Press release : Reversal of Type 1 diabetes through restoration of immune tolerance via the gut
Posted on | April 12, 2012 | No Comments
Type 1 diabetes melllitus (T1DM) is an autoimmune disease characterised by immune-mediated destruction of insulin-producing beta-cells in the pancreas. The incidence of T1DM in childhood is increasing at about 3% per year. T1DM is the most common metabolic disease in the young. In Europe, about two million people (around 0.5 % of the population) and several million people world-wide suffer from this disease. At present, T1DM cannot be prevented or arrested in its course and lifelong insulin therapy is needed for survival. Still, chronic complications, such as eye disease, kidney disease and vascular disease, affect lifespan and in particular quality of life. Since it carries such a significant chronic disease burden, T1DM has become a major public health concern worldwide, emphasizing the urgent need for safe and effective intervention and prevention strategies.
The true cause of T1DM remains elusive, but an autoimmune destruction of the insulin-producing beta-cell in the pancreas lies at the basis and finding ways to interfere with this immune system, aimed as restoring tolerance in a specific way towards the beta-cell without interfering with the immune defences of the subject opens the way for prevention of this disease. To date, several interventions have been assessed in patients with T1DM and treatment with antibodies directed against a marker of T lymphocytes, anti-CD3, have been the most promising. However, till now, solid evidence on the applicability of this intervention in a safe and acceptable way in patients is lacking.
The group at the University of Leuven (KU Leuven) has been involved in studies on prevention and intervention in T1DM, extending from bench to bedside. Prof. C. Mathieu leads a basic science laboratory specialised in in vitro studies and animal models of type 1 diabetes, and is head of the clinical Endocrinology department, where over 1000 patients with T1DM are being treated. In that clinical department, several clinical studies on diabetes therapies are currently taking place.
The laboratory is part of several research networks, funded by national and international agencies, amongst which the JDRF (Juvenile Diabetes Research Foundation), FWO (Fonds Wetenschappelijk Onderzoek Vlaanderen), and the European Commission. The latter supports a network on Immune Intervention in T1DM (NAIMIT), in the context of Framwork 7.
The work published on April 9th in the Journal of Clinical Investigation, is the fruit of a collaboration of several groups within the NAIMIT consortium, amongst which the company Actogenix, inventors of ActobioticTM, live biologically-contained genetically-modified Lactococcus lactis, able to deliver proteins and peptides of choice in the gut. The paper reports on the ability of ActoBioticTM (which secrete both the auto-antigen pro-insulin and the immune-modulatory cytokine interleukin-10 (IL-10), to arrest progression of diabetes in an animal model of T1DM, when administered in combination with a low dose of anti-CD3 antibody (5 days). When newly diagnosed, overtly diabetic NOD mice were treated with this regimen, a stable remission could be induced, lasting stably for weeks after therapy was interrupted. Extensive immune phenotyping of the mice revealed increased local regulatory T-cell frequencies which not only accumulated in the pancreatic islets, but also suppressed in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, arguing against excessive immunosuppression.
Considering the fact that these findings report on reversal of overt diabetes, without immune suppression, but with restoration of antigen-specific tolerance via the gut, these findings are of the utmost clinical relevance, as translation to the human setting is easily realizable.
NAIMIT Annual Meeting – 7 November 2011 – Leiden, The Netherlands
Posted on | September 2, 2011 | No Comments
Program
NAIMIT Annual Meeting – 7 November 2011 – Leiden, The Netherlands
Location:
Kasteel Oud-Poelgeest
Poelgeesterweg 1, 2341 NM Oegstgeest
, Leiden, The Netherlands
10.30 – 11.00 Arrival and welcome coffee
11.00 – 11.35 Jay Skyler – State of the art lecture on Clinical Prevention and Intervention Studies in Type 1 Diabetes
11.35 – 12.00 State of the Moment on NAIMIT – Chantal Mathieu
12.00 – 13.00 Lunch break
13.00 – 13.45 WP1 – Re-educating antigen-presenting cells
Introduction by WPL Bart Roep
Bart Roep: Tolerogenic Dendritic Cell Therapy
(25min talk + discussion)
13.45 – 14.30 WP2 – Restoring the T-cell balance
Introduction by WPL Mark Peakman
Mark Peakman: Towards T-cell tolerance
(25min talk + discussion)
14.30 – 14.50 Ezio Bonifacio: Update on FP7– DIAprepp
14.50 – 15.35 WP3 – TCR-directed immunotherapy
Introduction by WPL Chantal Mathieu
Rebecca Ashfield: ImmTAC technology applied to Cancer and Diabetes
(25min talk + discussion)
15.35 – 15.50 coffee break
15.50 – 16.35 WP4 – Mucosal intervention for tolerance restoration
Introduction by WPL Francesco Dotta
Pieter Rottiers: Mucosal tolerance induction with genetically engineered Lactococcus lactis
(25min talk + discussion)
16.35 – 16.55 Mikael Knip: DIABIMMUNE: Testing the hygiene hypothesis in type 1
diabetes and other immune-mediated diseases
16.55 – 17.40 WP5 – Beta-cell protection and restoration: dialogue with the immune
system. Introduction by WPL Decio Eizirik
Decio Eizirik: The beta-cell, more than a target in type 1 diabetes
(25min talk + discussion)
17.40 – 18.25 WP6 – Pharmacogenetics: towards individualised therapies.
Introduction by WPL Klaus Badenhoop
John Todd: Understanding genes- towards personalized medicine
(25min talk + discussion)
Registration is free, but please send an e-mail to
Lut.overbergh@med.kuleuven.be to confirm your participation before 1st of November
NAIMIT Annual Meeting – 22 – 24 November 2010 – Hannover, Germany
Posted on | November 20, 2010 | No Comments
Program
Monday 22 Nov 2010
12.00- 14.00 Arrival/Welcome – Lunch Buffet
Training Session – Part 1
14.30 – 15.30 Invited Speaker
G Breves (TiHo, Hannover),
Title: Probiotics as immunomodulatory agents and the function of the intestinal tract
15.30 – 15.45 Coffee Break
WP5 – Beta-cell protection and restoration: Dialogue with the immune system – WP leader DL Eizirik
15.45 – 15.50 DL Eizirik (ULB, Brussels) – Overview
15.50 – 16.10 F Moore (ULB, Brussels)
Title: The gene networks regulating STAT-1/IRF-1-induced insulitis
16.10 – 16.25 L Overbergh (KUL, Leuven)
Title: Gene networks modulated by cytokines and vitamin D in mice
16.25 – 16.40 F Dotta (UNISI, Siena)
Title: Islet regeneration
16.40 – 16.55 S Lenzen (MHH, Hannover)
Title: Diabetes prevention in the IDDM rat: Vitamin D and other compounds
16.55 – 17.10 Discussion
17.10 – 17.45 L Overbergh (KUL, Leuven)
Administrative Issues
19.00 Dinner in town
Tuesday, 23 Nov 2010
WP 1 – Re-educating antigen-presenting cells – WP leader B Roep
09.00 – 09.05 Bart Roep – Overview
09.05 – 09.20 T Nicolic (LUMC, Leiden)
Title: Generation of GMP grade DCs and future perspectives
09.20 – 09.35 F Kleijwegt (LUMC, Leiden)
Title: Mechanism of action of human Tregs generated by tolerogenic DCs
09.35 – 09.50 G Bomfim Ferreira (KUL, Leuven)
Title: Proteomic analysis of Vitamin D and Dexamethasone – modified DCs.
09.50 – 10.05 M-B Zocca (DanDrit, Denmark)
Title : SOPs and regulatory issues for clinical translation of DC therapy
10.05 – 10.20 Discussion
WP2 – Restoring the T-cell balance – WP leader M Peakman
10.20 – 10.25 M Peakman (KCL, London) – Overview
10.25 – 10.45 CM Dayan (CU, Cardiff)
Title: Progress on optimizing the tolerogenic potential of the skin for peptide immunotherapy
10.45 – 10.50 P Bingley (UB, Bristol)
Title: Establishing a clinical network for T1D mechanistic and intervention trials
10.50 – 11.00 M Peakman & V Gibson (KCL, London)
Title: Establishing a platform for multi-peptide immunotherapy
11.00 – 11.05 M Peakman (KCL, London)
Title: Phase Ib study of mono-peptide immunotherapy
11.05 – 11.20 Discussion
11.20 – 11.30 Coffee Break
WP3 – TCR-directed immunotherapy – WP leader C. Mathieu
11.30 – 11.35 C Mathieu (KUL, Leuven) – Overview
11.35 – 11.50 R Ashfield (IMC, Abingdon)
Title: Engineering T cell Receptors specific for beta-cell antigens
11.50 – 12.05 C Gysemans (KUL, Leuven)
Title: sTCR specific for beta-cell antigens in treatment of diabetes
12.05 – 12.15 S Megit (IMC, Abingdon)
Title: TCRs for human beta-cell antigens and future perspectives
12.15 – 12.35 J Demengeot (FCG, Lisboa)
Title: In vivo and in vitro suppression assays
12.35 – 12.50 Discussion
12.50 – 13.45 Lunch
13.45 – 14.30 Steering committee
WP 4 – Mucosal intervention for tolerance restoration – WP leader F Dotta
14.30 – 14.35 F Dotta (UNISI, Siena) – Overview
14.35 – 14.50 P Rottiers (AGX, Zwijnaarde/Ghent)
Title: Actobiotics™ in new onset T1D: development of prototypes of L. lactis strains expressing single and multiple beta-cell-specific antigen(s)
14.50 – 15.05 H Korf (KUL, Leuven)
Title: Use of recombinant ActoBiotics in preclinical mouse models
15.05 – 15.20 F Dotta (UNISI, Siena)
Title: L. rhamnosus GG and human iTreg in vitro induction
15.20 – 15.35 Discussion
15.35 – 15.55 Coffee Break
WP6 – Pharmacogenetics: towards individualised therapies – WP leader K Badenhoop
15.55 – 16.00 K Badenhoop (GUF, Frankfurt) – Overview
16.00 – 16.15 K Badenhoop (GUF, Frankfurt)
Title: Vitamin D genetics and peripheral immunity: Pilot study ViDDA1
16.15 – 16.30 E Ramos-Lopez (GUF, Frankfurt)
Title: Vitamin D pathway genes and vitamin D metabolites in T1D
