Role of lymphocyte and host-directed immunotherapy in severe pneumonia_West China Medical Journal

Authors：

JIA Qingqing , TONG Xiang ,  FAN Hong

Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

FAN Hong, Email: fanhong@scu.edu.cn

Keywords：

Severe pneumonia; lymphocyte; host-directed; immunotherapy

DOI：

10.7507/1002-0179.202404173

Video：

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Severe pneumonia remains a critical global concern. The immune and cytokine imbalance mediated by lymphocytes are related to the severe transformation and tissue damage of pneumonia, and are expected to become potential therapeutic targets for severe pneumonia. This article elaborates on the protection and pathogenic mechanism of lymphocyte in severe pneumonia, and further introduces the clinical application and research status of host-directed immunotherapy in severe pneumonia from two aspects: enhancing host immunity and improving immunopathological damage. It also introduces the challenges faced by immunotherapy in the future clinical translational application, aiming to provide new thinking directions for its clinical diagnosis, treatment, and research.

1.	Torres A, Cilloniz C, Niederman MS, et al. Pneumonia. Nat Rev Dis Primers, 2021, 7(1): 25.
2.	Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis, 2007, 2(Suppl 2): S27-S72.
3.	中华医学会呼吸病学分会. 中国成人社区获得性肺炎诊断和治疗指南(2016 年版). 中华结核和呼吸杂志, 2016, 39(4): 253-279.
4.	中华医学会呼吸病学分会感染学组. 中国成人医院获得性肺炎与呼吸机相关性肺炎诊断和治疗指南(2018 年版). 中华结核和呼吸杂志, 2018, 41(4): 255-280.
5.	Restrepo MI, Anzueto A. Severe community-acquired pneumonia. Infect Dis Clin North Am, 2009, 23(3): 503-520.
6.	Chaplin DD. Overview of the immune response. J Allergy Clin Immunol, 2010, 125(Suppl 2): S3-S23.
7.	陈双, 李莲, 彭余, 等. T 淋巴细胞及细胞因子在预测肺炎重症转化中的临床意义. 中华肺部疾病杂志(电子版), 2022, 15(5): 750-753.
8.	Moore BB, Moore TA, Toews GB. Role of T- and B-lymphocytes in pulmonary host defences. Eur Respir J, 2001, 18(5): 846-856.
9.	Blom B, Spits H. Development of human lymphoid cells. Annu Rev Immunol, 2006, 24: 287-320.
10.	Yoo JK, Kim TS, Hufford MM, et al. Viral infection of the lung: host response and sequelae. J Allergy Clin Immunol, 2013, 132(6): 1263-1276.
11.	Read KA, Powell MD, Sreekumar BK, et al. In vitro differentiation of effector CD4⁺ T helper cell subsets. Methods Mol Biol, 2019, 1960: 75-84.
12.	Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol, 2012, 30: 221-241.
13.	Schuster IS, Sng XYX, Lau CM, et al. Infection induces tissue-resident memory NK cells that safeguard tissue health. Immunity, 2023, 56(3): 531-546. e6.
14.	López-Rodríguez JC, Hancock SJ, Li K, et al. Type I interferons drive MAIT cell functions against bacterial pneumonia. J Exp Med, 2023, 220(10): e20230037.
15.	Ogongo P, Porterfield JZ, Leslie A. Lung tissue resident memory T-cells in the immune response to mycobacterium tuberculosis. Front Immunol, 2019, 10: 992.
16.	Wiseman DJ, Thwaites RS, Drysdale SB, et al. Immunological and inflammatory biomarkers of susceptibility and severity in adult respiratory syncytial virus infections. J Infect Dis, 2020, 222(Suppl 7): S584-S591.
17.	Pereira JM, Paiva JA, Rello J. Severe sepsis in community-acquired pneumonia--early recognition and treatment. Eur J Intern Med, 2012, 23(5): 412-419.
18.	Torres LK, Pickkers P, van der Poll T. Sepsis-induced immunosuppression. Annu Rev Physiol, 2022, 84: 157-181.
19.	McCulloch TR, Wells TJ, Souza-Fonseca-Guimaraes F. Towards efficient immunotherapy for bacterial infection. Trends Microbiol, 2022, 30(2): 158-169.
20.	Wallis RS, O’Garra A, Sher A, et al. Host-directed immunotherapy of viral and bacterial infections: past, present and future. Nat Rev Immunol, 2023, 23(2): 121-133.
