Inhaled innate immune ligands to prevent pneumonia.
Epithelial surfaces throughout the body continuously sample and respond to environmental stimuli. The accessibility of lung epithelium to inhaled therapies makes it possible to stimulate local antimicrobial defences with aerosolized innate immune ligands. This strategy has been shown to be effective in preclinical models, as delivery of innate immune ligands to the lungs of laboratory animals results in protection from subsequent challenge with microbial pathogens. Survival of the animal host in this setting correlates directly with killing of pathogens within the lungs, indicating the induction of a resistance mechanism. Resistance appears to be mediated primarily by activated epithelial cells rather than recruited leucocytes. Resistance reaches a peak within hours and persists for several days. Innate immune ligands can interact synergistically under some circumstances, and synergistic combinations of innate ligands delivered by aerosol are capable of inducing a high level of broad host resistance to bacteria, fungi and viruses. The induction of innate antimicrobial resistance within the lungs could have clinical applications in the prevention of lower respiratory tract infection in subjects transiently at high risk. These include cancer patients undergoing myeloablative chemotherapy, intubated patients being mechanically ventilated, vulnerable individuals during seasonal influenza epidemics, asthmatic subjects experiencing a respiratory viral infection, and healthy subjects exposed to virulent pathogens from a bioterror attack or emergent pandemic. In summary, stimulation of the lung epithelium to induce localized resistance to infection is a novel strategy whose clinical utility will be assessed in the near future.
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA.
Scott E
SE
Evans
Michael J
MJ
Tuvim
Cory J
CJ
Fox
Nidhi
N
Sachdev
Leonid
L
Gibiansky
Burton F
BF
Dickey
D000280:Administration, Inhalation; D000818:Animals; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000382:microbiology; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*
D008024:Ligands
Mol Immunol. 2007 May;44(12):3100-11
17403538
Proc Am Thorac Soc. 2004;1(3):222-30
16113438
Vaccine. 2009 May 26;27(25-26):3481-3
19200852
Cancer. 2003 Dec 1;98(11):2402-9
14635075
Evid Rep Technol Assess (Full Rep). 2010 Jan;(189):1-154, v-vi
20726625
Biofactors. 2009 Jan-Feb;35(1):82-7
19319850
Nat Immunol. 2003 Jul;4(7):702-7
12796777
J Immunol. 2008 Jul 1;181(1):586-92
18566425
Blood. 2009 Feb 12;113(7):1399-407
18757776
Respir Res. 2006 Feb 17;7:29
16503962
J Clin Invest. 2001 Jan;107(1):13-9
11134172
N Engl J Med. 2006 Sep 7;355(10):1018-28
16908486
Science. 2003 Aug 1;301(5633):640-3
12855817
PLoS Pathog. 2009 Apr;5(4):e1000379
19360122
J Immunol. 2010 Jul 15;185(2):1142-9
20566829
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12771-5
19625615
Curr Opin Immunol. 2001 Feb;13(1):89-95
11154923
Nat Rev Immunol. 2007 Dec;7(12):975-87
18007680
Nat Rev Immunol. 2007 Mar;7(3):179-90
17318230
Contrib Microbiol. 2008;15:147-163
18511860
Am J Respir Cell Mol Biol. 2009 Apr;40(4):474-81
18931326
Am J Respir Cell Mol Biol. 2006 May;34(5):527-36
16415249
Science. 2003 Jun 6;300(5625):1524-5
12791976
Am J Respir Crit Care Med. 2008 Jun 15;177(12):1322-30
18388354
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15858-63
17898169
Ann N Y Acad Sci. 2008 Nov;1143:1-20
19076341
PLoS Pathog. 2006 Jun;2(6):e53
16789835