16.30 – 16.45 Todd (UCAM, Cambridge)
Title: Vitamin D and TCR signaling: ongoing studies
16.45– 17.00 Discussion
WP8 – CP management and administration
17.00– 17.30 General Assembly
19.00 Dinner in town
Wednesday, 24 Nov 2010
Training Session – Part 2 – Location: Leibnizhaus Hannover – Room …
09.00 – 09.45 J Todd (UCAM, Cambridge)
Title: Genes and biomarkers in autoimmune diabetes
09.45 – 10.05 T Arndt (MHH, Hannover)
Title: Genetics of the IDDM (LEW.1AR1-iddm) rat model of human type 1 diabetes
10.05 – 10.35 H Korf (KUL, Leuven)
Title: Immune mouse models for type 1 diabetes
10.35 – 11.00 Coffee Break
11.00 – 11.45 S Lenzen (MHH, Hannover)
Title: Rat models of human type 1 diabetes
11.45 – 12.15 Discussion and closing remarks
End of Meeting
Scientific launch meeting of NAIMIT
Posted on | October 21, 2009 | No Comments
universiteitshallen
Universiteitshallen, Naamsestraat 22, B-3000 Leuven, Belgium
2 november 2009
PROGRAM
9.00 – 17.00 Poster exposition of the participating research groups
9.00 – 9.10 Welcome by Prof. Dr. M. Waer, Rector Magnificus of the K.U.Leuven
9.10 – 9.40 NAIMIT project presentation (overview of the scientific goals) – Coordinator C. Mathieu
9.40 – 10.15 WP1 – Re-educating antigen-presenting cells – Chair B. Roep
- B. Roep (LUMC, Leiden) 20’ – “Antigen-specific therapy with tolerogenic dendritic cells”
- A. Wakatsuki-Pedersen (DanDrit, Copenhagen) 15’ – “Clinical application of dendritic cells”
10.15 – 11.15 WP2 – Restoring the T-cell balance – Chair M. Peakman
- M. Peakman (KCL, London) 20 ’ – “Studies on T cells in Type 1 diabetes lead to new therapeutic options”
- C. Dayan (UNIVBRIS, Bristol) 20’ – “Optimizing Peptide Immunotherapy in Type 1 diabetes”
- P. Bingley (UNIVBRIS, Bristol) 20’ – “Assessing Type 1 diabetes risk: potential strategies and implications”
11.15 – 11.45 coffee break
11.45 – 12.40 WP3 – TCR-directed immunotherapy – Chair C. Mathieu
- C. Mathieu (KULeuven, Leuven) 20’ – “Vitamin D and Type 1 diabetes”
- J. Demengeot 20’ (FCG-IGC, Lisboa) – “Promoting regulatory T-cell differentiation and function: precursors, location and environmental factors”
- R. Ashfield (IMC, Oxford) 15’ – “Targeting beta-cell epitopes with high affinity T-cell receptors”
12.40 – 14.00 lunch
14.00 – 14.35 WP4 – Mucosal intervention for tolerance restoration – Chair F. Dotta
- F. Dotta (UNISI, Siena) 20’ – “Probiotics, gut immune system and islet autoimmunity”
- P. Rottiers (AGX, Ghent) 15’ – “ActoBiotics™: a novel tool for drug delivery”
14.35 – 15.35 WP5 – Beta-cell protection and restoration: dialogue with the immune system – Chair D. Eizirik
- D. Eizirik (ULB, Brussels) 20’ – “Gene networks regulating beta-cell apoptosis and proinflammatory signals”
- P. Marchetti (UPI, Pisa) 20’ – “Human islet isolation for Type 1 diabetes research”
- S. Lenzen (MHH, Hannover) 20’ – “Analysis of protection strategies in type 1 diabetes animal models”
15.35 – 16.00 coffee break
16.00 – 16.40 WP6 – Pharmacogenetics: towards individualised therapies – Chair K. Badenhoop
- K. Badenhoop (GUF, Frankfurt am Main) 20’ – “Vitamin D pathway genes and experimental Type 1 diabetes”
- J. Todd (CIMR, Cambridge) 20’ – “Genes and phenotypes in Type 1 diabetes”
16.40 – 17.00 General discussion & closure
Launch of NAIMIT project to cure diabetes (Type1)
Posted on | October 21, 2009 | No Comments
Natural immunomodulators as novel immunotherapies for type 1 diabetes
Type 1 diabetes melllitus (T1DM) is an autoimmune disease characterised by immune-mediated destruction of insulin-producing beta-cells in the pancreas. The incidence of T1DM in childhood is increasing at about 3% per year, equivalent to a doubling time of 20-25 years. T1DM is the most common metabolic disease in the young. In addition, 5-10% of patients originally diagnosed as T2DM have a less severe and more slowly progressing form of T1DM, usually referred to as “Latent Autoimmune Diabetes of Adults” (LADA).
About two million people in Europe (around 0.5% of the population) and several million people world-wide suffer from this disease.
