The immune system is a powerful machine

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1 Hemophagocytic lymphohistiocytosis: A unique immunoregulatory disorder Disclosure of Relevant Financial Relationships Michael B. Jordan, MD Divisions of Immunobiology, and Bone Marrow Transplantation and Immune Deficiency Cincinnati Children s Hospital Medical Center/ Univ. of Cinci. USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Jordan declares he is a consultant for Novimmune. michael.jordan@cchmc.org The immune system is a powerful machine Essential for survival, remarkably flexible, and potentially very dangerous Immune regulation and human disease Initiation / Context cues - Danger sensing - Modulate innate inflammation CAPS TRAPS auto-inflammatory Inborn errors of immune regulation Specificity -Thymic/ marrow selection APECED Inhibition/ Termination -Suppressive lymphocytes -Lymphocyte survival -Immunosuppresive mediators IPEX CTLA4/ LRBA ALPS Magnitude of T cell activation/ mobilization of innate effectors (feedback control of acute activation) Hemophagocytic Lymphohistiocytosis () What is? Hemophagocytic lymphohistiocytosis (): a highly fatal disorder treated with immune suppression /marrow transplantation, often associated with genetic impairment of perforin-mediated cytotoxicity Mouse models: Immune regulation and immunopathology Human disease: correlations, interventions, and complexity Trottestam H et al. Blood 211;118:

2 Mouse Model of : Infect with LCMV prf1-/-? Jordan et al, Blood, 211 LCMV-infected prf-/- mice display clinical and laboratory features of Modeling : U/mL ng/ml 8 ferritin Naïve WT Prf-/- LCMV 4 scd Infection 1 Naïve WT Prf-/- LCMV perforin Perforin: 1. Immune effector function: kill infected cells 2. Immune regulatory function? Jordan, M. B. et al. Blood 24;14: Immune activation and viral burden do not correlate in cytotoxic mutant (Ctx-) mice after LCMV infection In vivo CD8+ T-cell activation is heightened in Ctx mice after LCMV infection. Lykens J E et al. Blood 211;118: Lykens J E et al. Blood 211;118:

3 CD8+ T-cells in prf / mice have cell-signalling patterns suggesting heightened antigenic stimulation after LCMV infection. T cell activation is selectively heightened in lymphoid tissues of prf-/- mice after infection Lykens J E et al. Blood 211;118: Lykens et al, 211 Terrell et al, 213 Dendritic cells and T cell activation in prf / mice IFN- Abnormal antigen presentation by dendritic cells drives heightened T cell responses in cytotoxic deficient mice LCMV prf IFN- (ng/1 6 T cells) days Splenic cells + T cells (P14; LCMV specific) (from infected mice) APC s: Splenic DC s Non-DC s (CD11c - /TCR - ) APC: T cell Ratio Terrell et al, 213 IFN- (ng/1 6 T cells) DC s T cells WT P14 prf-/- P14 WT OT1 prf-/- OT1 DC depletion LCMV 6 days prf+/+ or prf / CD11cDTR.1 DC: T cell ratio 1 % IFN- + of CD8+ * 6 prf-/- ** 5 4 WT 3 * 2 1 Rx: PBS DT PBS DT Both CD8+ T cells and IFN- are necessary for the development of an -like disorder in LCMV-infected prf-/- mice Infection antigen (+) Dendritic cells CD8 + T cells (-) perforin IFN- Jordan, M. B. et al. Blood 24;14:

4 Sustained elevation of IFN- is sufficient to induce acute anemia.and hemophagocytosis. IFN Zoller et al, J. of Exp. Med., 211 Sustained exposure to IFN in vivo and macrophage endocytic phenotypes Human : macrophages in the CSF Antigen presentation X T cell phenotypes IFN as disease mediator/ target of therapy What do recently activated T cells look like in humans? Miller et al, 28 4

5 Characterizing T cells in patients with vs. sepsis Gated on CD3 + / CD8 + Ctrl Sepsis Phenotyping activated CD8 + T cells in Ctrl Sepsis HLA-DR PD1 CD5 Activated CD8 + T cells in patients are terminally differentiated Ctrl Activated CD8+ T cells in produce IFN- Gated on CD3 + /CD8 + high CD57 IFNγ CD28 Granzyme TNFα Tissue infiltrating CD8 + T Cells are activated: BM Tissue infiltrating CD8 + T Cells are activated: CSF Control Gated on CD3 + /CD8 + Patient 1 Patient 2 Patient 3 Control HLADR HLADR PD1 IFN PD1 CD5 CD5 5

6 IFN- is necessary for the development of an -like disorder in LCMV-infected prf-/- mice IFN- and downstream chemokines are elevated in patients with 1 1 pg/ml 1 1 Jordan, M. B. et al. Blood 24;14: Tang et al., Br J Haematol IFN CXCl9 CXCL1 CXCL11 (1/3>1pg/ml) Data courtesy of Novimmune NI 51 Mechanism of Action NI 51, an Anti interferon Gamma (Anti IFNγ) Monoclonal Antibody, in Paediatric Patients with Primary Phase 2/3 International, multicenter, open label, single arm study Open in Europe and in the United States Study population: children with p receiving NI 51 as 1 st or 2 nd line therapy IFN IFN R1 IFN R2 IFN R1 IFN R2 NI 51 IFN IFN R1 NI 51 X IFN R2 US Principal Investigator Michael Jordan E mail: michael.jordan@cchmc.org EU Principal Investigator Franco Locatelli E mail: franco.locatelli@opbg.net Cell membrane Cell membrane NO SIGNAL SIGNAL NI 51 clinical trial ongoing in US and European centers Europe Spain (3) UK (1) Germany (5) Italy (5) Sweden (1) United States Seattle Stanford Salt Lake City Denver Houston Boston Cincinnati New York Chapel Hill Wilmington Turkey (1) Miami Sites open Site activation ongoing BOARD Confidential MEETING MARCH 212 Patient enrolment in the NI 51 4 study Cut off date October 1 th, 216 Rapid normalization of fever Hours after first infusion of NI Pt. #1 39 Pt. #13 Body temperature ( C) Hours after infusion Hours after infusion Patients with body temperature > 37.5 C at initiation of NI 51 treatment BOARD Confidential MEETING MARCH

