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

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

WHERE DO T CELLS MEET TRANSPLANT ANTIGENS IN CONTEXT OF PLANNING AND INITIATING THE ALLO IMMUNE RESPONSE ?

GRAFT SECONDARY LYMPHOID ORGANS DENDRITIC CELLSNAIVE T CELLS

TWO POSSIBILITIES 1. GRAFT DENDRITIC CELLS MIGRATE TO SECONDARY LYMPHOID ORGANS DENDRITIC CELLSNAIVE T CELLS GRAFT LYMPHOID ORGANS

TWO POSSIBILITIES 2. RECIPIENT T LYMPHOCYTES RECOGNIZE ALLOGENEIC ANTIGENS PRESENTED BY GRAFT APC DENDRITIC CELLSNAIVE T CELLS GRAFT LYMPHOID ORGANS

HEART H-2 k aly/aly (without lymph nodes and Peyer’s patches) Hox 11 -/- (without spleen) Splenectomized aly/aly Control B6

Rôle essentiel des organes Lymphoïdes secondaires dans le rejet de Greffe de Coeur

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

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

MIGRATION DES CELLULES DENDRITIQUES CELLULE DENDRITIQUE IMMATURE CCR 7 CCR 5 CELLULE DENDRITIQUE MATURE LFA-1 VLA-4

CD 4 T CELL ANTI DONOR RESPONSES DIRECT INDIRECT

Activated T cells Migration / Maturation Immature DC Graft Mature DC Naive T cell Activation Lymphoid organ Graft Infiltration B cells macrophage NK eosinophil GRAFT REJECTION

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

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

THE EXPANDING B 7 FAMILY B 7.1 B 7.2 B 7 - H B 7 - H 3 B 7.1 B 7.2 PD - L 1 PD - L 2 LIGANDSIGNAL POSITIVE NEGATIVE CD 28 ICOS ? CTLA 4 PD 1

Transduction signal (signal 3) is induced by IL-2 Binding to its receptor

IL-2 IL-15 M.TOR G1G1 S

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 RECOGNITION BY TCR  T CELL ACTIVATION AND CLONAL PROLIFERATION  GRAFT INFILTRATION  PARENCHYMAL CELL DAMAGE

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

CXC CHEMOKINE FAMILY CXCL 1 CXCL 2 CXCL 3 CXCL 4 CXCL 5 CXCL 6 CXCL 7 CXCL 8 CXCL 9 CXCL 10 CXCL 11 CXCL 12 CXCL 13 CXCL 14 CXCL 15 GRO  GRO  GRO  PF4 ENA 78 GCP 2 NAP-2IL-8MigIP-10I-TACSDF1BLCBRAKLungkine

CC CHEMOKINE FAMILY CCL 1I 309 CCL 2MCP-1 CCL 3MIP-1a CCL 4MIP-1b CCL 5RANTES CCL 6CC10 CCL 7MCP-3 CCL 8MCP-2 CCL 9MIP-1d CCL 11Eotaxin CCL 12MCP-5 CCL 13MCP-4 CCL 14MCC-1 CCL 15MIP-1d CCL 16Hcc-4 CCL 17TARC CCL 18DC-CK 1 CCL 19ELC/Exodus 3 CCL 20MIP-3 a/Exodus 2 CCL 21SLC/Exodus 2 CCL 22MDC CCL 23MPIF-1 CCL 24Eotaxin-2 CCL 25T ECK CCL 26Eotaxin-3 CCL 27Skinkin

C CHEMOKINE FAMILY XCL 1Lymphotactin XCL 2SCM - 1 

CX3 CHEMOKINE FAMILY CX 3 CL1Fractalkine

CHEMOKINE RECEPTORS = SEVEN TRANSMEMBRANE RECEPTORS COUPLED TO G PROTEINS _ CXCR 1 to CXCR 5 _ XCR 1 _ Cx 3 CR 1 _ CCR 1 to CCR 11 G PROTEIN

 ONE CHEMOKINE CAN BIND TO SEVERAL RECEPTORS Rantes (CCL 5) bind to CCR 1, (mice), CCR 3, CCR 5 Mig  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

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

Rôle limité des organes lymphoïdes secondaires dans les rejets de greffe Peau Coeur Lta ¯ / ¯ Lta ¯ / ¯ splénectomisées

SIGNIFICANCE ? 1. REJECTION INDUCED BY GRAFT INFILTRATING MEMORY T CELLS ? 2. DIRECT ALLORECOGNITION BY GRAFT ENDOTHELIAL CELLS ?

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 ?

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 KREISEL, Nat. Med., 2002, 8 : 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

Rejet de greffe de cœur par CD8+ de souris BM3 déplétées en CD4+ B6B6 (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