Comparative Ability of Various Immunosuppressants as Adjuvants on the Activity of T1D Vaccine.

Abstract

Background: Type 1 diabetes (T1D) is an autoimmune disorder characterised by the destruction of insulin-producing beta cells in the pancreatic islets, resulting from a breakdown in immunological tolerance. Currently, T1D treatment primarily relies on insulin replacement or immunosuppressive therapies. However, these approaches often have significant drawbacks, including adverse effects, high costs, and limited long-term efficacy. Consequently, there is a pressing need for innovative immunotherapeutic strategies capable of inducing antigen-specific tolerance and protecting beta cells from autoimmune destruction. Among the various antigens, β-cell antigens like 65 kDa glutamic acid decarboxylase (GAD65) have been explored as vaccine candidates for T1D. Despite their potential, their effectiveness in humans remains modest, necessitating the use of appropriate adjuvants to enhance the vaccine's protective effects. Methods: In this study, we evaluated the therapeutic potential of kynurenine (KYN), dexamethasone (DXMS), tacrolimus (FK506), and aluminium hydroxide (Alum) in combination with the GAD65 phage vaccine as adjuvants. Results: Our findings demonstrate that KYN, when used in conjunction with the GAD65 vaccine, significantly enhances the vaccine's immunosuppressive effects. Compared to dexamethasone, FK506, and Alum adjuvants, KYN more effectively reduced the incidence and delayed the onset of T1D, preserved β-cell function, and promoted the induction of regulatory T cells and antigen-specific tolerance. These results suggest that KYN combined with vaccines could offer superior preventive and therapeutic benefits for T1D compared to existing treatments. Additionally, we investigated the dose-dependent effects of the GAD65 vaccine by including a low-dose group in our study. The results indicated that reducing the vaccine dose below 10¹⁰ plaque-forming units (pfu) did not confer any protective advantage or therapeutic benefit in combination with KYN. This finding underscores that 10¹⁰ pfu is the minimum effective dose for the GAD65 vaccine in achieving a protective response. In conclusion, KYN shows considerable promise as an adjuvant for the GAD65 vaccine in T1D therapy, potentially offering a more effective and durable treatment option than current immunosuppressive strategies.