7 Response to NI 51: disease features Immune regulation, Immunopathology, and : etiologic variation Flood the system Affect T cell??? Altering T cell signaling with antigen signaling/ (can t suppress SH2D1A, antigen Malignancy, (immune activation: presentation, ITK, but can MAGT1, still Immune suppression, activate) CD27, suppression malignancy) antigen (+) Dendritic cells CD8 + T cells Overwhelming innate immune stimuli:???? disseminated DNA viruses (HSV, in PID Adeno), mycobacteria, -like features or leishmania in infection directly activating macrophages Infection IFN- (-) Macrophages perforin Affect the Affect macrophage Affect PRF1, UNC13D, Artificial/ sustained inflammasome: Make T cells inflammatory more prone signalling: to granule- Impairing RAB27A, STX11, T cell activation XIAP, NLRC4, produce IFN- and/or make SLC7A7 (LPI) perforin-dependent STXBP2, LYST, SoJIA (genes macrophages unknown) hypersensitive to it (CAR or lymphoma) HO 1 cytotoxicty: negative feedback AP3B1, BLOC1S6 ACKNOWLEDGMENTS Familial / Genetic Predisposition Infections Rheumatologic Conditions Malignancy? Jordan Lab Vandana Chaturvedi Amber Hensley Rohan Srivastava Nora Lakes CCHMC Mol. Genetics Kejian Zhang Ammar Husami Diane Kissell Shannon Nortman Common Pathophysiology (T cell activation and IFN- ) Iatrogenic [CAR T cell] Overwhelming innate immune stimuli: disseminated DNA viruses (HSV, Adeno), disseminated mycobacterial or leishmanial infection Collaborators Carl Allen + Ken McClain The HIT trial group Novimmune SA Immunobiology Kasper Hoebe Cesar M. Rueda Claire A. Chougnet BMT/ID Rebecca Marsh Vijaya Chaturvedi Hilary Haines Alexandra H. Filipovich Jack J. Bleesing Acknowledgements: NI 51 4 Aproposal for diagnostic criteria informed by pathophysiology: 41 Philippe Jacqmin Christian Laveille Study NI 51 4 Investigators and Co investigators: M. Jordan, Cincinnati Children s Hospital, Cincinnati, Ohio F. Locatelli, H Pediatrico Bambino Gesu, Roma C. Allen, Texas Children s Cancer Center, Houston, Texas S. Cesaro, Policlinico G.B. Rossi, Verona F. Fagioli, A.O. Regina Margherita, Torino M. Henry, Phoenix Children Hospital, Phoenix, Arizona M.C. Putti, University Hospital, Padova C. Rizzari, H San Gerardo, Monza C. Rossig, University Children's Hospital, Münster J. Sevilla, Hospital Universitario Niño Jesús, Madrid NI 51 4 Scientific Steering Committee Patients and families Principal Investigator, US Michael Jordan E mail: michael.jordan@cchmc.org Principal Investigator, EU Franco Locatelli E mail: franco.locatelli@opbg.net Maureen Deehan Kathy de Graaf Marie Kosco Vilbois Geneviève Lapeyre Robert Nelson MarthaLee Reynolds Evidence of type I T cell activation Elevated scd25 Elevated CXCL9 For treatment, assess the presence of other diagnoses suggesting alternative/ adjunctive therapies Viral infection: HSV, Adeno, CMV, EBV Other: mycobacterial, leishmanial, or fungal Malignancy, esp. leuk/lymphoma Drug reactions (eg DRESS syndrome) > 2 corroborating findings of immune activation/ dysregulation Clinical: Fever >38.5 Splenomegaly Personal/ Family history Lab: Ferritin>2 elevated granzyme B MFI Decreased CD17 mob. Decreased: Perf, Sap, Xiap, or other protein > 2 signs of abnormal immunopathology > 2 cytopenias ALT>3x ULN fibrinogen<15 Hemophagocytosis CNS: pleocytosis, elevated protein, seizure, defects 7

8 A definition: is a disorder of immune regulation.which typically benefits from immunosuppressive therapies Triggers: Viruses: EBV, CMV, others Other infections: bacterial, fungal, protozoan Drug reactions: DRESS syndrome Malignancies: esp. lymphoma Rheumatologic conditions: esp. JIA : trigger vs. mimic? Anti- therapy: I favor the term syndrome for situations that meet criteria, but would not benefit from immune suppression Mimics: Viruses: HSV (in neonates), adenovirus (in PID), even CMV (if undiagnosed) Other spec. infections: leishmania, mycobacteria Drug reactions: if undiagnosed Malignancy: if undiagnosed 8