B-cell-mediated strategies to fight chronic allograft rejection

Frontiers in Immunology

Volumn 4, Issue DEC, 2013, Pages

  Dalloul, Ali ^a,b  

^a Universite Paris Sud   (France)

^b UNIVERSITY HOSPITAL OF NANCY   (France)

Author keywords

B cells; Chronic rejection; Immunomodulation; Regulatory B cells; Transplantation

Indexed keywords

EID: 84892189388     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2013.00444     Document Type: Review

References (95)

1. Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol (2012) 9:130-1. doi: 10.1038/nrneph.2012.81.
2. Platt JL. C4d and the fate of organ allografts. J Am Soc Nephrol (2002) 13:2417-9.
3. Sahu A, Lambris JD. Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics. Mol Immunol (2000) 49:133-48.
4. Libby P, Pober JS. Chronic rejection. Immunity (2001) 14:387-97. doi:10.1016/S1074-7613(01)00119-4.
5. Shi C, Lee WS, He Q, Zhang D, Fletcher DL Jr, Newell JB, et al. Immunologic basis of transplantation-associated atherosclerosis. Proc Natl Acad Sci U S A (1996) 93:4501-6. doi:10.1073/pnas.93.9.4051.
6. Koglin J, Glysing-Jensen T, Gadiraju S, Russell ME. Attenuated cardiac allograft vasculopathy in mice with targeted deletion of the transcription factor STAT4. Circulation (2000) 101:1034-9. doi:10.1161/01.CIR.101.9.1034.
7. Ron Y, Sprent J. T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes. J Immunol (1987) 138:2848-56.
8. Ronchese F, Hausmann B. B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes. J Exp Med (1993) 177:679-90. doi:10.1084/jem.177.3.679.
9. Ron Y, De Baetselier P, Gordon J, Feldman M, Segal S. Defective induction of antigen-reactive proliferating T cells in B-cell-deprived mice. Eur J Immunol (1981) 11:964-8. doi:10.1002/eji.1830111203.
10. Kitamura D, Roes J, Kühn R, Rajewsky K. A B-cell deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature (1991) 350:423-6. doi:10.1038/350423a0.
11. Baddoura FK, Nasr IW, Wrobel B, Li Q, Ruddle NH, Lakkis FG. Lymphoid neogenesis in murine cardiac allografts undergoing chronic rejection. Am J Transplant (2005) 5:510-6. doi:10.1111/j.1600-6143.2004.00714.x.
12. Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphoid infiltrates. J Am Soc Nephrol (2004) 15:603-12. doi:10.1097/01.ASN.0000113316.52371.2E.
13. Thaunat O, Field AC, Dai J, Louedec L, Patey N, Bloch MF, et al. Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A (2005) 102:14723-8. doi:10.1073/pnas.0507223102.
14. Motallebzadeh R, Rehakova S, Conlon TM, Win TS, Callaghan CJ, Goddard M, et al. Blocking lymphotoxin signaling abrogates the development of ectopic lymphoid tissue within cardiac allografts and inhibits effector antibody responses. FASEB J (2012) 26:51-62. doi:10.1096/fj.11-186973.
15. Canninga-van Dijk MR, van der Straaten HM, Fijnheer R, Sanders CJ, van den Tweel JG, Verdonck LF. Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood (2004) 104:2603-6. doi:10.1182/blood-2004-05-1855.
16. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, et al. Rituximab for steroid-refractory chronic versus graft host disease. Blood (2006) 108:756-62. doi:10.1182/blood-2006-01-0233.
17. Kim SJ, Lee JW, Jung CW, Min CK, Cho B, Shin HJ, et al. Weekly rituximab followed by monthly rituximab treatment for steroid refractory chronic graft versus host disease: results from a multicenter phase II study. Haematologica (2010) 11:1935-42. doi:10.3324/haematol.2010.026104.
18. Clatworthy MR, Watson CJ, Plotnek G, Bardsley V, Chaudhry AN, Bradley JA, et al. B-cell-depleting induction therapy and acute cellular rejection. N Engl J Med (2009) 360:2683-5. doi:10.1056/NEJMc0808481.
