Kevin J. Tracey, MD, Chief Executive, Feinstein Institute Investgator Lab Director ktracey@nshs.edu

Kevin Tracey, MD studies the immune system and diseases caused by inflammation. With his colleagues, he discovered that the brain coordinates the immune system by sending electrical signals through nerves. Much like it controls the heart and other organs, the brain controls the output of cells that comprise the immune system. This discovery has altered the way that people think about how the body protects itself from infection and injury, because previously most had not considered the immune system to be directly controlled by the brain.

One long standing question in immunology has been, "how does the body normally control the immune system to prevent it from damaging normal organs?" Surprisingly, the vagus nerve – a long, thin nerve that snakes from the brain down through the body – directly controls the body’s inflammatory response. It provides a natural brake on the immune system, which is necessary because unless tightly controlled, the products of  the immune system can damage normal organs, as well as invading pathogens. Although many investigators had studied the effects of the immune system on brain, Tracey found that signals from the brain held the key to understanding the immune system. This answer gave important insights into how it is possible to prevent damage from inflammation.

Using pacemaker-like devices, it is now possible to stimulate the vagus nerve to reduce the production of cytokines, molecules produced by the immune system during inflammation which damage normal organs. The brain utilizes a neural circuit, coined the “inflammatory reflex,” which is dependent upon the activity of a molecule released by the vagus nerve – acetylcholine. The molecular mechanism for how acetylcholine turns off inflammation is through the alpha7 nicotinic acetylcholine receptor subunit, which turns off cytokine release from monocytes and other immune cells. Dr. Tracey’s team is now involved in testing the effects of vagus nerve stimulation and of drugs that target alpha7 in preclinical studies that may someday be used to prevent inflammation in diseases as varied as arthritis, colitis, diabetes, and atherosclerosis.

Dr. Tracey, a Cornell University Medical Center and Rockefeller University trained neurosurgeon, has been studying the molecular basis of inflammation since the caring for one his first patients, an eleven month old girl named "Janice," fighting for her life on the burn unit at New York Hospital. As recounted in his book "Fatal Sequence," Tracey's inability to explain the Janice's complicated hospital course at that time pushed him onto the path of exploring the immune system, its capacity to cause tremendous damage, and the mechanisms that normally function to keep us healthy. His highly cited work has yielded a new understanding of how the immune system functions, as well as experimental therapies to block inflammation by either targeting newly discovered cytokines, including HMGB1, or by preventing their production.

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Lab Members:

Name: Sangeeta Chavan, PhD
Position: Assistant Investigator / Lab Manager
Research: Dr. Chavan is interested in studies of HMGB1 biology and cholinergic anti-inflammatory pathway.
E-mail: schavan@nshs.edu

Name: Valentin Pavlov, PhD
Position: Associate Investigator
Research: Dr. Pavlov is interested in studying brain mechanisms of regulating inflammation.
E-mail: vpavlov@nshs.edu

Name: Huan Yang, PhD
Position: Assistant Investigator
Research: Dr. Yang is interested in studying role of HMGB1 in sepsis pathogenesis.
E-mail: hyang@nshs.edu

Name: Mahendar Ochani, MD
Position: Assistant Investigator
Research: Dr. Ochani is an animal surgeon who is involved in day-to-day animal experiments.
E-mail: mochani@nshs.edu

Name: Mauricio Rosas-Ballina, MD, PhD
Position: Post-Doctoral Fellow
Research: Dr. Rosas-Ballina is interested in studying cholinergic anti-inflammatory pathway mechanisms controlling inflammation.
E-mail: mrosas@nshs.edu

Name: Jacob Levine, MS
Position: Research Assistant
Research: Mr. Levine is interested in the development of a device for removal of specific toxins in sepsis.
E-mail: jlevine@nshs.edu

Name: Jin Hua Li, MS
Position: Research Scientist
Research: Mr. Li is involved in purification of recombinant proteins and various polyclonal and monoclonal antibodies.
E-mail: jli@nshs.edu

Name: La Queta Hudson, MS
Position: Research Assistant
Research: Ms. Hudson provides technical support for the studies of cholinergic anti-inflammatory pathway signaling.
E-mail: lhudson@nshs.edu

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Select Publications:

Waldburger JM, Boyle DL, Pavlov VA, Tracey KJ, Firestein GS. Acetylcholine regulation of synoviocyte cytokine expression by the alpha7 nicotinic receptor. Arthritis Rheum. 2008 Nov;58(11):3439-49. PMID: 18975306 [PubMed - indexed for MEDLINE]

Huston JM, Wang H, Ochani M, Ochani K, Rosas-Ballina M, Gallowitsch-Puerta M, Ashok M, Yang L, Tracey KJ, Yang H. Splenectomy protects against sepsis lethality and reduces serum HMGB1 levels. J Immunol. 2008 Sep 1;181(5):3535-9. PMID: 18714026 [PubMed - indexed for MEDLINE]

Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, Chavan S, Tracey KJ. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11008-13. Epub 2008 Jul 31.PMID: 18669662 [PubMed - indexed for MEDLINE]

Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, Ochani M, Ochani K, Yang LH, Hudson L, Lin X, Patel N, Johnson SM, Chavan S, Goldstein RS, Czura CJ, Miller EJ, Al-Abed Y, Tracey KJ, Pavlov VA. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol Med. 2008 Sep-Oct;14(9-10):567-74. PMID: 18584048 [PubMed - indexed for MEDLINE]

Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M,  Ashok M, Goldstein RS, Chavan S, Pavlov VA, Metz CN, Yang H, Czura CJ, Wang H, Tracey KJ. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med. 2007 Dec;35(12):2762-8. PMID: 17901837 [PubMed - indexed for MEDLINE]

Sloan RP, McCreath H, Tracey KJ, Sidney S, Liu K, Seeman T. RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol Med. 2007 Mar/Apr; 13(3-4):178-84. PMID: 17592552 [PubMed - indexed for MEDLINE]

Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007 Feb;117(2):289-96. Review.PMID: 17273548 [PubMed - indexed for MEDLINE]

Qin S, Wang H, Yuan R, Li H, Ochani M, Ochani K, Rosas-Ballina M, Czura CJ, Huston JM, Miller E, Lin X, Sherry B, Kumar A, Larosa G, Newman W, Tracey KJ, Yang H. Role of HMGB1 in apoptosis-mediated sepsis lethality. J Exp Med. 2006 Jul 10;203(7):1637-42. Epub 2006 Jul 3. PMID: 16818669 [PubMed - indexed for MEDLINE]

Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, Gallowitsch-Puerta M, Ashok M, Czura CJ, Foxwell B, Tracey KJ, Ulloa L. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med. 2006 Jul 10;203(7):1623-8. Epub 2006 Jun 19. PMID: 16785311 [PubMed - indexed for MEDLINE]

Izuishi K, Tsung A, Jeyabalan G, Critchlow ND, Li J, Tracey KJ, Demarco RA, Lotze MT, Fink MP, Geller DA, Billiar TR. Cutting edge: high-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury. J Immunol. 2006 Jun 15;176(12):7154-8. PMID: 16751357 [PubMed - indexed for MEDLINE]

van Westerloo DJ, Giebelen IA, Florquin S, Bruno MJ, Larosa GJ, Ulloa L, Tracey KJ, van der Poll T. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology. 2006 May;130(6):1822-30. PMID: 16697744 [PubMed - indexed for MEDLINE]

Pavlov VA, Ochani M, Gallowitsch-Puerta M, Ochani K, Huston JM, Czura CJ, Al-Abed Y, Tracey KJ. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5219-23. Epub 2006 Mar 20.PMID: 16549778 [PubMed - indexed for MEDLINE]

Tracey KJ.  Fat meets the cholinergic antiinflammatory pathway. J Exp Med. 2005 Oct 17;202(8):1017-21. Review.PMID: 16230472 [PubMed - indexed for MEDLINE]

Metz CN, Tracey KJ. It takes nerve to dampen inflammation. Nat Immunol. 2005 Aug;6(8):756-7. No abstract available. PMID: 16034431 [PubMed - indexed for MEDLINE]

Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D, Huston J, Tracey  KJ, Al-Abed Y, Metz CN. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med. 2005 Apr 4;201(7):1113-23. PMID: 15809354 [PubMed - indexed for MEDLINE]

Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005 Apr;5(4):331-42. Review. PMID: 15803152 [PubMed - indexed for MEDLINE]

Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey  KJ, Geller DA, Billiar TR. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005 Apr 4;201(7):1135-43. Epub 2005 Mar 28.
PMID: 15795240 [PubMed - indexed for MEDLINE]

Yang H, Wang H, Czura CJ, Tracey KJ. The cytokine activity of HMGB1.J Leukoc Biol. 2005 Jul;78(1):1-8. Epub 2005 Feb 25. Review. PMID: 15734795 [PubMed - indexed for MEDLINE]

Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004 Nov;10(11):1216-21. Epub 2004 Oct 24. PMID: 15502843 [PubMed - indexed for MEDLINE]

Andersson U, Tracey KJ. HMGB1 as a mediator of necrosis-induced inflammation and a therapeutic target in arthritis. Rheum Dis Clin North Am. 2004 Aug;30(3):627-37, xi. Review. PMID: 15261345 [PubMed - indexed for MEDLINE]

Czura CJ, Yang H, Amella CA, Tracey KJ. HMGB1 in the mmunology of sepsis (not septic shock) and arthritis. Adv Immunol. 004;84:181-200. Review. No abstract available. PMID: 15246253 [PubMed - indexed for MEDLINE]

Tracey KJ, Warren HS. Human genetics: an inflammatory issue. Nature. 2004 May 6;429(6987):35-7. No abstract available. PMID: 15129268 [PubMed - indexed for MEDLINE]

Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis.J Intern Med. 2004 Mar;255(3):320-31. Review. PMID: 14871456 [PubMed - indexed for MEDLINE]

