IL-6 Promotes Cardiac Graft Rejection Mediated by CD4+ Cells

被引:54
作者
Booth, Adam Jared
Grabauskiene, Svetlana [2 ]
Wood, Sherri Chan [2 ]
Lu, Guanyi [2 ]
Burrell, Bryna E. [3 ]
Bishop, D. Keith [1 ,2 ]
机构
[1] Univ Michigan, Med Ctr, Sect Transplantat Surg, Dept Internal Med,Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Med Ctr, Dept Surg, Ann Arbor, MI 48109 USA
[3] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA
基金
美国国家卫生研究院;
关键词
HELPER T-LYMPHOCYTES; TGF-BETA; ALLOGRAFT-REJECTION; ENDOTHELIAL-CELLS; SOLUBLE RECEPTOR; DENDRITIC CELLS; CYTOKINE GENES; IN-VIVO; INDUCTION; EXPRESSION;
D O I
10.4049/jimmunol.1100766
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
IL-6 mediates numerous immunologic effects relevant to transplant rejection; however, its specific contributions to these processes are not fully understood. To this end, we neutralized IL-6 in settings of acute cardiac allograft rejection associated with either CD8(+) or CD4(+) cell-dominant responses. In a setting of CD8(+) cell-dominant graft rejection, IL-6 neutralization delayed the onset of acute rejection while decreasing graft infiltrate and inverting anti-graft Th1/Th2 priming dominance in recipients. IL-6 neutralization markedly prolonged graft survival in the setting of CD4(+) cell-mediated acute rejection and was associated with decreased graft infiltrate, altered Th1 responses, and reduced serum alloantibody. Furthermore, in CD4(+) cell-dominated rejection, IL-6 neutralization was effective when anti-IL-6 administration was delayed by as many as 6 d posttransplant. Finally, IL-6 deficient graft recipients were protected from CD4(+) cell-dominant responses, suggesting that IL-6 production by graft recipients, rather than grafts, is necessary for this type of rejection. Collectively, these observations define IL-6 as a critical promoter of graft infiltration and a shaper of T cell lineage development in cardiac graft rejection. In light of these findings, the utility of therapeutics targeting IL-6 should be considered for preventing cardiac allograft rejection. The Journal of Immunology, 2011, 187: 5764-5771.
引用
收藏
页码:5764 / 5771
页数:8
相关论文
共 71 条
[1]   Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation:: Evidence in Crohn disease and experimental colitis in vivo [J].
Atreya, R ;
Mudter, J ;
Finotto, S ;
Müllberg, J ;
Jostock, T ;
Wirtz, S ;
Schütz, M ;
Bartsch, B ;
Holtmann, M ;
Becker, C ;
Strand, D ;
Czaja, J ;
Schlaak, JF ;
Lehr, HA ;
Autschbach, F ;
Schürmann, G ;
Nishimoto, N ;
Yoshizaki, K ;
Ito, H ;
Kishimoto, T ;
Galle, PR ;
Rose-John, S ;
Neurath, MF .
NATURE MEDICINE, 2000, 6 (05) :583-588
[2]   Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells [J].
Bettelli, E ;
Carrier, YJ ;
Gao, WD ;
Korn, T ;
Strom, TB ;
Oukka, M ;
Weiner, HL ;
Kuchroo, VK .
NATURE, 2006, 441 (7090) :235-238
[3]   MOBILIZATION OF LYMPHOCYTES-T FOLLOWING CARDIAC TRANSPLANTATION - EVIDENCE THAT CD4-POSITIVE CELLS ARE REQUIRED FOR CYTOTOXIC LYMPHOCYTE-T ACTIVATION, INFLAMMATORY ENDOTHELIAL DEVELOPMENT, GRAFT INFILTRATION, AND ACUTE ALLOGRAFT-REJECTION [J].
BISHOP, DK ;
SHELBY, J ;
EICHWALD, EJ .
TRANSPLANTATION, 1992, 53 (04) :849-857
[4]   CD4-POSITIVE HELPER T-LYMPHOCYTES MEDIATE MOUSE CARDIAC ALLOGRAFT-REJECTION INDEPENDENT OF DONOR ALLOANTIGEN-SPECIFIC CYTOTOXIC T-LYMPHOCYTES [J].
BISHOP, DK ;
CHAN, S ;
LI, WH ;
ENSLEY, RD ;
XU, SX ;
EICHWALD, EJ .
TRANSPLANTATION, 1993, 56 (04) :892-897
[5]   HELPER T-LYMPHOCYTE UNRESPONSIVENESS TO CARDIAC ALLOGRAFTS FOLLOWING TRANSIENT DEPLETION OF CD4-POSITIVE CELLS [J].
BISHOP, DK ;
LI, WH ;
CHAN, SY ;
ENSLEY, RD ;
SHELBY, J ;
EICHWALD, EJ .
TRANSPLANTATION, 1994, 58 (05) :576-584
[6]   Immunobiology of allograft rejection in the absence of IFN-γ:: CD8+ effector cells develop independently of CD4+ cells and CD40-CD40 ligand interactions [J].
Bishop, DK ;
Wood, SC ;
Eichwald, EJ ;
Orosz, CG .
JOURNAL OF IMMUNOLOGY, 2001, 166 (05) :3248-3255
[7]   IL-4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis [J].
Black, Sylvester M. ;
Schott, Megan E. ;
Batdorf, Bjorn H. ;
Benson, Barbara A. ;
Rutherford, Mark S. ;
Levay-Young, Brett K. ;
Dalmasso, Agustin P. .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2010, 40 (03) :803-812
[8]   Connective Tissue Growth Factor Promotes Fibrosis Downstream of TGFβ and IL-6 in Chronic Cardiac Allograft Rejection [J].
Booth, A. J. ;
Csencsits-Smith, K. ;
Wood, S. C. ;
Lu, G. ;
Lipson, K. E. ;
Bishop, D. K. .
AMERICAN JOURNAL OF TRANSPLANTATION, 2010, 10 (02) :220-230
[9]   TGF-β, IL-6, IL-17 and CTGF direct multiple pathologies of chronic cardiac allograft rejection [J].
Booth, Adam J. ;
Bishop, D. Keith .
IMMUNOTHERAPY, 2010, 2 (04) :511-520
[10]   CD8+ Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice [J].
Burrell, Bryna E. ;
Csencsits, Keri ;
Lu, Guanyi ;
Grabauskiene, Svetlana ;
Bishop, D. Keith .
JOURNAL OF IMMUNOLOGY, 2008, 181 (06) :3906-3914