Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial

被引:310
作者
Francois, Bruno [1 ,2 ,3 ]
Jeannet, Robin [2 ]
Daix, Thomas [1 ,2 ]
Walton, Andrew H. [4 ]
Shotwell, Matthew S. [5 ]
Unsinger, Jacqueline [4 ]
Monneret, Guillaume [6 ,7 ]
Rimmele, Thomas [7 ,8 ]
Blood, Teresa [4 ]
Morre, Michel [9 ]
Gregoire, Anne [9 ]
Mayo, Gail A. [10 ]
Blood, Jane [4 ]
Durum, Scott K. [11 ]
Sherwood, Edward R. [10 ,12 ]
Hotchkiss, Richard S. [4 ,13 ,14 ]
机构
[1] Dupuytren Univ Hosp, Intens Care Unit, Limoges, France
[2] Dupuytren Univ Hosp, INSERM, CIC 1435, Limoges, France
[3] Univ Limoges, INSERM, UMR 1092, Limoges, France
[4] Washington Univ, Sch Med, Dept Anesthesiol, 660 South Euclid Ave, St Louis, MO 63110 USA
[5] Vanderbilt Univ, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA
[6] Hosp Civils Lyon, Edouard Herriot Hosp, Cellular Immunol Lab, Lyon, France
[7] Univ Claude Bernard Lyon 1, Hosp Civils Lyon, Biomerieux, EA Pathophysiol Injury Induced Immunosuppress 742, Lyon, France
[8] Hosp Civils Lyon, Edouard Herriot Hosp, Anesthesiol & Intens Care Med, Lyon, France
[9] Revimmune SAS, Paris, France
[10] Vanderbilt Univ, Med Ctr, Dept Anesthesiol, Nashville, TN USA
[11] NCI, Cytokines & Immun Sect, Bethesda, MD 20892 USA
[12] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA
[13] Washington Univ, Sch Med, Dept Med, 660 South Euclid Ave, St Louis, MO 63110 USA
[14] Washington Univ, Sch Med, Dept Surg, 660 South Euclid Ave, St Louis, MO 63110 USA
关键词
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; RECOMBINANT HUMAN INTERLEUKIN-7; APOPTOTIC CELL-DEATH; IMPROVES SURVIVAL; IMMUNE DYSFUNCTION; SEVERE SEPSIS; T-CELLS; 2-HIT MODEL; IL-7; EXPRESSION;
D O I
10.1172/jci.insight.98960
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
BACKGROUND. A defining pathophysiologic feature of sepsis is profound apoptosis-induced death and depletion of CD4(+) and CD8(+) T cells. Interleukin-7 (IL-7) is an antiapoptotic common gamma-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4(+) and CD8(+) lymphocyte counts, and improved immunity. METHODS. We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia. Twentyseven patients at academic sites in France and the United States received CYT107 or placebo for 4 weeks. Primary aims were to determine the safety of CYT107 in sepsis and its ability to reverse lymphopenia. RESULTS. CYT107 was well tolerated without evidence of inducing cytokine storm or worsening inflammation or organ dysfunction. CYT107 caused a 3-to 4-fold increase in absolute lymphocyte counts and in circulating CD4(+) and CD8(+) T cells that persisted for weeks after drug administration. CYT107 also increased T cell proliferation and activation. CONCLUSIONS. This is the first trial of an immunoadjuvant therapy targeting defects in adaptive immunity in patients with sepsis. CYT107 reversed the marked loss of CD4(+) and CD8(+) immune effector cells, a hallmark of sepsis and a likely key mechanism in its morbidity and mortality. CYT107 represents a potential new way forward in the treatment of patients with sepsis by restoring adaptive immunity. Such immune-based therapy should be broadly protective against diverse pathogens including multidrug resistant bacteria that preferentially target patients with impaired immunity.
引用
收藏
页数:18
相关论文
共 66 条
[1]   Treatment of Progressive Multifocal Leukoencephalopathy With Interleukin 7 [J].
Alstadhaug, Karl B. ;
Croughs, Therese ;
Henriksen, Stian ;
Leboeuf, Celine ;
Sereti, Irini ;
Hirsch, Hans H. ;
Rinaldo, Christine Hanssen .
JAMA NEUROLOGY, 2014, 71 (08) :1030-1035
[2]   The Search for Effective Therapy for Sepsis Back to the Drawing Board? [J].
Angus, Derek C. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2011, 306 (23) :2614-2615
[3]   Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques [J].
Beq, Stephanie ;
Rozlan, Sandra ;
Gautier, David ;
Parker, Raphaelle ;
Mersseman, Veronique ;
Schilte, Clementine ;
Assouline, Brigitte ;
Rance, Iann ;
Lavedan, Pascal ;
Morre, Michel ;
Cheynier, Remi .
BLOOD, 2009, 114 (04) :816-825
[4]   DEFINITIONS FOR SEPSIS AND ORGAN FAILURE AND GUIDELINES FOR THE USE OF INNOVATIVE THERAPIES IN SEPSIS [J].
BONE, RC ;
BALK, RA ;
CERRA, FB ;
DELLINGER, RP ;
FEIN, AM ;
KNAUS, WA ;
SCHEIN, RMH ;
SIBBALD, WJ .
CHEST, 1992, 101 (06) :1644-1655
[5]   Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure [J].
Boomer, Jonathan S. ;
To, Kathleen ;
Chang, Kathy C. ;
Takasu, Osamu ;
Osborne, Dale F. ;
Walton, Andrew H. ;
Bricker, Traci L. ;
Jarman, Stephen D., II ;
Kreisel, Daniel ;
Krupnick, Alexander S. ;
Srivastava, Anil ;
Swanson, Paul E. ;
Green, Jonathan M. ;
Hotchkiss, Richard S. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2011, 306 (23) :2594-2605
[6]   Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis [J].
Brahmamdam, Pavan ;
Inoue, Shigeaki ;
Unsinger, Jacqueline ;
Chang, Katherine C. ;
McDunn, Jonathan E. ;
Hotchkiss, Richard S. .
JOURNAL OF LEUKOCYTE BIOLOGY, 2010, 88 (02) :233-240
[7]   Severe Sepsis and Septic Shock REPLY [J].
Angus, Derek C. ;
van der Poll, Tom .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (21) :2063-2063
[8]   Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis [J].
Chang, Katherine C. ;
Unsinger, Jacqueline ;
Davis, Christopher G. ;
Schwulst, Steven J. ;
Muenzer, Jared T. ;
Strasser, Andreas ;
Hotchkiss, Richard S. .
FASEB JOURNAL, 2007, 21 (03) :708-719
[9]  
Cheever MAM, 2008, IMMUNOL REV, V222, P357, DOI 10.1111/j.1600-065X.2008.00604.x
[10]   Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity [J].
Chung, CS ;
Song, GY ;
Lomas, J ;
Simms, HH ;
Chaudry, IH ;
Ayala, A .
JOURNAL OF LEUKOCYTE BIOLOGY, 2003, 74 (03) :344-351