19. Brown K, Sacks SH, Wong W. Tertiary lymphoid organs in renal allografts can be associated with donor-specific tolerance rather than rejection. Eur J Immunol (2011) 41:89-96. doi:10.1002/eji.201040759.
20. Katz SI, Parker D, Turk JL. B cell suppression of delayed type hypersensitivity reactions. Nature (1974) 251:550. doi:10.1038/251550a0.
21. Neta R, Salvin SB. Specific suppression of delayed hypersensitivity: the possible presence of a suppressor B-cell in delayed type hypersensitivity. J Immunol (1974) 113:1716-25.
22. Matsushita T, Fujimoto M, Hasegawa M, Komura K, Takehara K, Tedder TF, et al. Inhibitory role of CD19 in the progression of experimental autoimmune encephalomyelitis by regulating cytokine response. Am J Pathol (2006) 168:812-21. doi:10.2353/ajpath.2006.050923.
23. Watanabe R, Fujimoto M, Ishiura N, Kuwano Y, Nakashima H, Yazawa N, et al. CD19 expression in B cells is important for suppression of contact hypersensitivity. Am J Pathol (2007) 171:560-70. doi:10.2353/ajpath.2007.061279.
24. Hussain S, Delovitch TL. Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner. J Immunol (2007) 179:7225-32.
25. Gonnella PA, Chen YH, Waldner H, Weiner HL. Induction of oral tolerization in CD86 deficient mice: a role for CD86 and B cells in the up-regulation of TGF-beta. J Autoimmun (2006) 26:73-81.
26. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus. Immunity (2010) 32:129-40. doi:10.1016/j.immuni.2009.11.009.
27. Iwata S, Saito K, Tokunaga M, Yamaoka K, Nawata M, Yukawa S, et al. Phenotypic changes of lymphocytes in patients with systemic lupus erythematosus who are in longterm remission after B cell depletion therapy with rituximab. J Rheumatol (2011) 38:633-41. doi:10.3899/jrheum.100729.
28. Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implications in multiple sclerosis. J Immunol (2007) 178:6092-9.
29. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest (2010) 120:1836-47. doi:10.1172/JCI39933.
30. Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, et al. Development of a cross-platform biomarker signature to detect renal transplantation tolerance in humans. J Clin Invest (2010) 120:1848-61. doi:10.1172/JCI39922.
31. Madan R, Demircik F, Surianarayanan S, Allen JL, Divanovic S, Trompette A, et al. Nonredundant roles for B cell-derived IL-10 in immune counter regulation. J Immunol (2009) 183:2312-20. doi:10.4049/jimmunol.0900185.
32. Gary-Gouy H, Harriague J, Bismuth G, Platzer C, Schmitt C, Dalloul AH. Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production. Blood (2002) 100:4537-43. doi:10.1182/blood-2002-05-1525.
33. Matsumoto M, Fujii Y, Baba A, Hikida M, Kurosaki T, Baba Y. The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity (2011) 34:703-14. doi:10.1016/j.immuni.2011.03.016.
34. Mauri C, Mars LT, Londei M. Therapeutic activity of agonistic monoclonal antibodies against CD40 in a chronic autoimmune inflammatory process. Nat Med (2000) 6:673-9. doi:10.1038/76251.
35. Deng S, Moore DJ, Huang X, Lian MM, Mohiuddin M, Velededeoglu E, et al. Cutting edge: transplant tolerance induced by anti-CD45RB requires B-lymphocytes. J Immunol (2007) 178:6028-32.
36. Sun JB, Flach CF, Czerkinsky C, Holmgren JB. lymphocytes promote expansion of regulatory T cells in oral tolerance: powerful induction by antigen coupled to cholera toxin B subunit. J Immunol (2008) 181:8278-87.
37. Carter NA, Vasconcellos R, Rosser EC, Tulone C, Muñoz-Suano A, Kamanaka M, et al. Mice lacking endogenous IL-10-producing regulatory B-cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol (2011) 186:5569-79. doi:10.4049/jimmunol.1100284.
38. Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol (2009) 10:1178-84. doi:10.1038/ni.1791.
39. Darrasse-Jèze G, Deroubaix S, Mouquet H, Victora GD, Eisenreich T, Yao KH, et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med (2009) 206:1853-62. doi:10.1084/jem.20090746.
40. Mann MK, Maresz K, Shriver LP, Tan Y, Dittel BN. B-cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental immune encephalitis. J Immunol (2007) 178:3447-56.
41. Ravetch JV, Lanier LL. Immune inhibitory receptors. Science (2000) 290:84-9. doi:10.1126/science.290.5489.84.
42. Muta T, Kurosaki T, Misulovin Z, Sanchez M, Nussenzweig MC, Ravetch JV. A 13 amino-acid motif in the cytoplasmic domain of FcgRIIB modulates B-cell receptor signaling. Nature (1994) 369:340-3. doi:10.1038/369340a0.
43. Daëron M, Latour S, Malbec O, Espinosa E, Pina P, Pasmans S, et al. The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. Immunity (1995) 3:635-46. doi:10.1016/1074-7613(95)90134-5.
44. Ono M, Bolland S, Tempst P, Ravetch JV. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcgRIIB. Nature (1996) 383:263-6. doi:10.1038/383263a0.
45. Choquet D, Partiseti M, Amigorena S, Bonnerot C, Fridman WH, Korn H. Cross-linking of IgG receptors inhibits membrane Immunoglobulin stimulated calcium influx in B lymphocytes. J Cell Biol (1993) 121:355-63. doi:10.1083/jcb.121.2.355.
46. Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, et al. Multiple defects in the immune system of Lyn-deficient mice culminating in autoimmune disease. Cell (1995) 83:301-11. doi:10.1016/0092-8674(95)90171-X.
47. Amigorena S, Bonnerot C, Drake JR, Choquet D, Hunziker W, Guillet JG, et al. Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science (1992) 256:1808-12.
48. Samuelsson A, Towers TL, Ravetch JV. Anti inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science (2001) 291:484-6. doi:10.1126/science.291.5503.484.
49. Gary-Gouy H, Bruhns P, Schmitt C, Dalloul A, Daëron M, Bismuth G. The pseudo immunoreceptor tyrosine-based activation motif of CD5 mediates its inhibitory action on B-cell receptor signaling. J Biol Chem (2000) 275:548-56. doi:10.1074/jbc.275.1.548.
50. Bouaziz JD, Yanaba K, Tedder TF. Regulatory B cells as inhibitors of immune responses and inflammation. Immunol Rev (2008) 224:201-14. doi:10.1111/j.1600065X.2008.00661.x.
51. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol (2012) 30:221-41. doi:10.1146/annurev-immunol-020711-074934.
52. Carsetti R, Rosado MM, Wardmann H. Peripheral development of B cells in mouse and man. Immunol Rev (2004) 197:179-91. doi:10.1111/j.0105-2896.2004.0109.x.
53. Dalloul A. CD5: a safeguard against autoimmunity and a shield for cancer cells. Autoimmun Rev (2009) 8:349-53. doi:10.1016/j.autrev.2008.11.007.
54. Hippen KL, Tze LE, Behrens TW. CD5 maintains tolerance in anergic B-cells. J Exp Med (2000) 191:883-90.
55. Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70-. J Exp Med (2011) 208:67-80. doi:10.1084/jem.20101499. Erratum in: J Exp Med (2011) 208(4):871; J Exp Med (2011) 208(2):409; J Exp Med (2011) 208(1):67.
56. Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, et al. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest (2011) 121:3645-56. doi:10.1172/JCI46274.
57. Kamphorst AQ, Ahmed R. Manipulating the PD-1 pathway to improve immunity. Curr Opin Immunol (2013) 25:381-8. doi:10.1016/j.coi.2013.03.003.
58. Yoshizaki A, Miyagaki T, Di Lillo D, Matsushita T, Horikawa M, Kountikov E, et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature (2012) 491:264-8. doi:10.1038/nature11501.
