglycemia could be achieved by transplantation of human or mouse islet cells (171).…”

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes

“…Such studies have, therefore, been extremely informative as a means to identify important cellular and molecular factors involved (Lally and Bone, 2003), although considerable effort needs to be made to verify that results are translatable to humans. While a large number of potential therapies have been identified in rodents, a means to prevent the human disease remains elusive (Brehm et al, 2012; In't Veld, 2014; Pugliese et al, 2014; Reed and Herold, 2015). …”