Can we vaccinate

TYPE 1 DIABETES

Presented By

R.Parthasarathy

"India will face one of the toughest struggles against diabetes in the region. India also accounts for most of the 112,000 children in the region with type 1 diabetes."

-Dhruba Lall Singh,

Chair of IDF's South-East Asia region.

"One person is dying from diabetes every seven seconds” -Dr Ramen Goel

Incidence

Four in every five diabetics are between 40 and 59 years.

Around 78,000 children are developing type 1 diabetes every year.

By 2030, one in every 10 adults

will have diabetes."

India is only second to China

India is home to over 61 million diabetic patients.

By 2030, India's diabetes burden is expected to cross the 100 million

983,000 deaths caused due to diabetes this year.

Incidence

The incidence of type 1 diabetes from Chennai was reported to be 10.5/100,000 per year.

Another study which was conducted for about ten years in South Indian based diabetes group suggested that the frequency of

type 1 diabetes is around 2-5 % of diabetes.

In Caucasian populations (Northern Europe), type1 diabetes incidence rates are high with rates in excess of

20 cases/year/100,000 individuals. Asian countries have extremely low type 1 diabetes incidence

rates, less than 1 case/year/100,000 individuals.

Introduction

Diabetes mellitus is a metabolic disease, characterized by high glucose level in blood (hyperglycemia).

Diabetes mellitusInsulin-dependent diabetes mellitus (IDDM)

Juvenile-onset diabetes

TYPE

TYPE

I

II

1

2Type 1 A Type 1 BAmerican Diabetes Association (ADA)

"Brittle" diabetes

IntroductionType1 diabetes is characterized by the presence of antibodies in blood.

•Glutamic Acid Decarboxylase antigen (GAD) - 65 kD •Insulinoma-associated protein-2 antibodies (IA-2 orICA512) or protein- tyrosinephosphatase (PTP),•Insulin autoantibodies (IAAs),•Islet cell autoantibodies (ICAs).

These are the markers of the immune destruction of the ß cell.Therefore, those with more than one autoantibody(i.e., ICA, IAA,

GAD, IA-2, and TTG) are at high risk.

During initial detection of fasting hyperglycemia, 85-90% of individuals shows presence of one or more of these autoantibodies.

Introduction

Recently a new autoantibody zinc transporter isoform 8(ZnT8) has shown strong association with type 1 diabetes.

ZnT8 causes changes in the secretory pathway, which lead to cell apoptosis and thus directly to reduction of ß cells mass or activation of underlying autoimmunity.

D to D

Environmental factors• viral infections;

• dietary factors in early infancy, • vaccination, • climatic influences, • toxins, and • stress.

Several population studies have found a link between exposure to cow’s milk and increased risk for type 1diabetes in genetically susceptible individuals.

It has been found that infants fed cows milk had increased levels of bovine insulin anti-bodies which appear to cross-react with human insulin.

Bovine insulin is considered immunogenic because it differs from human insulin by three amino acids.

The human intestinal microbial environment also influences type 1 diabetes pathogenesis.

Risk FactorsThere have been two ideas in developing type 1 diabetes autoimmune diseases –•One is to directly attack the ß cell,•Another by affecting the developing immune system thus interfering with the future self/non-self discrimination capacity.

BCG vaccination has an immune-modulatory role and is associated with decreased autoantibody positivity in South Indian diabetic patients.

Immunologists suggesting that infrequent infections and more widespread use of vaccinations lead to an increased risk of childhood diabetes.

Incidence of type 1 diabetes was reported after removal of either Bacille Calmett e-Guerin (BCG) or pertussis from the Swedish national immunization programme and vaccination programme in Finland.

The findings has given mixed results.

Genetic factors

The first diabetes susceptibility genes to be identified were the human leukocyte antigen (HLA) genes, located on chromosome 6p21.31

The disease has strong HLA associations, with linkage to the DQA and B genes, and also it is influenced by the DRB genes.

About 18 regions of the genome have been linked with influencing

type 1 diabetes risk (IDDM1 to IDDM18).

In humans, there are two major classes of T lymphocytes: •CD8 cytotoxic lymphocytes and •CD4 helper lymphocytes.

CD8 cytotoxic lymphocytes recognizes processed antigens bound to MHC class I molecules on the surface of cells (e.g. ß cell)

CD4 helper lymphocytes recognizes processed antigens bound to MHC class II molecules on the surface of antigen-presenting macrophages (APC) and dendritic cells.

In type 1 diabetes, the direct cell-to cell interaction between antigen-specific CD8 cytotoxic T lymphocytes and autoantigens on ß cells results in ß cell killing.

Antigen-specific CD4 helper T lymphocytes act by recognizing autoantigens that have been picked up and processed by APCs expressing class II molecules. This indirect mechanism results in the release of a variety of effector molecules and is

called as bystanderkilling.