59. Parsons RF, Vivek K, Rostami SY, Zekavat G, Ziaie SM, Luo Y, et al. Acquisition of humoral transplantation tolerance upon de novo emergence of B lymphocytes. J Immunol (2011) 186:614-20. doi:10.4049/jimmunol.1002873.
60. Snanoudj R, Beaudreuil S, Arzouk N, de Preneuf H, Durrbach A, Charpentier B. Immunological strategies targeting B cells in organ grafting. Transplantation (2005) 79:S33-6. doi:10.1097/01.TP.0000153298.48353.A4.
61. Ashton-Chess J, Meurette G, Karam G, Petzold T, Minault D, Naulet J, et al. The study of mitoxantrone as a potential immunosuppressor in transgenic pig renal xenotransplantation in baboons: comparison with cyclophosphamide. Xenotransplantation (2004) 11:112-22. doi:10.1111/j.1399-3089.2004.00040.x.
62. Walsh RC, Alloway RR, Girnita AL, Woodle ES. Proteasome inhibitor-based therapy for antibody-mediated rejection. Kidney Int (2012) 81:1067-74. doi:10.1038/ki.2011.502.
63. Gergis U, Arnason J, Yantiss R, Shore T, Wissa U, Feldman E, et al. Effectiveness and safety of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient with refractory GI graft-versus-host disease. J Clin Oncol (2010) 28(30):e602-4. doi:10.1200/JCO.2010.29.1682.
64. Diehl SA, Schmidlin H, Nagasawa M, van Haren SD, Kwakkenbos MJ, Yasuda E, et al. STAT3-mediated upregulation of BLIMP1 is coordinated with BCL2 downregulation to control human plasma cell differentiation. J Immunol (2008) 180:4805-15.
65. Maarof G, Bouchet-Delbos L, Gary-Gouy H, Durand-Gasselin I, Krzysiek R, Dalloul A. Interleukin-24 inhibits the plasma-cell differentiation program in human germinal center B-cells. Blood (2010) 115:1718-26. doi:10.1182/blood-2009-05-220251.
66. West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs (2009) 10:491-504.
67. Wootla B, Nicoletti A, Patey N, Dimitrov JD, Legendre C, Christophe OD, et al. Hydrolysis of coagulation factors by circulating IgG is associated with a reduced risk for chronic allograft nephropathy in renal transplanted patients. J Immunol (2008) 180:8455-60.
68. Lacroix-Desmazes S, Bayry J, Kaveri SV, Hayon-Sonsino D, Thorenoor N, Charpentier J, et al. High levels of catalytic antibodies correlate with favorable outcome in sepsis. Proc Natl Acad Sci U S A (2005) 102:4109-13. doi:10.1073/pnas.0500586102.
69. Vo AA, Peng A, Toyoda M, Kahwaji J, Cao K, Lai CH, et al. Use of intravenous immunoglobulins and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplants. Transplantation (2010) 89:1095-102. doi:10.1097/TP.0b013e3181d21e7f.
70. Le Texier L, Thebault P, Lavault A, Usal C, Merieau E, Quillard T, et al. Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile. Am J Transplant (2011) 11:429-38. doi:10.1111/j.1600-6143.2010.03336.x.
71. Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT. Inhibition of B cells by CD22: a requirement for Lyn. J Exp Med (1998) 187:807-11. doi:10.1084/jem.187.5.807.
72. Jordan SC, Kahwaji J, Toyoda M, Vo A. B cell immunotherapeutics: emerging role in solid organ transplantation. Curr Opin Organ Transplant (2011) 16:416-24. doi:10.1097/MOT.0b013e32834874f7.
73. Miyashita T, McIlraith MJ, Grammer AC, Miura Y, Attrep JF, Shimaoka Y, et al. Bidirectional regulation of human B-cell responses by CD40-CD40 ligand interaction. J Immunol (1997) 158:4620-33.
74. Yang M, Sun L, Wang S, Ko KH, Xu H, Zheng BJ, et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J Immunol (2010) 184:3321-5. doi:10.4049/jimmunol.0902551.
75. Buenafe AC, Bourdette DN. Lipopolysaccharide pretreatment modulate the disease course in experimental autoimmune encephalomyelitis. J Neuroimmunol (2007) 182:32-40. doi:10.1016/j.jneuroim.2006.09.004.
