MECHANISMS OF CELLULAR REJECTION IN ORGAN TRANSPLANTATION AN OVERVIEW

Transcription

1 MECHANISMS OF CELLULAR REJECTION IN ORGAN TRANSPLANTATION AN OVERVIEW YVON LEBRANCHU Service Néphrologie et Immunologie Clinique CHU TOURS

2 ANTIGEN PRESENTING CELL CD4 + T CELL CYTOKINE PRODUCTION CLONAL EXPANSION ACTIVATED MACROPHAGES ACTIVATED B CELLS CD 8 T CELLS

3 WHERE DO T CELLS MEET TRANSPLANT ANTIGENS IN CONTEXT OF PLANNING AND INITIATING THE ALLO IMMUNE RESPONSE? DENDRITIC CELLS NAIVE T CELLS GRAFT SECONDARY LYMPHOID ORGANS

4 TWO POSSIBILITIES 2. RECIPIENT T LYMPHOCYTES RECOGNIZE ALLOGENEIC ANTIGENS PRESENTED BY GRAFT APC DENDRITIC CELLS NAIVE T CELLS GRAFT LYMPHOID ORGANS TWO POSSIBILITIES 1. GRAFT DENDRITIC CELLS MIGRATE TO SECONDARY LYMPHOID ORGANS DENDRITIC CELLS NAIVE T CELLS GRAFT LYMPHOID ORGANS

5 aly/aly (without lymph nodes and Peyer s patches) Hox 11 -/- (without spleen) HEART H-2 k Splenectomized aly/aly Control B6 Rôle essentiel des organes Lymphoïdes secondaires dans le rejet de Greffe de Coeur

6 GRAFT REJECTION Immature DC Graft Naive T cell activation Graft infiltration Naive T cell Mature DC Lymphoid organ MIGRATION DES CELLULES DENDRITIQUES CCR 5 CCR 7 LFA-1 VLA-4 CELLULE DENDRITIQUE IMMATURE CELLULE DENDRITIQUE MATURE

7 CD 4 T CELL ANTI DONOR RESPONSES INDIRECT DIRECT

8 GRAFT REJECTION Migration / Maturation Immature DC Graft Naive T cell Activation B cells Graft Infiltration Lymphoid organ Mature DC macrophage NK eosinophil Activated T cells THE 4 STAGES OF ACUTE REJECTION ALLO-ANTIGEN ANTIGEN RECOGNITION BY TCR T CELL ACTIVATION AND CLONAL PROLIFERATION GRAFT INFILTRATION PARENCHYMAL CELL DAMAGE

9 THE 4 STAGES OF ACUTE REJECTION ALLO-ANTIGEN ANTIGEN RECOGNITION BY TCR T CELL ACTIVATION AND CLONAL PROLIFERATION GRAFT INFILTRATION PARENCHYMAL CELL DAMAGE THE 4 STAGES OF ACUTE REJECTION ALLO-ANTIGEN ANTIGEN RECOGNITION BY TCR T CELL ACTIVATION AND CLONAL PROLIFERATION GRAFT INFILTRATION PARENCHYMAL CELL DAMAGE

10 T cell proliferation requires four different signals to induce allograft rejection Signal 1 (TCR engagement) and signal 2 (costimulation) to induce cytokine synthesis Signal 3 (IL-2) binding to its receptor) to induce cell cycle progression Signal 4 (nucleotide synthesis) to induce clonal T lymphocyte expansion

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16 B 7 FAMILY 1. POSITIVE SIGNALS APC B 7.1 B 7.2 B 7.H B 7.H3 CD 28 ICOS? CD 4 T CELL

17 THE EXPANDING B 7 FAMILY LIGAND SIGNAL B 7.1 B 7.2 B 7 - H B 7 - H 3 CD 28 CD 28 ICOS? POSITIVE B 7.1 B 7.2 PD - L 1 PD - L 2 CTLA 4 CTLA 4 PD 1 PD 1 NEGATIVE Transduction signal (signal 3) is induced by IL-2 Binding to its receptor

18 IL-2 IL-15 M.TOR G 1 S

19 Nucleotide synthesis (signal 4) induces T cell proliferation This inhibitors of de novo nucleotide synthesis are immunosuppressive drugs THE 4 STAGES OF ACUTE REJECTION ALLO-ANTIGEN ANTIGEN RECOGNITION BY TCR T CELL ACTIVATION AND CLONAL PROLIFERATION GRAFT INFILTRATION PARENCHYMAL CELL DAMAGE

