Immunotherapy Treatment for Type 1 Diabetes

Immunotherapy treatment for an autoimmune disease (Type 1 diabetes) caused by genetics and exposure to viruses and other environmental factors

Introduction

 

Type 1 diabetes (T1D) or otherwise known as insulin-dependent diabetes is an autoimmune disease, where the body attacks the insulin-producing pancreatic beta cells in your body, caused by genetics, exposure to viruses and environmental factors, this leads to the body not being able to store and release enough insulin. Insulin is a hormone made in the pancreas which lowers the amount of sugar in the bloodstream. When the blood glucose levels drop, the secretion of insulin from the pancreas also reduces. Glucose comes from the food we eat and also from the liver. It is absorbed into the bloodstream, and enters the cells through the help of insulin. However, in type 1 diabetes, there is no insulin to help glucose to enter the cells, therefore glucose builds up in the bloodstream damaging the blood vessels and other vital organs over a period of time.

Signs and Symptoms

Symptoms occur, as there is too much glucose in the blood and it cannot be used as fuel for energy. The symptoms of T1D can be recognised in children much faster than adults. When a person has T1D, they can develop diabetic neuropathy (is nerve damage especially the ones in the legs and fee, symptoms such as numbness. Sharp pains or cramps and muscle weakness), diabetic nephropathy (is a serious kidney-related complication, causing symptoms and signs such as appetite loss, fatigue, high blood pressure and frequent urination) and diabetic retinopathy (damage to the retina. Causing symptoms such as blurring vision, floaters).  When excess glucose builds up in the blood, the kidneys filter and absorb the excess glucose. However, if the kidneys cannot keep up with the process, glucose is excreted into the urine. This causes symptoms such as frequent urination, thirst and fatigue. As the body can’t use glucose due to lack of insulin, it use fat for energy, causing weight loss. High levels of blood glucose can pull fluid from the tissues, including the lenses of the eyes. This affects the ability to focus, creating symptoms such as blurred vision. If the symptoms of T1D is left untreated, it can lead to signs such as diabetic ketoacidosis (DKA), stroke, atherosclerosis, (mention diabetic neuropathy, diabetic nephropathy and diabetic retinopathy if the word limits are high)

Diagnosis

Glycated haemoglobin (A1C) test can be used to diagnose type 1 diabetes. The A1C test indicates the average blood sugar levels for the past 2-3 months. It measures the percentage of blood glucose that is attached to the red blood cells (haemoglobin). If the test gives 6.5 % or higher this means that the blood glucose levels are high, meaning that there are more glucose attached to haemoglobin. This indicates that the person has diabetes. However, if A1C test is not available or the person has a condition (pregnancy or haemoglobin variant) which makes the test imprecise, there are other tests which are done. Random blood sugar test, this is where a blood sample will be taken during random times. If the blood glucose level is 200mg/dL or higher and the person is showing symptoms such as frequent urination and thirst this confirms that the patient has diabetes. Fasting blood sugar test, is when a blood sample is taken after an overnight fast. If the fasting blood glucose level is between 100 – 125mg/dL this is known as prediabetes. However, if the values are over 126mg/dL then this confirms that the person has diabetes. If the patient is diagnosed with diabetes, then the doctor may run a few blood tests to test for autoantibodies which is common in type 1 diabetes. The doctor may also use a urine test stick, which tests for ketones. The presence of ketones in the urine can also suggest that the patient has type 1 diabetes.

 

Pathogenesis (Immune Mechanisms)

The factors that lead to Type 1 diabetes are genetics, exposure to viruses and other environmental factors.

T1D is inherited therefore the autoimmune reaction may be genetic, if a patient has a family member/ close relative who have T1D then there is a high chance that the patient will get T1D than those without T1D relatives. 

