Tolerance and type 1 diabetes ‒ regulating immune pathways

Type 1 Diabetes

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 selftolerance 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.  


  1. Ziegler AG, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309:2473-2479. 
  2. Ilonen J, et al. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol. 2019;15(11):635-650. 
  3. Erdem N, et al. Breaking and restoring immune tolerance to pancreatic beta-cells in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2021;28:397-403.  
  4. (Accessed November 2022).
  5. Reinherz EL, et al. A monoclonal antibody blocking human T cell function. Eur J Immunol. 1980;10:758-762. 
  6. Gaglia J, Kissler S. Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance. Biochemistry. 2019;58:4107-4111. 
  7. Waldmann H, Cobbold S. Regulating the immune response to transplants. a role for CD4+ regulatory cells? Immunity. 2001;14(4):399-406. 
  8. Vossen AC, et al. Fc receptor binding of anti-CD3 monoclonal antibodies is not essential for immunosuppression, but triggers cytokine-related side effects. Eur J Immunol. 1995;25:1492-1496. 
  9. Woodle ES, et al. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation. 1999;68:608-616. 
  10. Chatenoud L, et al. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA. 1994;91(1):123-127. 
  11. Herold KC, et al; Type 1 Diabetes TrialNet Study Group. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019;381:603-613. Erratum in: N Engl J Med. 2020;382(6):586.
  12. Chatenoud L. Immune therapy for type 1 diabetes mellitus-what is unique about anti-CD3 antibodies? Nat Rev Endocrinol. 2010;6(3):149-157. 
  13. Kuhn C, Weiner HL. Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy. 2016;8:889-906.  
  14. (Accessed November 2022).
  15. Gregory GA, et al; International Diabetes Federation Diabetes Atlas Type 1 Diabetes in Adults Special Interest Group, Magliano DJ, Maniam J, Orchard TJ, Rai P, Ogle GD. Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study. Lancet Diabetes Endocrinol. 2022;10:741-760. 
  16. Besser REJ, et al. General population screening for childhood type 1 diabetes: is it time for a UK strategy? Arch Dis Child. 2022;107:790-795.  

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