20 GRAFT REJECTION Immature DC Graft Naive T cell activation Graft infiltration Naive T cell Mature DC Lymphoid organ

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22 CHEMOKINE RECEPTORS = SEVEN TRANSMEMBRANE RECEPTORS COUPLED TO G PROTEINS CXCR 1 to CXCR 5 XCR 1 Cx 3 CR 1 G PROTEIN CCR 1 to CCR 11 ONE CHEMOKINE CAN BIND TO SEVERAL RECEPTORS Rantes (CCL 5) bind to CCR 1, (mice), CCR 3, CCR 5 ONE CHEMOKINE RECEPTOR MAY TRANSDUCE SIGNALS FOR SEVERAL CHEMOKINES IP-10 (Cx CL 10), Mig (CxCL 9) and I-TAC (CxCL 11) bind to CXCR 3

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26 THE 4 STAGES OF ACUTE REJECTION ALLO-ANTIGEN ANTIGEN RECOGNITION BY TCR T CELL ACTIVATION AND CLONAL PROLIFERATION GRAFT INFILTRATION PARENCHYMAL CELL DAMAGE

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28 BUT, IN OTHER MODELS, MICE DEVOID OF PERIPHERAL LYMPHOID ORGANS CAN REJECT ALLOGENEIC GRAFTS. Lymphotoxin-α-deficient Lta - / -. Lymphotoxin-β-receptor deficient Ltbr - / - R. CHIN, P. ZHOU, M. ALEGRE and Y.X. FU Nature Med., 2001, 7 :

29 Rôle limité des organes lymphoïdes secondaires dans les rejets de greffe Peau Lta / Coeur Lta / splénectomisées SIGNIFICANCE? 1. REJECTION INDUCED BY GRAFT INFILTRATING MEMORY T CELLS? 2. DIRECT ALLORECOGNITION BY GRAFT ENDOTHELIAL CELLS?

30 SIGNIFICANCE? 1. REJECTION INDUCED BY GRAFT INFILTRATING MEMORY T CELLS? 2. DIRECT ALLORECOGNITION BY GRAFT ENDOTHELIAL CELLS? MHC CLASS I AND CLASS II MOLECULES AS WELL AS COSTIMULATORY MOLECULES ARE EXPRESSED ON VASCULAR ENDOTHELIUM, SPECIALLY UNDER INFLAMMATORY CONDITIONS IN VITRO STUDIES HAVE SHOWN THAT HUMAN T LYMPHOCYTES PROLIFERATE AFTER COCULTURE WITH VASCULAR ENDOTHELIAL CELLS BUT, IN VIVO?

31 ELEGANT TRANSGENIC ANIMAL MODEL BM3 T CELL RECEPTOR MICE (BACKGROUND CBA H-2 k ) RECOGNIZE A SINGLE ALLOGENEIC MHC CLASS I MOLECULE (H-2K b ) TWO NOVEL OBSERVATIONS 1. CD 8 + T CELLS CAN RECOGNIZE ALLO ANTIGENS ON GRAFT ENDOTHELIAL CELLS IN VITRO AND IN VIVO 2. T CELL-ENDOTHELIAL CELL INTERACTIONS, VIA DIRECT ALLORECOGNITION, CAN RESULT IN GRAFT REJECTION, EVEN IN THE ABSENCE OF CD4+ T CELLHELP AND PROFESSIONAL HEMATOPOIETIC ANTIGEN PRESENTING CELLS KREISEL, Nat. Med., 2002, 8 :

32 Rejet de greffe de cœur par CD8+ de souris BM3 déplétées en CD4+ B6 B6 (CBA) B6 (B6) infiltrat CD8+ CD4+ D. KREISEL Nature Médecine, 2002, 8 : IN SUMMARY TWO PATHWAYS CLASSICAL PATHWAY = ACTIVATION OF ALLOGENEIC CD4 + T CELLS VIA DIRECT AND INDIRECT PATHWAYS IN SECONDARY LYMPHOID ORGANS ALTERNATIVE PATHWAY = DIRECT ALLOPRESENTATION BY ENDOTHELIUM TO CD8 + T CELLS, ESPECIALLY IN SITUATIONS WHERE CD4 + T CELL ACTIVATION HAS BEEN INHIBITED

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