Christine T.N. Pham, M.D.
Associate Professor
Room 6621/6622
Clinical Sciences Research Building

Lab Phone: 314-362-9043
Fax: 314-454-1091
e-mail: Cpham@dom.wustl.edu

                       ABIM certification: Internal Medicine and Rheumatology

 

The focus of our laboratory is to define the role of proteases in immunity and autoimmunity. Traditionally, proteases are viewed as effector molecules owing to their ability to digest extracellular matrix (ECM). More recently, studies have extended the role of proteases beyond the degradation of ECM. For example, we have generated a mouse deficient in cathepsin C (or dipeptidyl peptidase I, DPPI) and established that this protease is crucial in the activation of many serine proteases including lymphocyte-associated granzymes, mast cell-derived chymase, and neutrophil-specific cathepsin G, neutrophil elastase and proteinase 3. We have further shown that DPPI and the serine proteases it activates are key molecules involved in cell-mediated cytotoxicity and leukocyte recruitment at sites of inflammation. The absence of DPPI rendered mice resistant to experimentally induced arthritis and death in a model of sepsis. Therefore, a more complete understanding of the functional physiology of proteases should lead to a better understanding of immune effector cell biology and may potential lead to novel therapeutic interventions.

Selected References:

1.      Dunn BM, Pham C, Raney L, Abayasekara D, Gillespie W, Hsu A: Interaction of alpha-dansylated peptide inhibitors with porcine pepsin: Detection of complex formation by fluorescence energy transfer and chromatography and evidence for a two step binding scheme.  Biochemistry 1981; 20: 7206-7211.

2.      Dunn BM, Lewitt M, Pham C: Inhibition of pepsin by analogues of pepsinogen-(1-12)-peptide with substitutions in the 4-7 sequence region.  Biochem. J.1983;209: 355-362.

3.      Pham CTN, MacIvor DM, Hug BA, Heusel JW, and Ley TJ: Long range distuption of gene expression by a selectable marker cassette.  Proc. Natl. Acad. Sci. USA 1996; 93:13090-13095. Abstract

4.      Pham CTN, Armstrong RJ, Zimonjic DB, Popescu NC, Payan DG, and Ley TJ: Molecular cloning, chromosomal localization, and expression of murine dipeptidyl peptidase I.  J. Biol. Chem. 1997; 272: 10695-10703.Abstract

5.      Pham CTN, Thomas DA, Mercer JD, and Ley TJ: Production of fully active recombinant granzyme B in yeast.  J. Biol. Chem. 1998; 273: 1629-1633. Abstract

6.      Makar KW, Pham CTN, Dehoff MH, O’Connor SM, Jacobi SM, and Holers VM: An intronic silencer regulates B lymphocyte cell- and stage-specific expression of human Complement Receptor type 2 (CR2, CD 21) gene.  J. Immunol. 1998; 160:1268-1278.Abstract

7.      MacIvor DM, Pham CTN, and Ley TJ: The 5’ flanking region of the human granzyme H gene directs expression to T/NK cell progenitors and lymphokine activated killer cells in transgenic mice.  Blood 1999; 93: 963-973.

8.      Pham CTN and Ley TJ: Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo.  Proc. Natl. Acad. Sci USA 1999; 96:8627-8632.

9.      Kaufman RM, Pham CTN, and Ley TJ: Transgenic analysis of a 100 kb human beta globin cluster-containing DNA fragment propagated as a Bacterial Artificial Chromosome (BAC).  Blood 1999, 94:3178-3184.

10.  MacIvor DM, Shapiro SD, Pham CTN, Belaaouaj A, Abraham SN, and Ley TJ: Normal neutrophil function in cathepsin G deficient mice.  Blood 1999, 94: 4282-4293. 

11.  Yoder J, Pham C, Iizuka YM, Kanagawa O, Liu SK, McGlade J, and Cheng AC: Requirement for the SLP-76 adaptor GADS in T cell development.  Science 2001, 291:1987-1991.