21.	Simões EAF, Madhi SA, Muller WJ, et al. Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials. Lancet Child Adolesc Health, 2023, 7(3): 180-189.
22.	François B, Jafri HS, Chastre J, et al. Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial. Lancet Infect Dis, 2021, 21(9): 1313-1323.
23.	Liu Y, Pan Y, Hu Z, et al. Thymosin alpha 1 reduces the mortality of severe coronavirus disease 2019 by restoration of lymphocytopenia and reversion of exhausted T cells. Clin Infect Dis, 2020, 71(16): 2150-2157.
24.	严锡祥, 郑爱东, 张振恩, 等. 胸腺肽α1 免疫治疗联合抗感染对重症肺部感染的影响. 中华肺部疾病杂志(电子版), 2021, 14(3): 301-304.
25.	Francois B, Jeannet R, Daix T, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight, 2018, 3(5): e98960.
26.	Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med, 2009, 180(7): 640-648.
27.	Leentjens J, Kox M, Koch RM, et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med, 2012, 186(9): 838-845.
28.	Madouri F, Barada O, Kervoaze G, et al. Production of Interleukin-20 cytokines limits bacterial clearance and lung inflammation during infection by Streptococcus pneumoniae. EBioMedicine, 2018, 37: 417-427.
29.	Batlle E, Massagué J. Transforming growth factor-β signaling in immunity and cancer. Immunity, 2019, 50(4): 924-940.
30.	Loh JT, Lam KP. Fungal infections: immune defense, immunotherapies and vaccines. Adv Drug Deliv Rev, 2023, 196: 114775.
31.	Berg J, Zscheppang K, Fatykhova D, et al. Tyk2 as a target for immune regulation in human viral/bacterial pneumonia. Eur Respir J, 2017, 50(1): 1601953.
32.	Ramasamy S, Subbian S. Critical determinants of cytokine storm and type I interferon response in COVID-19 pathogenesis. Clin Microbiol Rev, 2021, 34(3): e00299-20.
33.	Lukaszewicz AC, Venet F, Faure A, et al. Immunostimulation with interferon-γ in protracted SARS-CoV-2 pneumonia. J Med Virol, 2021, 93(10): 5710-5711.
34.	Hotchkiss RS, Colston E, Yende S, et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med, 2019, 45(10): 1360-1371.
35.	Wang JF, Li JB, Zhao YJ, et al. Up-regulation of programmed cell death 1 ligand 1 on neutrophils may be involved in sepsis-induced immunosuppression: an animal study and a prospective case-control study. Anesthesiology, 2015, 122(4): 852-863.
36.	Wang X, Cao Z, Jiang J, et al. Elevated expression of Tim-3 on CD8 T cells correlates with disease severity of pulmonary tuberculosis. J Infect, 2011, 62(4): 292-300.
37.	Washburn ML, Wang Z, Walton AH, et al. T cell- and monocyte-specific RNA-sequencing analysis in septic and nonseptic critically ill patients and in patients with cancer. J Immunol, 2019, 203(7): 1897-1908.
38.	Perruccio K, Tosti A, Burchielli E, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood, 2005, 106(13): 4397-4406.
39.	Bouch S, Litvack ML, Litman K, et al. Therapeutic stem cell-derived alveolar-like macrophages display bactericidal effects and resolve Pseudomonas aeruginosa-induced lung injury. J Cell Mol Med, 2022, 26(10): 3046-3059.
40.	Ackermann M, Kempf H, Hetzel M, et al. Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections. Nat Commun, 2018, 9(1): 5088.
41.	Volk HD, Reinke P, Krausch D, et al. Monocyte deactivation--rationale for a new therapeutic strategy in sepsis. Intensive Care Med, 1996, 22(Suppl 4): S474-S481.
42.	Kox WJ, Volk T, Kox SN, et al. Immunomodulatory therapies in sepsis. Intensive Care Med, 2000, 26(Suppl 1): S124-S128.
43.	Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet, 2011, 377(9782): 2023-2030.
44.	Martin-Loeches I, Torres A, Nagavci B, et al. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia. Eur Respir J, 2023, 61(4): 2200735.
45.	REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med, 2021, 384(16): 1491-1502.
46.	Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med, 2021, 9(12): 1407-1418.

