Type 1 diabetes (T1D) is an autoimmune disease that is associated with selective destruction of insulin-producing pancreatic islet b-cells. Islet-specific autoantibodies can be detected years or even decades before the onset of clinical disease, and destruction of islet cells ‒ predominantly mediated by autoreactive T lymphocytes ‒ also starts during the asymptomatic phase. The rate of progression to full-blown clinical disease depends on multiple factors including age, sex and HLA genotype of the individual.1
This prediabetic, asymptomatic phase, particularly in those more susceptible individuals, represents a potential ‘window’ during which the immune response can be manipulated to prevent or delay b-cell loss.2
In the pathogenesis of T1D, there is an incredibly complex interplay between various components of the innate and adaptive immune systems, and a variety of non-insulin, immune-targeting approaches have been tested, including restoring self‑tolerance to pancreatic b-cell autoantigens.3,4
An immunomodulation approach
CD3 was identified as a component of the T cell receptor in the late 1970s, and subsequent experiments with the anti-CD3 monoclonal antibody (mAb) OKT3 (Ortho Kung T3) showed that it prevented cytotoxic T cell binding to target cells, via disruption of the TCR-MHC interaction.5,6 This mAb went on to be widely used for prevention of acute graft rejection. Later, anti-CD3 mAbs were found to induce regulatory T cells (Tregs) and support maintenance of tolerance in graft recipients.7
The early anti-CD3 treatment was not without its problems, however; specifically, a potentially fatal cytokine-release syndrome. This acute systemic inflammatory response was associated with the mitogenic activity of anti-CD3 and release of proinflammatory cytokines including TNF-α. This was dependent on binding of the Fc portion of the anti-CD3 mAb, in an antigen-non-specific manner, to monocyte/macrophage FcgR.8 A mitigation strategy for this toxicity was to engineer FcR non-binding anti-CD3 mAbs.9
Observation of the immunosuppressive properties of anti-CD3 mAbs in transplantation tolerance led to research into potential utility of this treatment approach in autoimmune diseases, including in diabetes. Murine studies in the mid-1990s demonstrated prevention of onset as well as durable remission of established diabetes with an anti-CD3 approach,10 and subsequent human studies have shown improved metabolic control, preservation of C-peptide (a marker of residual b-cell function) levels, and, significantly, delayed progression to clinical disease.11
Immune pathways targeted by anti-CD3
The early studies with anti-CD3 mAbs showed disruption of the TCR-MHC interaction, and indeed disappearance of the CD3/TCR from the cell surface, inhibiting pathogenic T cells' ability to recognize the B-cell antigens. Induction of T cell anergy and apoptosis through anti-CD3 mAb-induced signalling can also occur via the CD3/TCR complex. A longer-lasting effect of an anti-CD3 approach is the induction of tolerance, and release of TGF-b by macrophages during phagocytosis of apoptotic pathogenic T cells is an important trigger. TGF-b can induce expansion of regulatory T cells as well as promote a more tolerogenic phenotype of antigen-presenting cells.12,13
Why is an immune-targeting approach appealing?
In T1D, a delay in progression to clinical disease is of considerable clinical importance given the challenges of daily management of the condition and long-term complications.14 The worldwide prevalence of T1D in 2021 was approximately 8.4 million, predicted to increase to 13.5–17.4 million by 2040, with the disease burden expected to worsen.15 Immune-targeting agents that delay the onset of T1D ‒ even by a few years ‒ could have a considerable impact on this projected worsening, not to mention improving the lives of individuals with T1D: “And this matters ‒ each day without type 1 diabetes counts.”14 It also begs the question of whether enhanced screening for T1D, especially in high-risk individuals, should now be a priority for health systems.16
Another question extends the discussion beyond diabetes ‒ would this approach work in other autoimmune diseases? Anti-CD3 mAbs have been trialed in inflammatory bowel disease and multiple sclerosis,13 so there is undoubtedly more to uncover for this approach.
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