Oral Tolerance Therapy in Type 1 Diabetes Mellitus

Oral Tolerance Therapy in Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by the T cell-mediated destruction of pancreatic beta cells, leading to a near-complete loss of insulin production. This insulin deficiency results in the inability to regulate blood sugar levels, necessitating exogenous insulin administration for patients to manage their blood sugar and reduce the risk of chronic diabetic complications. Additionally, a positive correlation has been observed between diabetes mellitus and hypertension. The autoimmune attack on pancreatic beta cells, mediated by T cells, is considered the final step in the development of T1DM. Various autoantibodies targeting different proteins can be detected months or even years before the clinical onset of T1DM. These autoantibodies serve as biomarkers of beta-cell injury rather than its cause. The exact mechanism triggering this autoimmune process remains elusive, posing a significant challenge in preventing T1DM. Current research suggests that interactions between genetic susceptibility and environmental factors are crucial in the development of T1DM. While genetic factors are relatively well understood, environmental determinants such as diet, viral infections, and the bacterial microbiome in the gastrointestinal tract (GIT) remain poorly characterized. Despite extensive research, few studies have successfully prevented the onset of T1DM.

Oral tolerance is an adaptive process where the immune system becomes unresponsive or hyporesponsive to an orally administered antigen. This process plays a vital role in maintaining a balance between reactions against exogenous antigens and the body’s self-components. As a physiological response to dietary antigens, oral tolerance primarily develops in the GIT. Although most orally delivered antigens are digested into short peptides or amino acids, a small amount of intact antigens can reach the intestinal epithelium. The gut-associated lymphoid tissue (GALT), composed of Peyer’s patches (PPs) and mesenteric lymph nodes (MLNs), is heavily involved in inducing oral tolerance. CD103+ dendritic cells (DCs) harboring autoantigens derived from the gut migrate to the MLNs, which are identified as a critical site for oral tolerance induction. However, PPs may not be necessary for this process. In the MLNs, CD103+ DCs presenting antigens meet naïve CD4+ and CD8+ T cells, and oral tolerance induction occurs in an antigen dose-dependent manner, including low- and high-dose tolerance. Repeated encounters with low-dose antigens result in the generation of regulatory T cells (Tregs), which help induce oral tolerance. A single encounter with a high-dose antigen induces anergy or deletion of antigen-specific T cells in GALT, contributing to oral tolerance.

Given that T1DM is a predictable disease, individuals at risk can be identified years before clinical onset, making oral tolerance an attractive antigen-specific immunotherapy (ASI) for delaying or preventing T1DM. Oral tolerance trials in non-obese diabetic (NOD) mice can be categorized into two types: direct oral administration of a single autoantigen and combinatorial therapy. The latter includes combinations of different autoantigens, autoantigens with various delivery vehicles, immune adjuvants, or immunomodulatory agents. Recent studies have shown that oral administration of HSP65-6�P277-loaded gut DCs-targeting nanoparticles prevented T1DM in all immunized NOD mice by repairing Th1/Th2 imbalance and increasing the proportion of functional CD4+Foxp3+CD25+ Tregs. Similarly, oral administration of a single-chain insulin analog delivered by bacterium-like particles suppressed T1DM progression in NOD mice through a similar mechanism.

In human clinical trials, insulin is the only autoantigen used for oral tolerance therapy. Oral insulin (7.5 mg/day) did not delay or prevent T1DM in autoantibody-positive individuals; however, subgroup analyses revealed a beneficial effect in patients with confirmed insulin autoantibody (IAA) levels ≥80 nU/mL. These findings suggest that IAA levels may be a crucial recruitment criterion for such studies. The Pre-POINT randomized clinical trial, a primary prevention trial, demonstrated that oral insulin (67.5 mg/day) induced a regulatory immune response without hypoglycemia in T1DM-high-risk children with no signs of islet autoimmunity. The enhanced saliva IgG towards insulin and regulatory profiles of T cells responding to insulin among treated individuals indicated successful oral tolerance induction.

As an ASI, oral tolerance therapy, when applied appropriately, can restore the immune system’s durable tolerance to disease-related autoantigens. Most previous studies indicate that oral administration of T1DM-related autoantigens has a positive effect in preventing, delaying, or reversing the disease in NOD mice. However, these preclinical reports are somewhat conflicting regarding the timing of therapy initiation, frequency and dosage of autoantigen administration, treatment duration, type of autoantigen applied, demand for combinational reagents, and, most importantly, the degree of efficacy. Some studies have shown that oral autoantigen therapy has no effect on delaying or preventing T1DM onset in animal models, possibly due to the degradation of antigens passing through the GIT, resulting in minimal autoantigen reaching the mucosal immune surface and subsequently influencing tolerance induction.

Despite the effectiveness of some oral insulin therapies in animal models, their clinical translation has not been achieved. Important differences in the progression of T1DM between animal models and humans may be responsible for this translation failure. Additionally, humans exhibit more complex immune system regulation compared to mouse models, potentially resulting in a lower immune response to similar dosages of autoantigens. It is also essential to note that efficacy rather than safety is more emphasized in animal studies, with potential treatment-associated complications less investigated or documented. However, the safety of oral tolerance induction must be considered in clinical trial design, leading to the application of lower doses of orally administered autoantigens and the exclusion of some combinational therapies using various delivery vehicles, immune adjuvants, or immunomodulatory agents.

As an antigen-based immunotherapy, oral tolerance therapy shows promise for restoring immune tolerance to autoantigens and subsequently preventing, delaying, or reversing T1DM. To achieve this aim in human clinical trials, several factors need careful consideration. First, immune biomarkers with improved sensitivity and specificity are required to identify individuals at risk of T1DM as early as possible. Second, since T1DM is a heterogeneous disease, not all patients may respond similarly to one therapy strategy, necessitating more personalized approaches for tolerance induction. Third, results from animal and human tests suggest that preventing T1DM through oral tolerance therapy may be more feasible than arresting or reversing its effects after clinical onset. Therefore, assuming it is safe, oral tolerance therapy should be introduced in at-risk subjects, often children, as early as possible before clinical onset. Finally, animal studies indicate that combinational therapies involving autoantigen administration with immune adjuvants or immunomodulatory agents have the potential to safely prevent or stably reverse disease processes. Although such combination studies in humans have not been published and may be challenging to conduct, these strategies still hold high therapeutic potential.

doi.org/10.1097/CM9.0000000000001130

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