T1D can develop in people with Human Leukocyte Antigen (HLA) complex. HLA complex helps the immune system to differentiate the body’s own protein from the proteins which are made by the foreign invaders (bacteria and viruses). There are different HLA complex’s which are linked with T1D, and all of them are on chromosome 6.  When a virus invades the body, T cells produce antibodies to fight the infection. However, if the virus has some antigens same as the beta cells (cells which produce insulin in the pancreas) then the antibodies can destroy the body’s beta cells thinking it is a foreigner. When all the beta cells are destroyed, it leads to the body not being able to produce enough insulin. It takes a very long time for the T cells to destroy beta cells, but the initial viral infection is what caused T1D to develop. This doesn’t mean that all viral infections make T cells turn against beta cells, the virus needs to have specific antigens similar to the ones in the body’s beta cells. And some of the viruses are; B4 strain of the coxsackie B virus, german measles, mumps, rotavirus.

Other environmental factors could include the gut microbiota, being overweight, environmental chemicals, vitamin D deficiency and diet/ nutrition (including cow’s milk or gluten).

Type 1 diabetes is the product from the destruction of insulin-producing pancreatic beta cells by T cells of the immune system. Both CD4+ and CD8+ T cells are needed for disease development, by destroying the insulin-producing β cells through the effector functions of Th1 cells and direct killing by cytotoxic T lymphocytes (CTLs). CD4+T cells (helper cells) are white blood cells which plays an important role in the immune system. The CD4 cell count can indicate the health of the immune system, this means that the healthier the immune system the better the body’s natural defence system against pathogens, infections and illnesses. CD4+T cells recognise peptides which are presented on the MHC class II molecules, located on the antigen presenting cells (APCs). Th1-polarised cells are responsible for the control of intracellular pathogens.  The important cytokines IL-12 and IFN-y are involved in TH1 responses and T-bet and STAT-4 are needed for cell differentiation and function for Th1.

CD8+T cells (killer cells) are important for the immune defence against intracellular pathogens, including viruses and bacteria. It is activated when it recognises its antigen, and it has three major mechanisms to kill the infected cells. First cytokines (TNF- and IFN-y) is secreted, which have anti-tumour and anti-viral microbial effects. Secondly the production and release of cytotoxic granules, which are found in the NK cells. These granules are released only in the direction of the target cell aligned along the immune response. This is so that it eludes non-specific bystander damage to the healthy tissues around it. CD8+T cells are able to release granules to kill an infected cell and then move onto a new target and kill the cell. Lastly CD8+T cell destruction of infected cells is via Fas/FasL interactions. Activated CD8+T cells express FasL onto the surface of the cell, which then binds to the receptor Fas on the target cell’s surface. This binding causes the Fas molecules to trimerise, this attracts other signalling molecules. This causes caspase cascade to activate, and also results in apoptosis of the target cell. CD8+T cells can express both Fas/FasL interaction are a mechanism in which CD8+T cells can kill each other, this is called fratricide, to remove the immune effector cells throughout the contraction phase towards the end of the immune response.

Treatment  

The immunotherapy treatments for type 1 diabetes are; Vitamin D, Antigen-specific therapy, Oral insulin, Anti-T-Lymphocyte Globulin, TNF and BCG 

Taking Vitamin D supplements regularly in early childhood reduces the risk of developing type 1 diabetes, even in later lifetime.

Antigen-specific therapy is used to prevent T1D from developing. The therapy is based on the theory that managing the diabetes autoantigen will be able to control the autoimmune responses by changing the immune system to be a protective rather than destructive response. The antigens which are used is very specific to T1D therefore this treatment is relatively safe.

Administer insulin orally is taken in in a pill form

There are so many different immunotherapy ways to treat T1D.

Administer insulin orally, in a pill form, it disrupts the development of the disease and the immune system is less likely to react aggressively towards it. However, insulin rapidly weakens when it is exposed to gastric acid or digestive enzymes.

 

Tumour necrosis factor ( TNF) could have an impact on the immune system targeting the β cells.

 

Bacillus Calmette-Guerin (BCG) is when the body produces higher levels of Tumor necrosis factor. TNF could have an impact on the immune system targeting beta cells.

 

Beta cell fragments is less of an inflammatory response from the immune system. Patients with less severe inflammatory responses tended to develop type 1 diabetes much slower than those with regular inflammation.

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