Beyond Insulin: Immunotherapy for Type 1 Diabetes-PII

Targeting B cells in T1D

B cells have also been associated with the development of T1D. In animal models, B-cell deficiency or absence inhibits the development of diabetes mellitus. In addition, B cells are also potent antigen-presenting cells that activate autoantigen-specific T cells, which can lead to diabetes.

Rituximab binds to CD20 expressed on the surface of B cells, leading to their destruction through antibody-dependent cell-mediated cytotoxicity, apoptosis, and complement-dependent cytotoxicity. Rituximab has shown efficacy in many different autoimmune diseases, including systemic lupus erythematosus, and rheumatoid arthritis.

Targeting inflammatory cytokines

L-1? secretion increases with the progression of diabetes and islet?-cell destruction. However, two randomized, double-blind, placebo-controlled trials, administered with Canakinumab (a human anti-IL-1 monoclonal antibody) and Anakinra (a human IL-1 receptor antagonist), respectively, did not show any protective effect. This is consistent with data from studies in IL-1 receptor or IL-1?-deficient NOD mice, in which no protective effect against the development of diabetes was observed. Similarly, in a recent trial of patients with newly diagnosed T1D, blockade of IL-6Ra did not appear to provide a benefit.

TNF-? has been a target of interest for T1D for some time. Studies in NOD mice have produced complex results suggesting that TNF? exerts site-specific, cell type-specific, and age-dependent effects. Injection of anti-TNF-? antibodies into neonatal mice significantly inhibited the development of diabetes, however, the protective effect was diminished if treatment was initiated in adult mice, and administration of TNF-? itself exacerbated disease in neonatal mice, but conversely delayed disease onset in adult mice.

IL-21 is also attractive as a target for T1D immunotherapy. IL-21 is a characteristic cytokine produced by follicular helper T cells (Tfh cells), which contributes to B-cell antibody production and thus plays an important role in humoral immunity. NOD mice lacking IL-21 or IL-21 receptor are protected from diabetes, whereas transgenic expression of IL-21 in pancreatic islets is sufficient to induce diabetes in non-autoimmune susceptible mice.

Microbial Derived Therapy

Environmental factors such as gut bacterial composition are important in shaping the immune response and regulating T1D susceptibility. These changes in bacterial composition have also been associated with the development of early?-cell autoantibody responses.

Probiotics, a type of bacteria with potential health benefits, have also been extensively studied for their role in modulating T1D susceptibility. In a double-blind randomized trial in healthy adults, Lactobacillus johnsonii N6.2 was shown to be safe to induce a tolerogenic immune response. Studies are currently underway in children, adolescents, and adults with T1D to determine safety, tolerability, and efficacy (NCT03961854 and NCT03961347).

In the 100 years since the discovery of insulin, there is still no cure for T1D. However, the promise of immunotherapy is gradually beginning to materialize, with early signs of progress in both the prevention and neoplastic settings. The key challenge moving forward is to discern which interventions are most appropriate for which disease stage, so a better understanding of the types of disease associated with age at diagnosis will ultimately inform individual stratification of different treatment options. To reduce heterogeneity in clinical response, indicators such as Tfh, Treg, and soluble IL-2R will be crucial.

A fan of biotechnology who likes to post articles in relevant fields regularly