Andersson UG, Tracey KJ. HMGB1, a pro-inflammatory cytokine of clinical interest: introduction. J Intern Med. 2004 Mar;255(3):318-9. PMID: 14871455 [PubMed - indexed for MEDLINE]

Wang H, Czura CJ, Tracey KJ.  Lipid unites disparate syndromes of sepsis. Nat Med. 2004 Feb;10(2):124-5. No abstract available. PMID: 14760415 [PubMed - indexed for MEDLINE]

Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, Czura CJ, Wang H, Roth J, Warren HS, Fink MP, Fenton MJ, Andersson U, Tracey KJ. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):296-301. Epub 2003 Dec 26.PMID: 14695889 [PubMed - indexed for MEDLINE]

Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ.  Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003 Jan 23;421(6921):384-8. Epub 2002 Dec 22. PMID: 12508119 [PubMed - indexed for MEDLINE]

Tracey KJ. The inflammatory reflex. Nature. 2002 Dec 19-26;420(6917):853-9. Review.PMID: 12490958 [PubMed - indexed for MEDLINE]

Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, Czura CJ, Fink MP,  Tracey KJ. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12351-6. Epub 2002 Sep 3.PMID: 12209006 [PubMed - indexed for MEDLINE]

Ivanova S, Batliwalla F, Mocco J, Kiss S, Huang J, Mack W, Coon A, Eaton JW,  Al-Abed Y, Gregersen PK, Shohami E, Connolly ES Jr, Tracey KJ. Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5579-84. Epub 2002 Apr 9. PMID: 11943872 [PubMed - indexed for MEDLINE]

Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, Sudan S, Czura  CJ, Ivanova SM, Tracey KJ. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. 2002 Mar 18;195(6):781-8.PMID: 11901203 [PubMed - indexed for MEDLINE]

Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ.  HMG-1 as a mediator of acute lung inflammation.J Immunol. 2000 Sep 15;165(6):2950-4.PMID: 10975801 [PubMed - indexed for MEDLINE]

Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ.  High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000 Aug 21;192(4):565-70.PMID: 10952726 [PubMed - indexed for MEDLINE]

Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to
endotoxin. Nature. 2000 May 25;405(6785):458-62.PMID: 10839541 [PubMed - indexed for MEDLINE]

Ombrellino M, Wang H, Ajemian MS, Talhouk A, Scher LA, Friedman SG, Tracey KJ. Increased serum concentrations of high-mobility-group protein 1 in haemorrhagic shock Lancet. 1999 Oct 23;354(9188):1446-7.PMID: 10543678 [PubMed - indexed for MEDLINE]

Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice.Science. 1999 Jul 9;285(5425):248-51.PMID: 10398600 [PubMed - indexed for MEDLINE]

Wang H, Zhang M, Bianchi M, Sherry B, Sama A, Tracey KJ.  Fetuin (alpha2-HS-glycoprotein) opsonizes cationic acrophagedeactivating
molecules.Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14429-34.
PMID: 9826717 [PubMed - indexed for MEDLINE] 38: Ivanova S, Botchkina GI, Al-Abed Y, Meistrell M 3rd, Batliwalla F, Dubinsky JM, Iadecola C, Wang H, Gregersen PK, Eaton JW, Tracey KJ. Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death. J Exp Med. 1998 Jul 20;188(2):327-40. PMID: 9670045 [PubMed - indexed for MEDLINE]

Tracey KJ. Suppression of TNF and other proinflammatory cytokines by the tetravalent guanylhydrazone CNI-1493. Prog Clin Biol Res. 1998;397:335-43. Review. No abstract available. PMID: 9575574 [PubMed - indexed for MEDLINE]

Wang H, Zhang M, Soda K, Sama A, Tracey KJ. Fetuin protects the fetus from TNF.Lancet. 1997 Sep 20;350(9081):861-2. No abstract available. PMID: 9310607 [PubMed - indexed for MEDLINE]

Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med. 1994;45:491-503. Review. PMID: 8198398 [PubMed - indexed for MEDLINE]

Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature. 1993 Oct 21;365(6448):756-9. Erratum in: Nature 1995 Nov 23;378(6555):419. PMID: 8413654 [PubMed - indexed for MEDLINE]

Teng MN, Park BH, Koeppen HK, Tracey KJ, Fendly BM, Schreiber H. Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3535-9. PMID: 2023898 [PubMed - indexed for MEDLINE]

Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF, et al. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J Exp Med. 1989 Nov 1;170(5):1627-33. PMID: 2809510 [PubMed - indexed for MEDLINE]

Tracey KJ, Wei H, Manogue KR, Fong Y, Hesse DG, Nguyen HT, Kuo GC, Beutler B, Cotran RS, Cerami A, et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988 Mar 1;167(3):1211-27. PMID: 3351436 [PubMed - indexed for MEDLINE]

Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17-23;330(6149):662-4. PMID: 3317066 [PubMed - indexed for MEDLINE]

Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ 3rd, Zentella A, Albert JD, et al. Shock and tissue injury induced by recombinant human cachectin.Science. 1986 Oct 24;234(4775):470-4. PMID: 3764421 [PubMed - indexed for MEDLINE]