Type 1 diabetes (T1D) prevalence is steadily increasing in industrialized countries, with an incidence of 15 new diagnoses/100,000 inhabitants/year in France, which further increases of 3-4% every year. As it mainly affects children and young adults leading to lifelong treatments and frequent long-term complications (cardiovascular diseases, end-stage renal failure, blindness), it is a highly debilitating disease and an important voice of public health expense.
Type 1 diabetes (T1D) is an autoimmune disease caused by autoreactive T lymphocytes which destroy insulin-producing pancreatic islet β-cells. Despite this knowledge, neither the diagnosis nor the therapy of T1D targets pathogenic T lymphocytes. Our research projects therefore aim at exploiting these T lymphocytes as disease biomarkers and as therapeutic targets to prevent β-cell destruction.
1. Islet-reactive CD8+ T cells are circulating in all individuals irrespective of T1D status. This key observation, made possible by the stringent tetramer analysis tools set up, is at variance with most T1D literature. It points to a general mechanism of defective central tolerance that is present in most individuals and imprints a generalized autoimmune potential, while the homing of autoreactive CD8+ T cells to the pancreas occurs preferentially in T1D. It enriches the ongoing debate about the role of thymic clonal deletion in establishing immune tolerance. It raises important questions on the definition of disease-associated versus physiological autoimmunity based on circulating T-cell biomarkers. It leads to new hypotheses regarding T1D pathogenesis, arguing that the key ingredient toward disease development may be the vulnerability of the target β cells and the preservation of peripheral ignorance and/or regulation in the face of similar autoimmune T-cell repertoires across individuals. These hypotheses will be addressed in our follow-up projects.
2. Tolerogenic vaccination strategies based on Fc-coupled antigens. Proof-of-concept studies using a transplacental vaccination route are described in two recent publications from our laboratory and are covered by a patent. This work fills a major knowledge gap by showing that it is possible to therapeutically induce immune tolerance by intervening on the first checkpoint in autoimmune progression that takes place in the thymus. The possibility of implementing this vaccination in the perinatal period is particularly relevant for T1D prevention, in light of recent evidence documenting that autoimmune activation occurs during the first months of life, thus calling for earlier intervention than those attempted to date. Of further note, the same strategy can be applied to other immune-mediated conditions, thus catalyzing new investigations beyond the T1D field. A less invasive oral vaccination route is now being explored.
3. Establishment of clinically applicable therapeutic protocols for inducing tolerance in T1D autoimmunity and transplantation (INSERM U1151, Necker hospital). We have defined the therapeutic properties of drugs or combination of drugs thereof presently in clinical development, including anti-CD3 mAbs, anti-CD28 mAbs (EU FP7 project), HDAC inhibitors. In particular, we demonstrated the therapeutic potential of anti-CD3 mAbs to induce long-term antigen-specific tolerance not only in autoimmunity, but also in transplantation, and the importance of the therapeutic window. T-cell deletion, anergy and Treg-mediated regulation are all key mechanisms that synergize to induce and maintain anti-CD3-driven tolerance. These observations challenge the prevailing dogma that therapeutic tolerance to self or foreign antigens relies mostly on the constant vigilance by Foxp3+ Tregs. Our results also unraveled novel mechanisms of CD8+ T-cell anergy namely a cell-intrinsic regulatory interplay between the TGF-β and PD-1/PD-L1 pathways acting as inhibitory checkpoints. Despite some efficacy, side effects narrowed the therapeutic use of anti-CD3 in the clinic. Our work is therefore critical to inform the design of new human studies, such as the phase II trial ongoing in T1D (NCT01030861).
T1D is an autoimmune disease in which autoreactive T cells drive the destruction of pancreatic β cells. The recognition of peptide fragments (epitopes) in the frame of HLA molecules confers specificity to this response, thus making T cells attractive both as autoimmune biomarkers and therapeutic targets. To achieve these goals, several requirements need to be fulfilled.
