OUTLINE

Introduction Prevalence Factors Key

and burden

affecting T1D

disease predictors

Pathophysiology Treatment Hypothesis

options: current & future

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T1D: AN AUTOIMMUNE DISORDER

Metabolic disorder of multiple etiology causing cell destruction of the islets of Langerhans cells in the pancreas Characterized by hyperglycemia and defects in the insulin secretion, its action or both. Constitute 5-10% of total diabetic populations Synonyms: Juvenile or childhood diabetes, Insulin dependent diabetes mellitus (IDDM) At the time of diagnosis 70-80% -cell destroyed

PREVALENCE AND BURDEN

WHO

estimates: 346 million diabetes patients

worldwide
Globally

ranked 6th cause of death 380 million T1D patients by the year

Estimated

2025 (vast proportion being juveniles <5 yr of age)

For

all age groups, estimates at 2.4% -2000 &

4.4%- 2030
Incurring

heavy care costs!!

Global Prevalence of Diabetes- Estimates for the year 2000 & projections for 2030; Sarah Wild et al. ; Diabetes care, Vol. 27, No. 5, May 2004

SIGN & SYMPTOMS

Polydypsia

( frequent thirst) Polyphagia (frequent hunger) Polyuria (frequent urination) Weight loss & weakness Frequent infections Blurred vision Poor wound healing Tingling/numbness in the hands/feet

COMPLICATIONS
Retinopathy Nephropathy Neuropathy Diabetes Heart

More common in T1D than T2D

foot disease (leading to amputation)

diseases (cholesterol?)

Hyperlipidemia Ketoacidosis

& coma
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NATURAL HISTORY OF T1D

PUTATIVE ENVIRONMENTAL TRIGGER
100%

CELLULAR (T CELL) AUTOIMMUNITY

HUMORAL AUTOANTIBODIES
(ICA, IAA, Anti-GAD65 etc.)

BETA CELL MASS

GLUCOSE INTOLERANCE
(OGTT)

GENETIC PREDISPOSI TION

INSULITIS BETA CELL INJURY

80%

PREDIABET ES

CLINICAL ONSET DIABET ES

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TIME

FACTORS AFFECTING T1D: GENETIC FACTORS

T1D Genetic Consortium (T1DGC) & Genome Wide Association Studies (GWAS)

Major histocompatibility complex (MHC) Human Leukocyte Antigen (HLA) on 6p21 chromosome. High susceptibility on HLA class II genes (especially alleles at DR &DQ position)

In contrast several HLA-II alleles are protective also (DQB1-0602) Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX): Mutation of FoxP3 gene

Autoimmune polyendocrinopathy syndrome type 1 (APS-1 or APECED): Mutation of AIRE gene Non-HLA risk associated gene: PTPN22, CTLA-4, INS and IL2RA identified in GWAS
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FACTORS AFFECTING T1D: ENVIRONMENTAL

Virus: Enterovirus (EV) , Coxsackie (CBV), rubella, mumps, rotavirus, cytomegalovirus and Epstein Barr virus (EBV). Most of the evidence is in favor correlating EV with T1D. Biopsy and isolation of HEV from pancreatic islet. Dietary factors:

Cows milk, Gluten, Vitamin D and Nitroso compounds

BABYDIAB & TEDDY STUDY (PROSPECTIVE) ONGOING!!!

KEY T1D PREDICTORS

o o

HLA typing Immunological autoantibodies - Insulin or proinsulin autoantibody (IAA), different isoforms of glutamic acid decarboxylase (GAD65 or GAD67), Insulin-associated antibody (IA2) & recently identified zinc transporter (ZnT8) Cytoplasmic islet-cell antibody assay used Metabolic marker - C-peptide secretion (marker of insulin production) HbA1C level (glycated haemoglobin)

o o

No single method is appropriate marker hence a combination approach adopted!!!

PATHOPHYSIOLOGY
Self-antigens normally not pathogenic

APC (DC, macrophage)

Major role as APC rather than autoantibody

Activation of autoreactive CD4+ & CD8+ T cell in peripheral lymph nodes

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TREATMENT OPTIONS: CURRENT & FUTURE

No

treatment till date!! Only management or little protection possible Insulin replacement Drawbacks: Not a permanent remedy Risk of hypoglycemia Pancreatic & Islet transplant Drawbacks : Transplant rejection Pancreas & islet shortage Intense Immunosuppression

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TREATMENT OPTIONS: CURRENT & FUTURE

Stem cells Human ES cells- Ethical issues and risk of teratocarcinoma MSC & HSC cells substitute to ES cells Adult human MSC (Prochymal) Phase II Autologous umbilical cord blood infusion Phase I/II Hematopoietic stem cell- Phase I/II

ViaCyte 1st company to engineer hESCs into definitive endoderm Encaptra- Encapsulation technology

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TREATMENT OPTIONS: CURRENT & FUTURE

Humanized

Anti-CD3 mAbs : blocks antigen presentation to T-cells Prolonged -cell function in new-onset of disease for > 1 yr with single course of treatment (Herold et al., 2005) Anti-CD20 mAbs (Rituximab) : transient depletion of B-lymphocytes (Pescovitz et al., 2009) Several other non-antigen based methods such as Cytotoxic T lymphocyte associated immunoglobulin (CTLA4Ig/Abatacept) : blocks the interaction of CD28:B7 (APC:T-cell) Cytokine therapy : dual sword Th1 (IL-1, IL-2, TNF- & IFN-) type or Th2/Th3 (IL-10 & TGF-) type 13

ANTIGEN SPECIFIC THERAPY

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ANTIGEN SPECIFIC THERAPY

GOAL:

To re-educate the immune system Downside: Uncertainty in maturation based on signal strength & costimulation Questions unresolved: 1. Optimal antigen dose 2. Most appropriate adjuvants to induce Tregs 3. Antigen design for delivery to the lymphatic system T-cell recognition 4. Route of vaccine delivery best suited to tolerization
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CONTINUED
1st

peer review clinical trials on GAD65 vaccination by

Diamyd (GAD65-alum) full length recombinant GAD65 used

Proven

safe in Phase II studies, however, failed to

show any improvement in Phase III

Elevated

levels of cytokines (IL-5, IL-10, IL-13, IL-17)

& higher levels of TGF- & Foxp3+

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PRO-INSULIN

Specific to islets Auto Abs to pro-insulin common to T1D Muir et al., 1995 : SC immunization with A-chain & Bchain in IFA. 93% protection seen with B-chain (9-23) (infiltration of cytokines but protective) Potent effect with 9-23 sequence compared to native insulin or full-length B-chain NBI-6204 (B-chain: 9-23) in Phase II (safety confirmed) but no report on immunogenic capability
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