12.  Wolters PJ, Pham CTN, Muilenburg DJ, Ley TJ, and Caughey GH: Dipeptidyl Peptidase I is essential for activation of mast cell chymases, but not tryptases, in mice. J. Biol. Chem 2001, 276:18551-18556.

13.  Adkison AM, Raptis SZ, Kelley DG and Pham, CTN.  Dipeptidyl peptidase I activates neurophil-derived serine proteases and regulates the development of acute experimental arthritis.  J. Clin. Invest. 2002, 109: 363-371.

14.  Mallen-St. Clair, Pham CTN, Ley TJ, Caughey GH and Wolters PJ. Mast cell dipeptidyl peptidase I mediates survival from sepsis.  J. Clin. Invest. 2004, 113:628-634.

15.  Levesque JP, Liu F, Takamatsu Y, Simmons P, Betsuyaku T, Senior R, Pham CTN and Link DC.  Characterization of hematopoietic progenitor mobilization in protease deficient mice.  Blood 2004, 104:65-72.

16.  Ondr JK, Pham CT.  Characterization of murine cathepsin W and its role in cell-mediated cytotoxicity. J. Biol. Chem. 2004, 279:27525-27533.

17.  Gerth AJ, Pham CT, Peng SL. Regulation of the symmetry and intensity of immune-complex synovitis by nuclear factor of activated T cells. Arthritis Rheum. 2004, 50:3392-3395.

18.  Pham CT, Ivanovich JL, Raptis SZ, Zenhbauer B, and Ley TJ.  Papillon-Lefevre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J. Immunol. 2004, 173:7277-7281.

19.  Raptis SZ, Shapiro SD, Simmons PM, Cheng AM, Pham CTN.  Serine protease cathepsin G regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering. Immunity 2005, 22:679-691.

20.  Hu Y and Pham CTN.  Dipeptidyl peptidase I regulates collagen-induced arthritis.  Arthritis Rheum. 2005, 52:2553-2558.

21.  Pagano MB, Bartoli MA, Ennis TL, Mao D, Simmons PM, Thompson RW, and Pham CTN.  Critical role of dipeptidyl peptidase I in neutrophil recruitment during abdominal aortic aneurysm development.  Proc. Natl. Acad. Sci USA 2007 (direct track II submission) 2007, 104:2855-2860. Abstract

22.  Akk A, Simmons PM, Chan HW, Agapov E, Holtzman MJ, Grayson MH, Pham CTN.  The absence of DPPI attenuates the acute inflammatory response to Sendai virus infection. J. Immunol. 2008, 180:3535-3542. Abstract

23.  Soehnlein O, Zernecke A, Eriksson EE, Rothfuchs AG, Pham CT, Herwald H, Bidzhekov K, Rottenberg ME, Weber C, Lindbom L. Neutrophil secretion products pave the way for inflammatory monocytes (under revision for Blood, #BLOOD/2008/139634).

24.  Kim K-H, Pham CTN, Sleat D, Lobel P.  Dipeptidyl-peptidase I does not functionally compensate for the loss of tripeptidyl-peptidase I in the neurodegenerative disease late-infantile neuronal ceroid lipofuscinosis(under revision for Biochemical Journal, #BJ32008/0411).

25. Tye CE, Pham CT, Simmer JP, Bartlett JD. Dipeptidyl peptidase I may activate kallikrein-4 during enamel formation. J. Dent. Res. 2009, 88:323-327.
 

26. Pagano MB, Zhou H, Ennis TL, Wu X, Lambris JD, Atkinson JP, Thompson RW, Hourcade DE, and Pham CTN. Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm. Circulation 2009, 119:1805-1813.
 

27. Zhou H, Chan HW, Wickline SA, Lanza GM, Pham CTN. Alpha v beta 3-targeted nanotherapy suppresses inflammatory arthritis in mice. FASEB J. 2009, 23:2978-2985.

28. Joosten LAB, Netea MG, Fantuzzi G, Koenders MI, Helsen MMA, Sparrer H, Pham CT, van der Meer JVM, Dinarello CA, and van den Berg WB. Inflammatory arthritis in caspase-1-deficient mice: contribution of proteinase 3 for caspase-1-independent production of bioactive IL-1β. Arthritis Rheum. 2009, 60:3651-3662.