First, the target β-cell epitopes need to be identified.
Second, circulating islet-reactive T cells are also found in non-diabetic subjects. Understanding this difference between pathologic and ‘benign’ autoimmunity is therefore critical to devise better T-cell biomarkers and therapeutic strategies.
Third, this information needs to be translated into novel T-cell therapeutics.
The overall objective is to understand the autoimmune pathophysiology of T1D and to develop novel T-cell-based biomarkers and therapeutics. Our research program is organized into 3 specific themes:
1) Target β-cell epitopes and T-cell biomarkers of β-cell autoimmunity.
2) Mechanisms of pathologic and benign autoimmunity.
3) Immunotherapies for T1D prevention and intervention.
1. Target β-cell epitopes and T-cell biomarkers of β-cell autoimmunity. Identifying pancreatic β-cell antigens is the first step to understand the mechanisms by which autoimmunity arise, to identify their cognate T cells and to incorporate these antigens into vaccines aimed at restoring immune tolerance. We have pioneered the mapping of target epitopes recognized by the autoimmune T cells of T1D patients [Mallone R, Diabetes 2007; Scotto M, Diabetes 2012; Perol L, Nat Commun 2016]. These efforts and the patented T-cell assays developed have been instrumental in tracking these T cells along autoimmune progression or regression following immune intervention [Rosenzwajg M, J Autoimmun 2015], and have found applications beyond the T1D field [Lissina A, J Immunol 2016; Masat E, Sci Rep 2016]. The next challenge ahead is to use epitope identification to gain insights into the active role that β cells may play in their own destruction and to integrate these biomarker discovery efforts into a model of T1D pathophysiology.
2. Mechanisms of pathologic and benign autoimmunity. We have found that circulating autoreactive CD8+T cells are mostly naïve and present in both T1D and healthy individuals, while they are enriched in the pancreas of T1D patients [Culina S, Lalanne AI, Sci Immunol 2018]. Additionally, we and others have shown that CD4+ T effector cells (Teffs) from NOD mice are less sensitive to Treg-mediated suppression than CD4+ Teffs from non-autoimmune strains [You S, PNAS 2007], an observation also reported for T1D patients. In addition, our data in NOD mice points to an age-dependent progressive resistance to Treg- and TGF-β-mediated immune regulation as disease develops [You S, Diabetes 2005]. We will now test different hypotheses that may explain the (un)balance between pathologic and ‘benign’ autoimmunity in both the human and the mouse. Understanding what flips this balance may help identifying critical immune tolerance mechanisms amenable to therapeutic targeting.
3. Immunotherapies for T1D prevention and intervention. The Team has a long-standing expertise in the preclinical development of immunomodulatory therapies, which target pathways involved in autoimmune progression [You S, PNAS 2007; Grinberg-Bleyer T, J Exp Med 2010; Kuhn C, Sci Transl Med 2011; Kuhn C, J Autoimm 2016]. Moreover, it has a more recent interest in antigen-specific strategies, by which Fc-coupled antigens are used as tolerogenic vaccines to selectively impact the cognate T cells [Gupta, Sci Transl Med 2015; Culina, Diabetes 2015]. While the latter strategies are ideal for prevention purposes due to their superior safety profile, immunomodulation may be required at later stages of T1D, once autoimmune responses are floridly ongoing. The next steps ahead are to pursue the development of non-invasive therapies, to deepen our understanding of therapeutic mechanisms and to exploit the synergy between immunomodulatory and antigen-specific strategies.
Long-term perspectives. The ultimate goal is the combination of immune monitoring and intervention strategies to predict/prevent and stage/revert T1D in humans. Such strategies could offer a veritable shift in paradigm in the approach to T1D, as they would identify and correct immune pathogenesis rather than its metabolic consequences. The association with the Diabetology clinic and clinical research pipelines is an additional asset towards these goals.
For more details, please click here.