Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease

被引:64
作者
Blaser, BW
Roychowdhury, S
Kim, DJ
Schwind, NR
Bhatt, D
Yuan, WF
Kusewitt, DF
Ferketich, AK
Caligiuri, MA [1 ]
Guimond, M
机构
[1] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
[2] Ohio State Univ, Integrated Biomed Sci Grad Program, Div Human Canc Genet, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[3] Ohio State Univ, Dept Vet Biosci, Div Hematol & Oncol, Columbus, OH 43210 USA
[4] Ohio State Univ, Dept Internal Med, Div Epidemiol & Biometr, Columbus, OH 43210 USA
关键词
D O I
10.1182/blood-2004-05-1687
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Interleukin-15 (IL-15) is a pleiotropic proinflammatory cytokine with inefficient posttranscriptional processing. We hypothesized that endogenous IL-15 could affect disease progression in the well-described C57Bl/6 (B6) --> (C57Bl/6 x DBA/2) F1 hybrid (B6D2F1) murine model of acute allogeneic graft-versus-host disease (GVHD). B6D2F1 allogeneic recipients received transplants of IL-15(-/-) B6 bone marrow cells or B6 bone marrow cells expressing a murine IL-15 transgene (IL-15 tg) modified for efficient translation and secretion. Mice that received transplants of IL-15(-/-) B6 bone marrow cells displayed a significantly longer median survival time (MST) compared with mice that received transplants of wild-type (wt) B6 bone marrow; in contrast, mice that received transplants of IL-15 tg B6 bone marrow cells had a dramatically decreased MST. This decrease in survival was associated with a substantial activation and expansion of effector-memory (CD44(high)CD62L(low)) CD8(+) T lymphocytes. Finally, in vivo depletion of either CD4(+) or CD8(+) T lymphocyte subsets significantly prolonged survival in mice receiving IL-15 tg B6 marrow, while depletion of both CD4(+) and CD8(+) T cells provided complete protection from acute GVHD. We thus show that acute GVHD is attenuated in the absence of donor bone marrow-derived IL-15 and conclude that donor-derived IL-15 is a critical mediator of T-cell function in acute GVHD. (C) 2005 by The American Society of Hematology.
引用
收藏
页码:894 / 901
页数:8
相关论文
共 73 条
[1]  
ANASETTI C, 1991, BONE MARROW TRANSPL, V7, P375
[2]  
ANDERSON DM, 1995, J BIOL CHEM, V270, P29862
[3]  
ANTIN JH, 1992, BLOOD, V80, P2964
[4]   The current status of hematopoietic cell transplantation [J].
Appelbaum, FR .
ANNUAL REVIEW OF MEDICINE-SELECTED TOPICS IN THE CLINICAL SCIENCES, 2003, 54 :491-512
[5]  
Bamford RN, 1998, J IMMUNOL, V160, P4418
[6]   Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I R region/IL-15 fusion message that lacks many upstream AUGs that normally attenuate IL-15 mRNA translation [J].
Bamford, RN ;
Battiata, AP ;
Burton, JD ;
Sharma, H ;
Waldmann, TA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (07) :2897-2902
[7]   THE INTERLEUKIN (IL)-2 RECEPTOR-BETA CHAIN IS SHARED BY IL-2 AND A CYTOKINE, PROVISIONALLY DESIGNATED IL-T, THAT STIMULATES T-CELL PROLIFERATION AND THE INDUCTION OF LYMPHOKINE-ACTIVATED KILLER-CELLS [J].
BAMFORD, RN ;
GRANT, AJ ;
BURTON, JD ;
PETERS, C ;
KURYS, G ;
GOLDMAN, CK ;
BRENNAN, J ;
ROESSLER, E ;
WALDMANN, TA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (11) :4940-4944
[8]   IL-15 promotes the survival of naive and memory phenotype CD8+ T cells [J].
Berard, M ;
Brandt, K ;
Paus, SB ;
Tough, DF .
JOURNAL OF IMMUNOLOGY, 2003, 170 (10) :5018-5026
[9]   Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15 [J].
Brentjens, RJ ;
Latouche, JB ;
Santos, E ;
Marti, F ;
Gong, MC ;
Lyddane, C ;
King, PD ;
Larson, S ;
Weiss, M ;
Rivière, I ;
Sadelain, M .
NATURE MEDICINE, 2003, 9 (03) :279-286
[10]   IL-15Rα expression on CD8+ T cells is dispensable for T cell memory [J].
Burkett, PR ;
Koka, R ;
Chien, M ;
Chai, S ;
Chan, F ;
Ma, A ;
Boone, DL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (08) :4724-4729