Can we vaccinate TYPE 1DIABETES 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 IDFs South-East Asia region."One person is dying from diabetes every seven seconds” -Dr Ramen Goel
Incidence India is home to over 61 million diabetic patients. 983,000 deaths caused due to diabetes this year. 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." By 2030, Indias diabetes burden is expected to cross the 100 millionIndia is only second to China
IncidenceIn Caucasian populations (Northern Europe), type1 diabetes incidence rates are high with rates in excess of20 cases/year/100,000 individuals.Asian countries have extremely low type 1 diabetes incidence rates, less than 1 case/year/100,000 individuals.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.
Introduction Diabetes mellitus is a metabolic disease, characterized by high glucose level in blood (hyperglycemia). TYPE I 1 Insulin-dependent diabetes mellitus (IDDM) Juvenile-onset diabetesDiabetes mellitusAmerican Diabetes Association TYPE Type 1 A II 2 1 B Type (ADA) "Brittle" diabetes
IntroductionType1 diabetes is characterized by the presence of antibodies inblood.•Glutamic Acid Decarboxylase antigen (GAD) - 65 kD•Insulinoma-associated protein-2 antibodies (IA-2 orICA512) orprotein- 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.
IntroductionRecently 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.
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 Factors There 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.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.BCG vaccination has an immune-modulatory role and is associated with decreased autoantibody positivity in South Indian diabetic patients.
Genetic factors The disease has strong HLA associations, with linkage to the DQA and B genes, and also it is influenced by the DRB genes. The first diabetes susceptibility genes to be identified were the human leukocyte antigen (HLA) genes, located on chromosome 6p21.31 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 Imolecules on the surface of cells (e.g. ß cell)CD4 helper lymphocytes recognizes processed antigens bound to MHC class IImolecules on the surface of antigen-presenting macrophages (APC) and dendriticcells.In type 1 diabetes, the direct cell-to cell interaction between antigen-specific CD8cytotoxic T lymphocytes and autoantigens on ß cells results in ß cell killing.Antigen-specific CD4 helper T lymphocytes act by recognizing autoantigens thathave been picked up and processed by APCs expressing class II molecules. Thisindirect mechanism results in the release of a variety of eﬀector molecules and iscalled as bystanderkilling.These events in the thymus could aﬀect both the CD4 and CD8 T cell repertoires.
Immune regulatory mechanismsPicking 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.Particular interest has focused on positive selection of autoreactive T cells by Susceptibility may arise through post-thymic, peripheral Treg function. positively associated class II alleles.The most extreme example of an etiological link between Treg defects and Type1 Protection may occur via negative selection of T regulatory cells, mediated by diabetes is seen in children born with mutations in the gene encoding theessential Treg transcription factor FOXP3, who develop diabetes with marked negatively associated alleles.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.
Clinical Trials 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.
Limitations Identification of biomarkers Lack of animal model • There is no report of a humanized mouse that regulates glucose via synthesis of endogenous human preproinsulin, is the basis for several vaccine approaches. Exceration • Fate of exogenous antigen administered to man and its interaction with the immune system. Finding the best combination or adjunct therapy is challenging. • 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.
Opportunities and developmentsOne 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