Of concern are the reports of a steady increase of T1DM over the last decades in virtually all European countries and a particular escalation in the 1-5-year age group. Since it carries a significant chronic disease burden, T1DM has thus become a major public health concern worldwide, emphasizing the urgent need for safe and effective intervention and prevention strategies. At the same time that this gloomy picture has emerged, a series of key basic and clinical scientific advances have promoted the concept that reversing autoimmunity in type 1 diabetic (T1DM) patients has become a reachable challenge through growing insight in the pathogenesis of the disease and the availability of novel tools allowing interference with the disease process.
We propose an original concept, in which natural immune modulators will be introduced in interventional approaches that will modify the immune system through an antigen-specific route to achieve beta-cell protection.
Only by intervening in an antigen specific way can one guarantee beneficial immunomodulation with minimal unwanted immune perturbation in the quest to reverse autoimmunity. In NAIMIT we propose to come to tailored interventions with minimal immune system interference in new onset T1DM, leading to beta-cell protection and restoration, based on a solid understanding of the disease pathogenesis. This will enable experimental findings to be adopted for future clinical application. To achieve these ambitious goals, we have established a multidisciplinary consortium of leading European diabetologists and immunologists from 11 academic research institutions, in co-operation with 3 SMEs developing novel technologies allowing translation of basic research results towards clinical applications.
The NAIMIT approach is integrated, moving from a specific hypothesis on the pathogenesis of T1DM, supported by present state-of-the-art research, to interventions targeting the different players in the destruction of the beta-cell. The concept of this proposal is to target the immune components using natural immunomodulators and novel technologies for their delivery, thereby modulating the immune system in a targeted fashion and to a minimal degree only. This will allow arrest of autoimmunity while avoiding undesirable side effects. Two key players of the immune system in beta-cell destruction will be targeted: the DC (WP1: Re-educating antigen-presenting cells) and the T lymphocyte (WP2: Restoring the T-cell balance). In both cell types, interventions using steroid hormones (vitamin D and glucocorticoids) will be used in order to induce tolerogenic cell types. Moreover, novel interventions using soluble TCR to target immune cells and beta-cells in an antigen-specific way (WP3: TCR-mediated immunotherapy). Novel mucosal interventions using recombinant L. lactis (ActoBiotics™) as a carrier for specific peptides in combination with cytokines (WP4: Mucosal intervention for tolerance restoration) will be studied for their potential to interfere with the immune system.
An important asset of NAIMIT is that in addition to consideration of immune cells, the role of the beta-cell in its own destruction and the pathways involved in its demise will be studied.
Particular attention will be paid to understanding the communication pathways between beta-cells and the immune system, opening new ways to arrest progression of autoimmunity and preserve beta-cell mass (WP5: Beta-cell protection and restoration). Finally, we will move towards individual tailoring of therapy. Using a pharmacogenetic approach, applicable to the designed interventions, we will evaluate the potential for individualised intervention strategies (WP6: Pharmacogenetics). The results to be obtained will not only open the door to novel intervention therapies with minimal modulation of the immune system in newly diagnosed T1DM individuals, but will also improve our understanding of the disease process.