Annu Rev Physiol. 2010;72:413-35
20148683
Science. 2004 Mar 5;303(5663):1526-9
14976262
Proc Am Thorac Soc. 2005;2(5):403-11
16322590
Am J Respir Cell Mol Biol. 2004 Oct;31(4):382-94
15191915
Nat Rev Immunol. 2007 May;7(5):353-64
17457343
Annu Rev Immunol. 2009;27:229-65
19302040
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14614-9
9405661
Immunol Rev. 2008 Dec;226:160-71
19161423
Eur Respir J. 2004 Feb;23(2):327-33
14979512
Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L231-4
18487354
Dis Model Mech. 2010 Sep-Oct;3(9-10):545-56
20699479
Nat Rev Immunol. 2007 Nov;7(11):862-74
17948019
Nat Immunol. 2000 Nov;1(5):398-401
11062499
J Immunol. 2004 Oct 15;173(8):5148-55
15470059
Clin Dev Immunol. 2004 Mar;11(1):77-85
15154616
Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):410-7
17194755
Nat Immunol. 2010 May;11(5):373-84
20404851
Semin Respir Crit Care Med. 2004 Feb;25(1):95-108
16088453
J Immunol. 2002 Jan 15;168(2):810-5
11777976
J Biol Chem. 2004 Aug 27;279(35):36426-32
15215247
Immunol Rev. 2008 Dec;226:10-8
19161412
Am J Respir Cell Mol Biol. 2004 Jun;30(6):777-83
14656745
Am J Respir Crit Care Med. 1998 Dec;158(6):1702-8
9847256
Am J Respir Cell Mol Biol. 2005 Jun;32(6):490-7
15746433
J Biol Chem. 2003 Jan 17;278(3):2043-50
12419803
Am J Respir Cell Mol Biol. 2009 Apr;40(4):443-53
18927348
Nat Med. 2008 Oct;14(10):1023-4
18841139
Am J Respir Cell Mol Biol. 2010 Jan;42(1):40-50
19329554
Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L731-8
16024722
J Immunol. 2005 Sep 15;175(6):3927-34
16148139
PLoS One. 2009;4(1):e4176
19137067
Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1068-75
18375743
Curr Opin Pulm Med. 2009 Jan;15(1):4-11
19077699
Cytokine Growth Factor Rev. 2009 Apr;20(2):97-113
19268625
Microbes Infect. 2007 Apr;9(5):629-36
17379560
Expert Opin Biol Ther. 2007 Jun;7(6):907-18
17555375
J Leukoc Biol. 2007 Sep;82(3):509-18
17586660
J Clin Invest. 2002 Mar;109(5):571-7
11877463
Thorax. 1996 Nov;51(11):1100-4
8958892
Am J Respir Cell Mol Biol. 2008 Jun;38(6):629-38
18096867
Nat Rev Immunol. 2008 Nov;8(11):829-35
18949018
J Immunol. 2008 Nov 15;181(10):7157-65
18981137
Mol Med. 2008 Sep-Oct;14(9-10):645-59
18584047
J Aerosol Med Pulm Drug Deliv. 2010 Dec;23 Suppl 2:S71-87
21133802
Semin Immunol. 2007 Dec;19(6):377-82
18054248
J Immunol. 2011 May 15;186(10):5916-26
21482737
Science. 2004 Mar 5;303(5663):1529-31
14976261
Nature. 2007 Oct 18;449(7164):819-26
17943118
Curr Opin Immunol. 2008 Aug;20(4):377-82
18585455
Ann Allergy Asthma Immunol. 1995 Aug;75(2):177-9
7648384
Leuk Lymphoma. 2003 Dec;44(12):2069-76
14959849
Nature. 1997 Jul 24;388(6640):394-7
9237759
Infect Immun. 2007 Jul;75(7):3382-93
17485459
Nature. 2006 May 4;441(7089):101-5
16625202
Exp Lung Res. 2007 Dec;33(10):507-18
18075825
Semin Immunopathol. 2007 Sep;29(3):275-88
17690885
Cell Death Differ. 2006 May;13(5):816-25
16410796
Nature. 2003 Nov 6;426(6962):33-8
14603309
Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):972-7
11805339
Immunol Rev. 2000 Feb;173:27-38
10719665
Science. 2006 Nov 10;314(5801):994-7
17038590
Curr Opin Immunol. 1999 Feb;11(1):23-7
10047545
Am J Respir Cell Mol Biol. 2004 Sep;31(3):358-64
15191912
Respir Res. 2009 Jul 27;10:70
19635139
Am J Respir Cell Mol Biol. 2007 Feb;36(2):244-53
16980555
Am Rev Respir Dis. 1983 Aug;128(2 Pt 2):S46-8
6881708
Curr Opin Immunol. 2003 Aug;15(4):396-401
12900270
J Allergy Clin Immunol. 2010 Jun;125(6):1212-7
20513518
Annu Rev Biochem. 2007;76:141-65
17362201