76. Quintana FJ, Rotem A, Carmi P, Cohen IR. Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese mice: modulation of 60kVa heat shock protein autoimmunity. J Immunol (2000) 165:6148-55.
77. Wu HJ, Sawaya H, Binstadt B, Brickelmaier M, Blasius A, Gorelik L, et al. Inflammatory arthritis can be reined in by CpG-induced DC-NK cell cross talk. J Exp Med (2007) 204:1911-22. doi:10.1084/jem.20070285.
78. Neves P, Lampropoulou V, Calderon-Gomez E, Roch T, Stervbo U, Shen P, et al. Signaling via the MyD88 adaptor protein in B-cells suppresses protective immunity Salmonella typhimurium during infection. Immunity (2010) 33:777-90. doi:10.1016/j.immuni.2010.10.016.
79. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive properties of apoptotic cells. Nature (1997) 390:350-1. doi:10.1038/37022.
80. Gray M, Miles K, Salter D, Gray D, Savill J. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci U S A (2007) 104:14080-5. doi:10.1073/pnas.0700326104.
81. Miles K, Heaney J, Sibinska Z, Salter D, Savill J, Gray D, et al. A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interactions with DNA complexes expressed on apoptotic cells. Proc Natl Acad Sci U S A (2012) 109:887-92. doi:10.1073/pnas.1109173109.
82. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self tolerance maintained by activated T cells expressing IL2 receptor a chains (CD25). J Immunol (1995) 155:1151-64.
83. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity? Nat Cell Biol (2010) 12:842-6. doi:10.1038/ncb0910-842.
84. Fishman JA. Infections in solid organ transplantation recipients. N Engl J Med (2007) 357:2601-14. doi:10.1056/NEJMra064928.
85. Fishman JA. Opportunistic infections-coming to the limits of immunosupression. Cold Spring Harb Perspect Med (2013) 3(10):a015669. doi:10.1101/cshperspect.a015669.
86. Spangenberg HC, Viazov S, Kersting N, Neumann-Haefelin C, McKinney D, Roggendorf N, et al. Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection. Hepatology (2005) 42:828-37. doi:10.1002/hep.20856.
87. Chong AS, Alegre ML. The impact of infection and tissue damage in solid organ transplantation. Nat Rev Immunol (2012) 12:459-71. doi:10.1038/nri3215.
88. Jeong Y-I, Hong S-H, Cho S-H, Lee W-J, Lee S-E. Induction of IL-10-producing CD1dhiCD5+ regulatory B-cells following Babesia microti-infection. PLoS One (2013) 7:e46553. doi:10.1371/journal.pone.0046553.
89. Oberholzer A, Oberholzer C, Moldawer LL. Interleukin-10: a complex role in the pathogenesis of sepsis syndromes and its potential as an anti-inflammatory drug. Crit Care Med (2002) 30:S58-63. doi:10.1097/00003246-200201001-00008.
90. Burke GW, Ciancio G, Cirocco R, MArkou M, Coker D, Roth D, et al. Association of interleukin-10 with rejection-sparing effect in septic kidney transplant recipients. Transplantation (1996) 61:1114-6. doi:10.1097/00007890-199604150-00023.
91. Boehler A. The role of interleukin-10 in lung transplantation. Transpl Immunol (2002) 9:121-4. doi:10.1016/S0966-3274(02)00045-X.
92. Fischbein MP, Yun J, Laks Irie Y, Oslund-Pinderski L, Fischbein MC, Bonavida B, et al. REgulated interleukin-10 expression prevents chronic rejection of transplanted hearts. J Thorac Cardiovasc Surg (2003) 126:216-23. doi:10.1016/S0022-5223(03)00026-6.
93. Florquin S, Amraoui Z, Abramovicz D, Goldman M. Sustemic release and protective role of IL-10 in staphylococcal enterotoxin B-induced shock in mice. J Immunol (1994) 153:2618-23.
94. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med (2009) 15:42-9. doi:10.1038/nm.1905.
95. Latifi SQ, O'Riordan MA, Levine AD. Interleukin-10 controls the onset of irreversible septic shock. Infect Immun (2002) 70:4441-6. doi:10.1128/IAI.70.8.4441-4446.2002.