Type 1 diabetes (T1D) is a complex T-cell-mediated autoimmune disease that results in the destruction of insulin-producing beta cells and inadequate insulin secretion. Prior to the discovery of insulin in 1921, patients with T1D died within a year or two of diagnosis. Since the discovery and mass production of insulin, T1D is no longer a terminal disease. However, over time, many patients still develop complications, including cardiovascular disease, retinopathy, neuropathy, and nephropathy.

 

T1D goes through several stages before the onset and the clinical diagnosis is obtained. In fact, the immune response is activated before T1D is diagnosed, and by the time the diagnosis is made, islet autoantigen-specific T cells have destroyed a considerable number of beta cells. In the early stages of the disease, however, the patient's body responds positively to islet antigens. This creates a window of opportunity to intervene and reset the immune system before significant tissue damage occurs.

 

Early attempts at immunomodulation included the use of the calcium-regulated neurophosphatase inhibitor cyclosporine, which was based on successful research in the T1D rat model. In an exceptional result, 16 of the 30 patients treated within 6 weeks of diagnosis reverted to normal C-peptide levels and were insulin-independent. In new-onset T1D, corticosteroids combined daily azathioprine have also shown to be beneficial, and while these approaches have not been employed due to side effects, these trials are nonetheless crucial in highlighting the potential of immunomodulation in T1D.

 

Since then, various immunotherapeutic studies have been conducted with the goal of reducing beta cell loss by focusing on critical immune cells implicated in the disease process and the cytokines they release. A variety of non-antigen-specific immunotherapies have shown promise in preserving beta-cell activity and even slowing T1D progression.

 

Targeting T cells in T1D

CD4+ and CD8+ T cells orchestrate the inflammatory process that ultimately destroys islet β cells and leads to the development of T1D. In T cells, many genes linked to type 1 diabetes risk are highly activated. T cells infiltrate diabetic patients' islets, and in a mouse model, diabetes can be passed from one animal to another via T cell relay. As a result, immunotherapy that targets T cells has attracted a lot of attention.

 

Anti-CD3 immunotherapy

Orthoclone (OKT3) was created in 1979 to target the CD3 receptor's epsilon chain. OKT3 was found to successfully reverse allograft rejection after being administered to the first patients in 1981. OKT3 was the first monoclonal antibody to be approved for transplantation when it became commercially available in 1985. However, due to negative side effects, OKT3 has been used in clinical trials only to a limited extent. Teplizumab is a modified OKT3 antibody that has the same binding area as OKT3 but does not contain the ADCC function.

 

Antithymocyte globulin (ATG)

ATG is a polyclonal IgG that mediates cellular depletion by targeting several T-cell antigens. ATG treatment was able to reverse diabetes in NOD mice in a similar way to anti-CD3 administration. ATG treatment may help protect beta-cell activity, according to preliminary small studies in patients with recent-onset T1D.

 

Abatacept

Abatacept, a CTLA-4-Ig fusion protein, is another type of T cell targeted immunotherapy. CTLA-4 is highly expressed in regulatory T cells, where it interacts with the same ligands as the T cell co-stimulatory receptor CD28 but with a higher affinity.

 

IL-2 therapy

The use of the cytokine IL-2 to selectively amplify Treg cells is another immunotherapeutic strategy for targeting T cells. Because of IL-2's role in immune control, it's possible that mutations in IL-2 or genes involved in IL-2 signaling are linked to autoimmune diseases like T1D. High doses of IL-2 are used to increase antitumor responses in cancer patients, therefore the use of IL-2 to decrease immune responses is an extraordinary example of the same drug being used at different doses for opposite objectives.