Recombinant Lactococcus lactis can make the difference in antigen-specific immune tolerance induction, the Type 1 Diabetes case

Sofie Robert, Lothar Steidler, Sofie Robert, Lothar Steidler

Abstract

Especially in western civilizations, immune diseases that are driven by innocuous (auto- or allo-) antigens are gradually evolving to become pandemic threats. A particularly poignant example is type 1 diabetes, where young children are confronted with the perspective and consequences of total pancreatic β-cell destruction. Along these disquieting observations we find ourselves equipped with impressively accumulating molecular immunological knowledge on the ins and outs of these pathologies. Often, however, it is difficult to translate this wealth into efficacious medicines. The molecular understanding, the concept of oral tolerance induction, the benefit of using recombinant Lactococcus lactis therein and recent openings towards their clinical use may well enable turning all colors to their appropriate fields on this Rubik's cube.

Trial registration: ClinicalTrials.gov NCT00729872 NCT00938080.

Figures

Figure 1
Figure 1
T1D onset and development. Genetic predisposition and environmental exposure interact with an impaired immune system to break tolerance towards pancreatic insulin-producing β-cells. Initial β-cell destruction leads to release of β-cell-specific auto-Ags, such as pro-insulin, GAD65, IA-2 and others. Upon auto-Ag-recognition, auto-reactive T cells expand, migrate to the pancreas (insulitis) and induce progressive β-cell destruction. In healthy individuals these auto-reactive T cells are controlled by regulatory T cells (Tregs). However, in T1D patients this regulatory counterpart is impaired causing a significant imbalance of this immune control mechanism. In addition, auto-Ag-activated B lymphocytes produce β-cell-specific auto-Abs. When patients present with clinical symptoms caused by insufficient β-cell-mass and subsequent aberrant glucose regulation, this auto-Ab profile allows for specific diagnosis of immune-mediated T1D. In general, T1D patients can only rely on exogenous insulin substitutions to stabilize their glucose metabolism. Possible therapeutic targets involved in the pathology of T1D are highlighted (gray boxes). Both systemic immunomodulation, amongst others monoclonal anti-CD3 antibodies and cyclosporine A, and Ag-based approaches have been explored to restore tolerance.
Figure 2
Figure 2
L. lactis can bridge the gaps towards Ag-specific immune therapy. State of the art research on (auto-) immune diseases allows for mechanistic understanding of these pathologies, in terms of onset, precise localization (red circle), cellular compartment and specificity of the auto-Ag (Ag; wedge). The current standard of care exists of systemic immune suppression which may alleviate some aspects of the immune pathology but very often, due to its systemic and Ag-nonspecific nature, comes associated with moderate to even severe toxicity in otherwise non-affected organs. Purified Ag (blue triangle), delivered through the oral route, aims to make proficient use of inherent oral tolerance induction at the intestinal mucosal immune system to provoke Ag-specific suppression of the immune disease without affecting areas that do not share the Ag (X). This route of administration however suffers from major practical obstacles which make it difficult to administer sufficient, high quality Ag to the intestinal mucosa. To circumvent this, recombinant L. lactis expressing the Ag (blue circle holding white triangle) can be delivered through the oral route. These bacteria can then synthesize Ag of reproducible quality directly at the intestinal immune system and by co-synthesis of immune modulatory components can further enhance tolerance induction. In this way, Ag-specific oral tolerance induction is rendered practically feasible.

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