Immune system and diabetes. Chairmen: J. Belkhadir (Morocco) N.M. Lalic (Serbia)

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1 Immune system and diabetes Chairmen: J. Belkhadir (Morocco) N.M. Lalic (Serbia)

2 Autoimmunity and prevention of type 1 diabetes R. Mallone (France)

3 Autoimmunity and Prevention of Type 1 Diabetes Roberto Mallone, MD PhD DeAR Lab Immunology of Diabetes Team INSERM U1016 Institut Cochin Clinical Dept. of Diabetology, Hôpital Cochin Paris, France

4 Type 1 diabetes (T1D): some history T1D is an autoimmune disease Hyperglycemia is only the consequence of autoimmune β-cell destruction We need to target the autoimmune process in order to treat and prevent T1D

5 How the immune system works: innate and adaptive immunity Adaptive immune system (late, targeted) Dendritic cell B cell CD4+ T cell CD8+ T cell Antibodies T-cell Receptors (TCRs) Innate immune system (early, unspecific) Dendritic cell Natural killer T cell Dendritic cell Natural killer cell Macrophage Complement Infection Cancer Autoimmunity Self tissues Bacteria Tumor cells Viruses Granulocyte (e.g. neutrophil) Mast cell Brezar, Endocr. Rev. 2011

6 T1D autoimmunity: inappropriate β-cell target, same actors dendritic cell activated neutrophil activated macrophage peptide epitope HLA TCR CD3 IL-1β IFN-γ TNF-α environmental triggers (?) CD20 IL-2 B cell autoreactive T cell Auto-antibodies autoreactive T effector cell Pancreatic Lymph Node autoreactive T regulatory cell IL-2 dendritic cell antigens β cell Islet

7 T1D immunotherapy: the risk-benefit balance is a delicate one Type 1 diabetes subjects: - Mostly children and young adults - Disease is not life-threatening At-risk subjects: - Typically autoantibody-positive - Not yet diabetic - Risk prediction is imperfect Immunotherapies: - Experimental treatment - Benefit uncertain - Risk uncertain

8 β-cell antigen vaccination is safe dendritic cell activated neutrophil activated macrophage peptide epitope HLA TCR CD3 IL-1β IFN-γ TNF-α environmental triggers (?) CD20 IL-2 B cell autoreactive T cell β-cell antigen(s) auto-antibodies autoreactive T effector cell IL-2 β cell autoreactive T regulatory cell dendritic cell antigens

9 How to develop a counter-vaccine to neutralize autoimmune T lymphocytes? Viral vaccine: to stimulate T lymphocytes that recognize the administered antigen Subcutaneous or intramuscular route + adjuvant T1D vaccine: to neutralize T lymphocytes that recognize the administered antigen Oral route Intranasal route

10 Clinical trials: seeing is believing Caravaggio, The Incredulity of Saint Thomas, 1601

11 T1D immune therapies: whom for? β-cell mass Environmental Triggers Genetic Predisposition Cellular Autoimmunity Primary prevention Autoantibody Production Secondary prevention Loss of First Phase Insulin Response Glucose Intolerance Clinical Onset Diagnosis Tertiary prevention Overt Diabetes Genetically (HLA) predisposed subjects Time Islet Ab+ subjects (Intervention) New-onset T1D subjects

12 Intranasal insulin vaccination in new-onset T1D: no clinical benefit but immunological efficacy Insulin-specific response Tetanus-specific response Intranasal insulin Intranasal placebo IFN-γ+ T cells / 10 6 PBMCs Decrease in PI-specific T-cell responses in intranasal insulin arm Fourlanos, Fourlanos, Diabetes, 60:1237 Diabetes (2011)

13 Earlier intranasal insulin vaccination in at-risk subjects: again no clinical benefit but immunological efficacy Insulin-specific IFN-γ T-cell responses Early: T cells recognizing insulin Release of new antigens t t Islet t Later: T cells recognizing multiple antigens Harrison & Mallone, unpublished

14 The perinatal period offers the most suitable time window for T1D prevention Ziegler, Diabetologia 2012; Parikka, Diabetologia 2012; Ziegler, JAMA 2013

15 The environmental triggers of T1D remain elusive 1) Environment weighs more than genetics: - Concordance between monozygotic twins: 30-65% - Migrant studies: T1D incidence reflects that of the hosting region - Comparison between regions with same genetic background and different environmental exposure - Steady increase in T1D incidence cannot be explained by any major genetic drift 2) Environmental factors are gaining importance: diagnoses diagnoses X 1X HLA DR-DQ Afonso & Mallone, Diabetes Obes. Metab. 2013

16 Candidate environmental triggers: Early introduction of cow milk? Possible mechanisms for T1D triggering: Cross-reactivity between bovine albumin and β-cell antigens Lack of maternal breast milk antibodies Increased intestinal permeability, loss of mucosal tolerance Knip, N. Engl. J. Med. 2010

17 Very early oral insulin vaccination: The Pre-POINT pilot trial Oral insulin Safety trial Immune changes suggestive of insulin-specific tolerance Clinical efficacy on T1D protection? Phase II/III trial awaited Bonifacio, JAMA 2015

18 The immune system learns to tolerate self tissues during the perinatal period Caravaggio, Narciso 1547

19 Learning of the immune self identity takes place in the thymus β cell Don t touch! Maturing T lymphocyte Specialized thymic antigen-presenting cell β-cell antigen HLA (e.g. insulin) molecule X T lymphocytes Autoreactive effector T cell: pathogenic eliminated Autoreactive regulatory T lymphocyte: protective rescued

20 Can we introduce β-cell antigens into the thymus to force selection of autoreactive T cells? Transfer of maternal antibodies: To the fetus, via the placenta To the newborn, via the gut Neonatal Fc Receptor (FcRn) Antibody Insulin (Ins) Insulin-Fc (Ins-Fc) Placental and intestinal epithelium X

21 PPI-Fc is delivered to the thymus of newborns, improves T-cell selection and protects from T1D development Effector T lymphocytes (pathogenic) 100 Ins-Fc (n=60) Ins (n=73) Ins-Fc + αvcam-1 (n=26) Regulatory T lymphocytes (protective) % diabetes-free mice PI B immunizations Days Gupta, Sci Transl Med 2015; Culina, Diabetes 2015

22 Take-home messages T1D prevention strategies should be implemented in the perinatal period Environmental triggers remain elusive, precluding their therapeutic targeting Vaccination immunotherapies using insulin are therefore favored, due to their selectivity and safety Intervening on the earliest thymic checkpoint in autoimmune progression by perinatal vaccination with insulin-fc may lead to novel prevention strategies

23 Acknowledgements DeAR Lab INSERM U1016 Cochin Institute Magali MAS, PhD Emanuela MARTINUZZI, PhD Slobodan CULINA, PhD Klaudia KURANDA, PhD Ana-Ines LALANNE, PhD Georgia AFONSO Marie-Claude GAGNERAULT Anna JONES Sergio GONZALEZ-DUQUE Valentina ROCCHETTI, MD

24 Acknowledgements Diabetology Dept., Cochin Hospital Paris E. Larger D. Dubois-Laforgue C. Boitard Walter & Eliza Hall Institute Melbourne, Australia L.C. Harrison Les Cordeliers Research Center Paris N. Gupta S. Lacroix-Desmazes University of Cardiff, UK F.S. Wong Contact: