Targeting innate immunity to downmodulate adaptive immunity and reverse type 1 diabetes

Abstract

Type 1 diabetes (T1D) is characterized by specific destruction of pancreatic insulin-producing beta cells accompanied by evidence of beta-cell-directed autoimmunity such as autoreactive T cells and islet autoantibodies (IAAs). Currently, T1D cannot be prevented or reversed in humans. T1D is easy to prevent in the nonobese diabetic (NOD) spontaneous mouse model but reversing new-onset T1D in mice is more difficult. Since the discovery of the T-cell receptor in the 1980s and the subsequent identification of autoreactive T cells directed toward beta-cell antigens (eg, insulin, glutamic acid decarboxylase), the dream of antigen-specific immunotherapy has dominated the field with its promise of specificity and limited side effects. While such approaches have worked in the NOD mouse, however, dozens of human trials have failed. Broader immunosuppressive approaches (originally cyclosporine, subsequently anti-CD3 antibody) have shown partial successes (e.g., prolonged C peptide preservation) but no major therapeutic efficacy or disease reversal. Human prevention trials have failed, despite the ease of such approaches in the NOD mouse. In the past 50 years, the incidence of T1D has increased dramatically, and one explanation is the “hygiene hypothesis”, which suggests that decreased exposure of the innate immune system to environmental immune stimulants (e.g., bacterial products such as Toll-like receptor (TLR) 4-stimulating lipopolysaccharide [LPS]) dramatically affects the adaptive immune system and increases subsequent autoimmunity. We have tested the role of innate immunity in autoimmune T1D by treating acute-onset T1D in NOD mice with anti-TLR4/MD-2 agonistic antibodies and have shown a high rate of disease reversal. The TLR4 antibodies do not directly stimulate T cells but induce tolerogenic antigen-presenting cells (APCs) that mediate decreased adaptive T-cell responses. Here, we review our current knowledge and suggest future prospects for targeting innate immunity in T1D immunotherapy.

T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes

“…While several hundred protocols have prevented diabetes in NOD mice, very few of these have successfully reversed disease, and none have yet been translated to standard clinical practice ( 124 , 125 ). Briefly, tolerance-promoting therapies have generally focused on inhibiting autoreactive T or B cells, decreasing inflammation prior to diabetes onset, or some combination of these approaches.…”

Development of early-stage type 1 diabetes in germ-free interleukin-10 deficient mice

“…The IL-10 KO mouse model allows for the investigation of gut-mediated signaling in disease pathogenesis of the intestine and the pancreas in the presence and absence of the microbiome. While further characterization is required to dissect specific immune compartments and the role of microbial-mediated signaling pathways, our findings support the notion that targeting the microbiome and/or microbial-mediated immune signaling pathways could treat, prevent, or even reverse disease (Kondrashova and Hyöty, 2014; Burrows et al ., 2015; Itoh and Ridgway, 2017). Our work and the amalgamation of knowledge from future studies will perhaps conceive the development of microbe-mediated prophylactic strategies for patients (Gulden, Wong and Wen, 2015; Garyu, Meffre and Cotsapas, 2016).…”

Current understanding of the role of gut dysbiosis in type 1 diabetes

“…Newborn individuals are dependent on their innate immunity to combat pathogens. The hygiene hypothesis suggests that decreased exposure to microbial antigens during early life could result in insufficient stimulation of the gut innate cells that eventually leads to autoimmunity and diabetes . Non‐obese diabetic (NOD) mice reared under strict hygienic conditions exhibit an increased incidence of diabetes than those maintained under specific pathogen‐free conditions .…”

“…The hygiene hypothesis suggests that decreased exposure to microbial antigens during early life could result in insufficient stimulation of the gut innate cells that eventually leads to autoimmunity and diabetes. 92,93 Non-obese diabetic (NOD) mice reared under strict hygienic conditions exhibit an increased incidence of diabetes than those maintained under specific pathogen-free conditions. 94,95 Environmental exposures and immune adaptation were also found to contribute to the incidence of diabetes in human subjects.…”