Immunotherapy: From Treating Diabetes to Preventing Diabetes

Diabetes mellitus was a fatal disease for humans 100 years ago. Its development of begins with the fact that the child's immunity after some trigger (stress, illness) starts to damage his beta-cells of the pancreas that produce insulin. Insulin is a hormone that helps the body remove excess glucose from the bloodstream, store sugar, and use it when energy is needed. With the destruction of the insulin-producing beta cells, the blood sugar becomes too high. Therefore, the kidneys, which in a healthy state return sugar to the blood, cease to retain it in the body. And the diabetes patient loses sugar in the urine. In addition, the entire carbohydrate metabolism breaks down due to a violation of glucose metabolism, and because of this, the body does not have enough energy, the acidity of the blood changes, and the person weakens. A person with severe type 1 diabetes is a pale child with yellowish skin and hair that is falling out. He cannot get out of bed and loses more energy through sugar in the urine than he receives from food. [1, 2]

In the early 1920s, that all changed when scientists isolated insulin from the animal pancreas. Then it turned out that pancreatic extract is able to restore the health of patients with diabetes mellitus, roughly balancing carbohydrate metabolism [1]. Later in the 1970s, scientists learned how to make the hormone by inserting the human insulin gene into bacteria. Synthetic insulin turned out to be less immunogenic than animal insulin and became a breakthrough in the field of biotechnology [3]. However, insulin is not a drug because it does not treat the cause of type 1 diabetes - the immune system's destruction of the beta cells that produce insulin. To cure type 1 diabetes mellitus, it is necessary to influence the human immune system. So today various methods of immunotherapy of the disease are being developed.

In their search for a cure for diabetes, scientists turned their attention to a protein that helps T cells that kill beta cells acquire autoimmunity. An antibody called teplizumab was created against this CD3 receptor. 25 years ago, this antibody was found to reverse diabetes in mice [4]. Now, in human trials, teplizumab has even been found to delay the onset of diabetes in people at high risk of diabetes by at least two years (compared to placebo) [5]. Teplizumab is under consideration for US Food and Drug Administration approval as a biologic therapy for type 1 diabetes. Teplizumab is the most successful drug targeting T cells, with many other options currently in the early stages of development.

However, not only T cells but also B cells are involved in the pathogenesis of diabetes mellitus. Different B cells can activate T cells against pancreatic beta cells and synthesize antibodies to insulin, which trigger the attack of beta cells and inflammation. Therefore, an antibody to the CD20 B-cell receptor, rituximab, was created. CD20 is involved in B cell activation, and rituximab has helped in diabetic mice. But rituximab alone could not effectively weaken the autoimmunity against its own beta cells in humans [6]. Nevertheless, suppression of B-cell activity with rituximab may help if combined with anti-T cell therapy [7]. Rituximab successfully helps young patients due to the fact that they have a particularly large number of B cells.

Immunotherapy can help patients with diabetes mellitus at different stages of the disease. But now researchers are trying to prevent diabetes before it develops. After all, type 1 diabetes is a genetic disease, the predisposition to which is inherited. Scientists know many genes that are associated with a high likelihood of developing diabetes as a child grows older. And now they are discussing how it is possible to prevent the onset of diabetes mellitus with the help of genetic tests and pre-prescribed immunotherapy [8].

Alexander Khazanov

References:

1. Banting, Frederick Grant, et al. "Pancreatic extracts in the treatment of diabetes mellitus." Canadian Medical Association Journal 12.3 (1922): 141.
2. de Leiva-Hidalgo, Alberto, and Alejandra de Leiva-Pérez. "Experiences of first insulin-treated patients (1922–1923)." American journal of therapeutics 27.1 (2020): e13-e23.
3. Fineberg, S. E., et al. "Immunogenicity of recombinant DNA human insulin." Diabetologia 25.6 (1983): 465-469.
4. Chatenoud, Lucienne, and Jeffrey A. Bluestone. "CD3-specific antibodies: a portal to the treatment of autoimmunity." Nature Reviews Immunology 7.8 (2007): 622-632.
5. Sims, Emily K., et al. "Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals." Science translational medicine 13.583 (2021).
6. Pescovitz, Mark D., et al. "Rituximab, B-lymphocyte depletion, and preservation of beta-cell function." New England Journal of Medicine 361.22 (2009): 2143-2152.
7. Smith, Mia J., John C. Cambier, and Peter A. Gottlieb. "Endotypes in T1D: B lymphocytes and early onset." Current Opinion in Endocrinology, Diabetes and Obesity 27.4 (2020): 225-230.
8. Dayan, Colin M., et al. "Preventing type 1 diabetes in childhood." Science 373.6554 (2021): 506-510.