These events in the thymus could affect both the CD4 and CD8 T cell repertoires.

Picking of T-lymphocytes with high affinity receptors for self-antigens through a process that takes place in the thymus is termed negative selection.

Thymic positive selection of a cohort of Tregs with receptors for self-antigens, and the generation, maintenance, expansion and function of Tregs in the periphery.

Partial or complete failure of one or all of these mechanisms is required to allow a damaging autoimmune response against the β-cell will leads to Type 1 diabetes.

Immune regulatory mechanisms

Susceptibility may arise through positive selection of autoreactive T cells by positively associated class II alleles.

Protection may occur via negative selection of T regulatory cells, mediated by negatively associated alleles.

Particular interest has focused on post-thymic, peripheral Treg function.

The most extreme example of an etiological link between Treg defects and Type 1 diabetes is seen in children born with mutations in the gene encoding the essential Treg transcription factor FOXP3, who develop diabetes with marked abnormalities in Treg number and function.

In classical vaccination, a powerful protective immune response is induced, with generation of pathogen-specific antibodies, T-lymphocytes that secrete inflammatory cytokines such as interferon-ɣ (known as T helper 1 or T H1 cells) when pathogens are encountered, and T-lymphocytes that kill pathogen-infected cells (cytotoxic T-lymphocytes, [CTLs]).

In vaccination for autoimmune disease, the converse is the aim: to induce self-reactive T-lymphocytes that have potent immune regulatory properties, such as the secretion of anti-inflammatory cytokines like IL-10 and transforming growth factor (TGF)-β.

Currently, the lead setting for using antigens to impact upon an inflammatory disease in man is clinical allergy. (as “allergic desensitization” or “allergen-specific immunotherapy”).

The antigen(s) (allergen extract) are injected as simple solutions into the subcutaneous tissue, typically in the clinical setting of prevention of intractable seasonal pollen allergy or anaphylactic responses to wasp and bee stings. Treatment is typically undertaken for a 1-2 year period, during which the majority of patients show sustained clinical benefit.

“Peptide immunotherapy” has the advantage that only the relevant parts of the allergen need be used in the vaccine, avoiding the risk of antibody allergen

complex formation that can precipitate anaphylactoid responses.

Peptide selection can also be tailored to a particular immune response, thus introducing a step towards personalized medicine.

What antigens could be used in vaccination?Selection of the appropriate antigen(s), is the key step in the development of

vaccine. Tregs utilize a conventional T-cell receptor for antigen, through which signaling

is required to initiate suppressor functions. These implies that the vaccine should be based on the same autoantigens that

are the target of the inflammatory autoimmune response.

First, autoantigens are given to the patients as part of a vaccine strategy. There has been no evidence of hypersensitivity induction.

A second noteworthy point is that a sub-study of oral insulin administration to degree relatives (the Diabetes Prevention Trial-1) demonstrated a significant delay of progression to diabetes, suggesting that a therapeutic effect is achievable.

Heat shock protein-derived peptide 277 (Diapep), a putative diabetes autoantigen, has beneficial metabolic effects when administered parenterally in the context of a recent phase III study.

Clinical Trials

Limitations

Identification of biomarkers

• There is no report of a humanized mouse that regulates glucose via synthesis of endogenous human preproinsulin, is the basis for several vaccine approaches.

Lack of animal model

• Fate of exogenous antigen administered to man and its interaction with the immune system.

Exceration

• Preclinical models suggest that combinations of antigen and anti-CD3 monoclonal antibody therapy can synergise to induce sustained disease protection via induction of immune regulatory pathways.

Finding the best combination or adjunct therapy is challenging.

Opportunities and developments

One example is a novel approach to antigen delivery, using nanoparticles coated with peptide-major histocompatibility complex (MHC) complexes, a technology that appears to work through induction of T cells with regulatory phenotypes.

Another is the use of greater refinement in antigen or peptide selection. The use of naturally processed and presented epitopes.

A particularly novel approach is the delivery of antigen plus IL-10 using Lactococcus lactis as the “Trojan horse”, which has shown considerable promise at the preclinical stage

References:

http://mohfw.nic.in/WriteReadData/l892s/9457038092AnnualReporthealth.pdf

http://articles.timesofindia.indiatimes.com/2011-12-14/india/30515422_1_diabetic-patients-high-blood-sugar-levels-type

http://www.idf.org/atlasmap/atlasmap

http://www.diabetesindia.com/diabetes/itfdci.htm

http://www.dnaindia.com/analysis/column_is-gujarat-the-diabetic-capital-of-india_1652211

http://www.dnaindia.com/mumbai/interview_for-type-1-diabetes-artificial-pancreas-is-ideal-treatment_1655426

http://www.ansi.gov.in/download/APPROACHES_IN_TYPE_1_DIABETES_RESEARCH.pdf

Thanks for your Attention