29. Hockett F, Wallace K, Schmieder A, Caruthers S, Pham C, Wickline S, Lanza G. Simultaneous dual frequency 1H and 19F open coil imaging of arthritic rabbit knee at 3T. IEEE TMI 2010, 30:22-27.

30. Zhou H, Hu G, Wickline S, Lanza G, Pham CTN. Synergistic effect of antiangiogenic nanotherapy combined with methotrexate in the treatment of inflammatory arthritis. Nanomedicine (Lond) 2010, 5:1065-1074.

31. Pham CTN, Mitchell LM, Huang JL, Lubniewski CM, Schall OF, Killgore JK, Pan D, Wickline SA, Lanza GM, and Hourcade DE. Variable antibody-dependent activation of complement by functionalized phospholipids nanoparticle surfaces. JBiol. Chem. 2011, 286:123-130.

32. Soehnlein O, Wantha S, Simsekyilmaz S, Döring Y, Megens RTA, Mause SF, Drechsler M, Smeets R, Weinandy S, Schreiber F, Gries T, Jockenhoevel S, Moller M, Vijayan S, van Zandvoort MAMJ, Agerberth N, Pham CT, Gallo RL, Hackeng TM, Liehn EA, Zernecke A, Klee D, and Weber C. Neutrophil-derived cathelicidin
protects from neointimal hyperplasia. Sci. Transl. Med. 2011, 3:103ra98.

33. Vethanayagam RR, Almyroudis NG, Grimm MJ, Lewandowski DC, Pham CTN, Blackwell TS, Petraitiene R, Petraitis V, Walsh TJ, Urban CF, and Segal BH. Role of NADPH oxidase versus neutrophil proteases in antimicrobial host defense. Plos One
2011, 6:e28149.

34. Schreiber A, Pham CTN, Hu Y, Schneider W, Luft FC, Kettritz R. Neutrophil serine proteases promote IL-1β generation and injury in necrotizing crescentic glomerulonephritis. J. Am. Soc.
Neprhol. 2012, 23:470-482.

35. Zhou H-F, Yan H, Stover CM, Montes Fernandez T, Rodriguez de Cordoba S, Song W-C, Wu X, Thompson RW, Schwaeble WJ, Atkinson JP, Hourcade DE, Pham CTN. Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm. Proc. Natl. Acad. Sci. USA. 2012, 109:E415-422.
 

b.  Invited Reviews and Book Chapters:

1.    Pham CTN and Ley TJ: The role of granzyme B cluster proteases in cell-mediated cytotoxicity.  Sem. Immunol. 1997; 9: 127-133. Abstract

2.    Shresta S, Pham CTN, Thomas DA, Graubert TA, and Ley TJ: How do cytotoxic lymphocytes kill their targets?  Curr. Opin. Immunol. 1998; 10: 581-587. Abstract

3.    Raptis SZ and Pham CTN.  Neutrophil-derived serine proteases in immune complex-mediated diseases.  Immunol. Res. 2005, 32:211-216. Abstract

4.    Pham CTN: Neutrophil serine proteases: Specific regulators of inflammation. Nature Rev. Immunol. 2006, 6:541-550. Abstract

5.    Thompson RW, Curci JA, Ennis TL, Mao D, Pagano MB, and Pham CTN. Pathophysiology of addominal aortic aneurysms: Insights from the elastase-induced model in mice with different genetic backgrounds. Ann N Y Acad Sci. 2006; 1085:59-73. Abstract

6.    Pham CTN. Neutrophil serine proteases fine-tune the inflammatory response. Int. J. Biochem. Cell Biol. 2008; 40:1317-1333.  Abstract

7.  Pham CTN: Nanotherapeutic approaches for the treatment of            rheumatoid arthritis. Wiley Interdiscip. Rev. Namomed. Nanobiotechnol. 2011 doi: 10.1002/wnan.157