Abstract | Investigators | News | Background | Resources

Rationale: Insulin has been implicated as being a key autoantigen in autoimmune diabetes. Reintroduction of autoantigen in autoimmune disease can generate protective antigen-specific cell mediated immunity. Several animal data suggest that the Th1/Th2 balance plays a crucial roles in the pathogenesis of the disease. Insulin B-chain in IFA has been shown to reduce IFN-gamma (Th1) expression and reduce insulitis. Our preliminary animal data show that insulin B-chain in IFA reduces the diabetes incidence in NOD scid/scid model and prevents insulitis. Our preliminary human studies show extreme Th1 bias in invariant V alpha 24 Jalpha Q+ T-cells of patients with Type 1 diabetes further supporting Th1/Th2 paradigm in human diabetes. This cellular marker can be used along with humoral (IAA, GAD65Ab and IA2Ab and heterophile AB) and metabolic markers (FFIR) to predict development of diabetes in humans, an existing prerequisite for prevention.

Significance: This adjuvant enhanced autoantigen vaccine is a novel approach in human diabetes. It is aimed to stop or slow down the ongoing autoimmunity against pancreatic beta cells at the clinical onset of the disease by immune modulation. At the onset, 15-40% of the beta cells is still intact. Arrest of autoimmune destruction of these beta cells would lead to prolonged or lifelong remission, which is characterized by little or no exogenous insulin requirement. Even only prolongation of the remission time would result in major reduction of insulin therapy and better control; also in delaying the late complications of diabetes it would significantly ameliorate the invasive treatments involved. If successful, this vaccine can be directly applied as prevention in individuals at high-risk for Type 1 diabetes mellitus.

Clinical protocol: We inject human insulin B-chain in IFA once, within a month of diagnosis with Type 1 diabetes mellitus to individuals having insulin autoantibodies. We will assess beta-cell function by repeated measurements of the mixed meal (Sustacal) stimulated C-peptide levels throughout the study as a primary surrogate marker for preservation of beta cell function. We will monitor humoral and cellular markers as secondary markers for effect of vaccine. The endpoint of the study is 24 months.

Mechanistic Studies: Humoral studies include measurements of insulin autoantibodies (IAA), insulin antibody isotyping (IAA isotypes), insulin B-chain antibodies (IBCAb), GAD65 autoantibodies (GAD65Ab), GAD65Ab isotyping, IA2 autoantibodies (IA2-icAb) and heterophile antibodies. The changes in insulin and GAD65 antibody isotype profile could indicate shift in Th1/Th2 balance with increase in IgG1, IgG4 and IgE would support Th2 predominance.

Cellular studies include measurements of CD4- CD8- Vα24JαQ+ T cells cloned from the peripheral blood and stimulated with antiCD3 to analyze their IL-4 and INF-gamma secretion profile. Study frequency and the stimulated cytokine secretion, proinsulin, insulin and insulin B-chain reactive T cell lines generated from peripheral blood mononuclear cells and their relationship to the disease progression. The change if any in the cytokine secretion profile of these T cells would indicate the change of Th1/Th2 balance overtime.

Participating Investigators

	Tihamer Orban,Joslin Diabetes Center, Boston, MA
	Joseph Wolfsdorf, Children’s Hospital, Boston, MA
	David Hafler, Brigham & Women’s Hospital, Boston, MA
	Sally Kent, Brigham & Women’s Hospital, Boston, MA
	Alyne Ricker, Children’s Hospital, Boston, MA

News & Recent Developments

GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes - J Clin Invest [go]

Background Articles

	Randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus - NEJM [go]
	Extreme Th1 bias of invariant V 24J Q T cells in type 1 diabetes - Nature [go]

Resources & Interesting Links

	Joslin Diabetes Center Research [go]
	The Immunology of Diabetes Society (IDS) News [go]