Type 1 Diabetes: Immunology and Interventions

Type 1 Diabetes is a complex metabolic disorder. Around the globe, nearly 346 million people have diabetes and in United States alone, 215,000 people below the age of 20 years had type 1 diabetes in the year 2010.Type 1 Diabetes results when the beta cells of pancreas, which produce the hormone insulin, get destroyed by the individual’s own immune system. This reflects a failure in immunological tolerance. In people with normal immunological tolerance, the immune system does not mount an attack against the self antigens. So in type 1 diabetes, the immune system attacks the self antigens, better known as autoantigens.These are chiefly insulin and gluatmic acid decarboxylase (GAD).

Understanding the basic functions of cells of the immune system and key junctions or pathways that contribute to the disease development is vital.

• Briefly, in type 1 diabetes, dendritic cells that constitute one of the antigen presenting cells (APC’s) degrade or process the autoantigenic peptide fragments and present them to the T cell receptor (TCR) present on T helper (Th) cells via major histocompatibility complex (MHC) molecules. During this autoantigen processing, activated dendritic cell secretes interleukin (IL)-12 which converts Th0 cells to become very potent auto reactive effector (Th1) cells. These cells secrete interferon gamma and IL-2 which in turn activate and enable the cytotoxic lymphocytes to cause insulitis or pancreatic islet inflammation. Ultimately, there will be a rise in insulin deficiency and blood sugar levels leading to hyperglycemia-an important pathological and confirmatory sign of type 1 diabetes. However, this basic immunological mechanism was better explored and exploited for the intervention strategies where the main objective was to diminish the activity of detrimental Th1 cells that damage the pancreatic beta cells.

  To date, well-known strategies include the development of antigen specific vaccines namely insulin, GAD65, DiaPep277, Diamyd, whole antigen administration through oral, nasal or intradermal routes etc. Other strategies are of combinatorial approaches where an autoantigen is linked with an adjuvant and administered to animal models or human subjects. An adjuvant is a substance which when linked with an immunogenic agent increases its potential and stimulates the production of antibodies when administered. So, in this approach non-toxic B subunit of the cholera enterotoxin (CTB) from Vibrio cholera is combined with the islet auto antigen.Examples are CTB-INS and CTB-GAD, CTB-GAD + IL-10.

• The above mentioned strategies and relevant examples indicate that antigen specific immunotherapy (ASI) is emerging in the modern biologic era to provide a therapeutic relief to the type 1 diabetic individuals. ASI is based on inverse vaccination where the autoreactive Th1 cells are targeted and inactivated without disturbing the routine immune system schedule.
• Next, intestinal microbe interaction with the host’s immune system has great significance in the pathogenesis of type 1 diabetes. This biological mechanism has also been explored by the investigators which laid a foundation for ‘Probiotic‘ research in the path of diabetic therapy. Probiotics constitute microorganisms in a lively condition, generally bacteria that play a beneficial role in the health and hygiene of individuals. In a recent study reported in the Journal of Clinical Investigation, bacteria Lactococcus lactis was genetically modified to produce the autoantigen proinsulin and IL-10. This approach proved instrumental in reversing the autoimmune mediated type 1 diabetes in experimental animal models like mice, thus raising new hopes for humans.

So, it can be concluded that interventions focusing on immune-targeting of type 1 diabetes are evolving and have great future implications. Precise understanding of immunological machinery of the host, adjuvant usage, pros and cons of interventions currently in use and experimental stages, is essential to gain insights on the treatment strategies of type 1 diabetes mellitus.