Type 1 Diabetes (1976-2017): Where do we stand?
It’s fascinating how the body’s own cells are recognised as a threat by our immune system. Extensive research has been done so far on different pathways contributing autoimmunity.
Autoimmune diseases are caused due to immune response against self-antigens (body’s own cells/ tissues). The incidence of autoimmune diseases is increasing every year and nearly 3-5% of the world population are affected by autoimmune diseases. The most common diseases are Rheumatoid arthritis, Multiple sclerosis, Type 1 diabetes and Myasthenia gravis. Type I diabetes (T1D) is an autoimmune disease condition caused due to body’s inability to produce insulin (because the beta cells that produce insulin in pancreas are destroyed by our own immune system). A physical anthropologist called Dupertuis examined 225 patients with diabetes from a New York clinic. He was puzzled to observe two distinctive forms of the disease among the patients. He grouped the disease into two types: Type I and Type II diabetes.
In the last 50 years, the disease (causes, symptoms and possible therapeutic interventions) has been extensively studied. T1D is a T cell mediated disease, there are infiltrates of effector T cells (CD4) and cytotoxic T cells (CD8) in the pancreas.
The timeline shows influence of genes in T1D from 1974- 2011, studies has shown that genetic and environmental factors triggers the disease condition.
There are preventive trials (vitamin D3, oral insulin, nasal insulin etc.) approved for type 1 diabetes in the market. The intervention therapies are more effective in T1D; like Antigen-specific immunotherapy (Ag-SIT) treats the disease condition at the specific site and targets the specific antigen that causes the disease. Ag-SIT is used to generate immune tolerance at the target site, by administering the required doses of Ag into the patient (by promote antigen specific T regulatory cells) non-specific therapies usually suppress the entire immune system and insulin substitution therapies.
Some of the promising antigen specific, non-specific and cell based therapeutic intervention under trials (as of 2013)
|Diap277||Induction of Treg via TLRs||Phase III (adults)||Phase I: preserved C-peptide out to 18 mo|
|Ins B in IFA||Tolerance vaccination to insulin B chain||Phase I/II||Ongoing|
|NBI-6024||Tolerance vaccination to insulin||Phase I /II||Phase I: shift Th1 to protective Th2|
|(APL of insulin)||NCT00873561||Phase II: no effect on residual β-cell mass and insulin needs|
|(Proinsulin vaccine)||NCT00453375||No adverse effects|
|GAD65-Alum||Tolerance to GAD65, skewing Th1 to Th2||Phase II (LADA)||Preservation of residual insulin secretion, GAD-specific humoral and cellular immune response, but no protective effect of treatment ≥6 mo after diagnosis, no change in fasting C-peptide after 15 mo|
|Anti-CD20 mAb||B-cell depletion||Phase II/III||C-peptide AUC in MMTT better ≤12 mo|
|CTLA4-Ig Abatacept, Belatacept||Costimulation blockade||Phase II||N/A, recruiting|
|TNF-α blockade etanercept||Anti-inflammatory||Phase I/II||Lower HbA1C and insulin need, increased C-peptide AUC|
|Hematopoietic stem cells||Immune resetting effect||Phase I/II||Some insulin independence, C-peptide AUC increased, HbA1C lower|
|Autologous dendritic cell therapy||Tolerogenic vaccine||Phase I||Ongoing|
Beta-cells replacement (transplantation) is implemented in various scenarios to improve the quality of T1D patient’s life. Combination therapies like immune modulators with islet antigen vaccines and compounds protecting the beta-cells have shown promising results in pre-clinical and early clinical trials (GAD65 plasmid vaccination, anti- CD3 +extenide etc.). Cytokine based therapeutics are used to promote regulatory function (IL-2) and suppress the anti-inflammatory responses.
There is still no definitive treatment for T1D. Insulin injection is the most effective therapy till date.
Ag-SIT is promising compared to other therapies (where the whole immune system is not affected, depends on disease progression and promotes antigen specific T regulatory responses). Successful Ag-SIT depends on the (1) dosage (2) route of administration (3) disease type (4) protein/peptide used and (5) the delivery vehicle. The route of administration and the delivery vehicle play a crucial role in terms of safety of the antigen, its half-life and bio-distribution profile. Nanoparticle mediated delivery is gaining scope and reduces multiple injections for the disease. Some of the nanoparticle based delivery systems are chitosan-insulin nanoparticles, PLGA-insulin nanoparticles, dextran-insulin nanoparticles, polyalkylcyanoacrylated-insulin nanoparticles and solid lipid-insulin nanoparticles. These systems are suitable for oral and pulmonary routes of administration. The nanoparticles system is advantageous over current therapies (biodegradable and easy modifiable). In the future, Nanoparticle mediated drug delivery is believed to improve efficacy of the treatment and quality of patient’s life in T1D.
What are we missing?
NOD (Non-obese diabetes) mice model has been widely used to understand the pathogenesis of T1D. It is used to understand the disease progression and test the therapeutic interventions. Other animal models (mice and rat models) should be considered. In the future, human stem cells can be used to study the pathogenesis of the disease and study the drug targets (can also be used for pre-clinical testing). The type and progression of the disease should be considered before grouping the patients for clinical trial.
Autoimmune diseases, on the whole are prevalent in countries like US, Australia and New-Zealand. But, lesser people suffer from autoimmune disease in south-Asian countries. A population screening and genome wide association studies could potentially give us some insight on T1D pathogenesis.http://www.geneticengg.com/2017/11/22/type-1-diabetes-1976-2017-stand/http://www.geneticengg.com/wp-content/uploads/2017/11/Picture1.pnghttp://www.geneticengg.com/wp-content/uploads/2017/11/Picture1-150x150.pngHealth and MedicineUncategorizedTherapeutic interventionIt’s fascinating how the body’s own cells are recognised as a threat by our immune system. Extensive research has been done so far on different pathways contributing autoimmunity. Autoimmune diseases are caused due to immune response against self-antigens (body’s own cells/ tissues). The incidence of autoimmune diseases is increasing...Ashmitha SundarrajanAshmitha Sundarrajanashmitha.firstname.lastname@example.orgAdministratorGeneticEngg.com