Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched renal allografts from chronic rejection

被引:25
作者
Benigni, Ariela
Tomasoni, Susanna
Turka, Laurence A.
Longaretti, Lorena
Zentilin, Lorena
Mister, Marilena
Pezzotta, Anna
Azzollini, Nadia
Noris, Marina
Conti, Sara
Abbate, Mauro
Giacca, Mauro
Remuzzi, Giuseppe
机构
[1] Mario Negri Inst Pharmacol Res, Negri Bergamo Labs, I-24125 Bergamo, Italy
[2] Chiara Cucchi Alessandri Gilberto Crespi, Transplant Res Ctr, Bergamo, Italy
[3] Osped Riuniti Bergamo, I-24100 Bergamo, Italy
[4] Univ Penn, Dept Med, Philadelphia, PA 19104 USA
[5] Int Ctr Genet Engn & Biotechnol, Mol Med Lab, I-34012 Trieste, Italy
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2006年 / 17卷 / 06期
关键词
D O I
10.1681/ASN.2006010090
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Short-term results of renal transplantation have improved considerably in the past 20 yr; however, similar improvements in long-term outcome have not been achieved. The primary cause of late graft loss is chronic rejection that might be treated by gene therapeutic approaches. Ideally, one would like to impair locally the contact between transplant antigen and the host immune system without compromising the generalized immune competence of the recipient. This can be achieved by local expression of the therapeutic protein in the site of interest using gene therapy. Here it is shown that chronic allograft rejection can be prevented effectively by local delivery of recombinant adeno-associated virus (AAV) vectors that encode the CTLA4Ig immunosuppressant protein to the donor kidney in a fully MHC-mismatched rat strain combination. AAV CTLA4Ig prevented progressive proteinuria and protected transplant kidneys from renal structural injury. A population of anergic T cells with regulatory activity, which eventually were responsible for the induction of tolerance, were found in recipient lymph nodes and in the graft as long as 120 d after transplantation. These data indicate that AAV-mediated CTLA4Ig gene transfer to donor graft represents a promising tool to prevent the onset of chronic rejection and circumvent the unwanted systemic adverse effects of the administration of immunomodulatory protein.
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收藏
页码:1665 / 1672
页数:8
相关论文
共 34 条
[1]  
Amuchastegui SC, 1998, J AM SOC NEPHROL, V9, P1948
[2]   Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection [J].
Azuma, H ;
Chandraker, A ;
Nadeau, K ;
Hancock, WW ;
Carpenter, CB ;
Tilney, NL ;
Sayegh, MH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (22) :12439-12444
[3]   Nonviral and viral gene transfer to the kidney in the context of transplantation [J].
Benigni, A ;
Tomasoni, S ;
Lutz, J ;
Amuchastegui, S ;
Capogrossi, MC ;
Remuzzi, G .
NEPHRON, 2000, 85 (04) :307-316
[4]   Immune responses to gene therapy vectors: influence on vector function and effector mechanisms [J].
Bessis, N ;
GarciaCozar, FJ ;
Boissier, MC .
GENE THERAPY, 2004, 11 (Suppl 1) :S10-S17
[5]   Pretransplant donor peripheral blood mononuclear cells infusion induces transplantation tolerance by generating regulatory T cells [J].
Cavinato, RA ;
Casiraghi, F ;
Azzollini, N ;
Cassis, P ;
Cugini, D ;
Mister, M ;
Pezzotta, A ;
Aiello, S ;
Remuzzi, G ;
Noris, M .
TRANSPLANTATION, 2005, 79 (09) :1034-1039
[6]   Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection [J].
Chandraker, A ;
Azuma, H ;
Nadeau, K ;
Carpenter, CB ;
Tilney, NL ;
Hancock, WW ;
Sayegh, MH .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (11) :2309-2318
[7]   CD28-B7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury - Rapid Communication [J].
Chandraker, A ;
Takada, M ;
Nadeau, KC ;
Peach, R ;
Tilney, NL ;
Sayegh, MH .
KIDNEY INTERNATIONAL, 1997, 52 (06) :1678-1684
[8]   Gene delivery in renal tubular epithelial cells using recombinant adeno-associated viral vectors [J].
Chen, SF ;
Agarwal, A ;
Glushakova, OY ;
Jorgensen, MS ;
Salgar, SK ;
Poirier, A ;
Flotte, TR ;
Croker, BP ;
Madsen, KM ;
Atkinson, MA ;
Hauswirth, WW ;
Berns, KI ;
Tisher, CC .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (04) :947-958
[9]   Generation of antigen-specific, Foxp3-expressing CD4+ regulatory T cells by inhibition of APC proteosome function [J].
Cong, YZ ;
Konrad, A ;
Iqbal, N ;
Hatton, RD ;
Weaver, CT ;
Elson, CO .
JOURNAL OF IMMUNOLOGY, 2005, 174 (05) :2787-2795
[10]   Recombinant adeno-associated virus vectors for gene therapy [J].
Conlon, TJ ;
Flotte, TR .
EXPERT OPINION ON BIOLOGICAL THERAPY, 2004, 4 (07) :1093-1101