Reverse Vaccine in Type 1 DM

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Reverse Vaccine in Type 1 DM Phase II study

Immune intervention for type 1 diabetes mellitus http://onlinelibrary.wiley.com/doi/10.1111/j.1742-1241.2010.02580.x/pdf

The exact mechanism of how antigen-specific tolerance is achieved is not clear, but induction of regulatory T cells has been postulated

Anti CD-3 Teplizumab and otelixizumab are non-Fc receptor binding CD3-specific humanized monoclonal antibodies (mAbs) that act in a biphasic manner. Initially, there is a partial depletion of activated pathogenic T cells, and this effect is short-lived. The second durable response is postulated to involve the induction of regulatory T (TReg) cells. Interleukin-10 (IL-10)-producing and FOXP3+ CD4+ and CD8+ TReg cells have been described. The CD4+ TReg cell population is thought to act through the production of transforming growth factor-β (TGFβ) and IL-10. This induced TReg population may inhibit autoreactive T cells to pancreatic islet β-cells and thereby restore tolerance. (APC, antigen-presenting cell; MHC, major histocompatibility complex)

What is Type 1 A diabetes? The major form of type 1 diabetes (T1D) is characterized by immune-mediated pancreatic islet b-cell destruction Has also been called type 1A diabetes to distinguish it from idiopathic forms of islet b-cell loss.

Who is the culprit in Beta Cell Destruction? Since the first demonstration of islet cell antibodies in 1974, the concept has been that this form of diabetes is autoimmune in nature. The commonly accepted concept is that antibodies (representing the humoral arm of the immune system) do not mediate the b-cell destruction but rather serve as markers of that destruction. The cellular arm of the immune system, specifically T-lymphocytes, mediate the b-cell destruction.

Who helps T cells? The T-lymphocytes do not act alone. They receive help in initiating the response from antigen-presenting cells such as dendritic cells and macrophages, and appear to receive help also from B-lymphocytes. In addition, the initial immune response engenders secondary and tertiary responses –involving the whole immunological army – which collectively result in impairment of b-cell function, progressive destruction of b-cells, and consequent development of type 1A diabetes.

How does this destruction happen? The process is insidious and may evolve over many years, with the overt expression of clinical symptoms becoming apparent only when most b-cells have been destroyed. Yet, the process clearly evolves at different speeds – much more rapidly in young children, much more slowly in older individuals.

The hope! Although it has been thought that ultimately there is complete b-cell destruction, several studies have now demonstrated some degree of persistent b-cell function or existence (at autopsy) in long-standing T1D. A major focus of investigation in T1D is the preservation of b-cell function (and, it is hoped, of b-cells themselves), in the expectation that continuing endogenous insulin secretion will contribute towards better glycemic control, reduce episodes of severe hypoglycemia, and slow the development of complications such as retinopathy and nephropathy

Studies on Immune system alternations. There have been many studies designed to interdict the T1D disease process, mostly by altering the immune system, both during the stage of evolution of the disease and at the time of disease onset.

CD3 antibody trial Relatively short courses of treatment (6 or 14 days) with an anti-CD3 monoclonal antibody can have sustained effects on b-cell function – as measured by C-peptide – for a long as 4 to 5 years. Both of the anti-CD3 antibodies used – otelixizumab and teplizumab – are now being studied in full-scalephase 3 trials for potential commercialisation for use in recent-onset T1D. Thus, the fact that there are long-term beneficial effects is important. Nonetheless, in the original trialswith both of these antibodies, there was progressive decline in b-cell function, suggesting that there may be a need for repeated courses of administration. Alternatively, the efficacy of these antibodies might be improved if used in combination therapy with another agent (or agents) acting synergistically to improve b-cell function.

TOL-3021 TOL-3021 may have the potential to alleviate or even shut down the destructive disease process in type 1 diabetes. TOL-3021 preserved pancreatic beta-cell function while reducing destructive disease-specific T-cell activity in patients with type 1 diabetes. 

What does TOL-3021 supposed to do? Unlike conventional vaccines, which act to stimulate the immune system, the reverse vaccine TOL-3021 is designed to selectively suppress specific elements of the immune system that are inappropriately activated in type 1 diabetes. TOL-3021 contains an engineered DNA plasmid that expresses proinsulin, which is associated with the autoimmune-caused destruction characterizing type 1 diabetes. The Phase 2 trial was designed to assess whether TOL-3021 could decrease these autoimmune attacks on pancreatic beta cells and improve their functioning.

What was the study? The Phase 2 trial was a randomized, blinded, placebo-controlled, dose escalation trial in 80 adult type 1 diabetics. Patients received one of four doses of TOL-3021 as an injection once a week for 12 weeks The data indicate that TOL-3021 was safe and well-tolerated, with no serious adverse events and no increase in adverse events overall compared to placebo.   C-peptide, a marker of pancreatic beta cell function, improved after administration of all doses of TOL-3021 compared to placebo. For example, at week 15, C-peptide increased by 19.5% from baseline with the 1 mg dose of TOL-3021, compared to a decrease of 8.8% in patients on placebo (p<0.026).  Furthermore, an indicator of underlying disease activity, the number of CD8 T-cells reactive to proinsulin, declined with TOL-3021 treatment, while T-cells against other antigens, such as infectious pathogens, were unaffected (p<0.006). 

Was the effect permanent? One finding of the new study was that once patients stopped injections, the body's insulin-production capabilities appeared to drop again, so the treatment's effect was not permanent.

Which dose worked? The trial was done in 80 patients ages 18 to 40 who had been diagnosed with Type 1 diabetes within 5 years.  Patients were given an injection of the compound or placebo once a week for 12 weeks, and researchers looked at levels of C-peptide as a marker of the function of insulin-producing beta cells. Patients taking a 1-milligram dose of TOL-3021 had their C- peptide levels rise 20 percent, compared with a decline of 8.8 percent for patients on placebo