1. Torres A, Cilloniz C, Niederman MS, et al. Pneumonia. Nat Rev Dis Primers, 2021, 7(1): 25.
2. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis, 2007, 2(Suppl 2): S27-S72.
3. 中华医学会呼吸病学分会. 中国成人社区获得性肺炎诊断和治疗指南(2016 年版). 中华结核和呼吸杂志, 2016, 39(4): 253-279.
4. 中华医学会呼吸病学分会感染学组. 中国成人医院获得性肺炎与呼吸机相关性肺炎诊断和治疗指南(2018 年版). 中华结核和呼吸杂志, 2018, 41(4): 255-280.
5. Restrepo MI, Anzueto A. Severe community-acquired pneumonia. Infect Dis Clin North Am, 2009, 23(3): 503-520.
6. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol, 2010, 125(Suppl 2): S3-S23.
7. 陈双, 李莲, 彭余, 等. T 淋巴细胞及细胞因子在预测肺炎重症转化中的临床意义. 中华肺部疾病杂志(电子版), 2022, 15(5): 750-753.
8. Moore BB, Moore TA, Toews GB. Role of T- and B-lymphocytes in pulmonary host defences. Eur Respir J, 2001, 18(5): 846-856.
9. Blom B, Spits H. Development of human lymphoid cells. Annu Rev Immunol, 2006, 24: 287-320.
10. Yoo JK, Kim TS, Hufford MM, et al. Viral infection of the lung: host response and sequelae. J Allergy Clin Immunol, 2013, 132(6): 1263-1276.
11. Read KA, Powell MD, Sreekumar BK, et al. In vitro differentiation of effector CD4⁺ T helper cell subsets. Methods Mol Biol, 2019, 1960: 75-84.
12. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol, 2012, 30: 221-241.
13. Schuster IS, Sng XYX, Lau CM, et al. Infection induces tissue-resident memory NK cells that safeguard tissue health. Immunity, 2023, 56(3): 531-546. e6.
14. López-Rodríguez JC, Hancock SJ, Li K, et al. Type I interferons drive MAIT cell functions against bacterial pneumonia. J Exp Med, 2023, 220(10): e20230037.
15. Ogongo P, Porterfield JZ, Leslie A. Lung tissue resident memory T-cells in the immune response to mycobacterium tuberculosis. Front Immunol, 2019, 10: 992.
16. Wiseman DJ, Thwaites RS, Drysdale SB, et al. Immunological and inflammatory biomarkers of susceptibility and severity in adult respiratory syncytial virus infections. J Infect Dis, 2020, 222(Suppl 7): S584-S591.
17. Pereira JM, Paiva JA, Rello J. Severe sepsis in community-acquired pneumonia--early recognition and treatment. Eur J Intern Med, 2012, 23(5): 412-419.
18. Torres LK, Pickkers P, van der Poll T. Sepsis-induced immunosuppression. Annu Rev Physiol, 2022, 84: 157-181.
19. McCulloch TR, Wells TJ, Souza-Fonseca-Guimaraes F. Towards efficient immunotherapy for bacterial infection. Trends Microbiol, 2022, 30(2): 158-169.
20. Wallis RS, O’Garra A, Sher A, et al. Host-directed immunotherapy of viral and bacterial infections: past, present and future. Nat Rev Immunol, 2023, 23(2): 121-133.
21. Simões EAF, Madhi SA, Muller WJ, et al. Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials. Lancet Child Adolesc Health, 2023, 7(3): 180-189.
22. François B, Jafri HS, Chastre J, et al. Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial. Lancet Infect Dis, 2021, 21(9): 1313-1323.
23. Liu Y, Pan Y, Hu Z, et al. Thymosin alpha 1 reduces the mortality of severe coronavirus disease 2019 by restoration of lymphocytopenia and reversion of exhausted T cells. Clin Infect Dis, 2020, 71(16): 2150-2157.
24. 严锡祥, 郑爱东, 张振恩, 等. 胸腺肽α1 免疫治疗联合抗感染对重症肺部感染的影响. 中华肺部疾病杂志(电子版), 2021, 14(3): 301-304.
25. Francois B, Jeannet R, Daix T, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight, 2018, 3(5): e98960.
26. Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med, 2009, 180(7): 640-648.
27. Leentjens J, Kox M, Koch RM, et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med, 2012, 186(9): 838-845.
28. Madouri F, Barada O, Kervoaze G, et al. Production of Interleukin-20 cytokines limits bacterial clearance and lung inflammation during infection by Streptococcus pneumoniae. EBioMedicine, 2018, 37: 417-427.
29. Batlle E, Massagué J. Transforming growth factor-β signaling in immunity and cancer. Immunity, 2019, 50(4): 924-940.
30. Loh JT, Lam KP. Fungal infections: immune defense, immunotherapies and vaccines. Adv Drug Deliv Rev, 2023, 196: 114775.
31. Berg J, Zscheppang K, Fatykhova D, et al. Tyk2 as a target for immune regulation in human viral/bacterial pneumonia. Eur Respir J, 2017, 50(1): 1601953.
32. Ramasamy S, Subbian S. Critical determinants of cytokine storm and type I interferon response in COVID-19 pathogenesis. Clin Microbiol Rev, 2021, 34(3): e00299-20.
33. Lukaszewicz AC, Venet F, Faure A, et al. Immunostimulation with interferon-γ in protracted SARS-CoV-2 pneumonia. J Med Virol, 2021, 93(10): 5710-5711.
34. Hotchkiss RS, Colston E, Yende S, et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med, 2019, 45(10): 1360-1371.
35. Wang JF, Li JB, Zhao YJ, et al. Up-regulation of programmed cell death 1 ligand 1 on neutrophils may be involved in sepsis-induced immunosuppression: an animal study and a prospective case-control study. Anesthesiology, 2015, 122(4): 852-863.
36. Wang X, Cao Z, Jiang J, et al. Elevated expression of Tim-3 on CD8 T cells correlates with disease severity of pulmonary tuberculosis. J Infect, 2011, 62(4): 292-300.
37. Washburn ML, Wang Z, Walton AH, et al. T cell- and monocyte-specific RNA-sequencing analysis in septic and nonseptic critically ill patients and in patients with cancer. J Immunol, 2019, 203(7): 1897-1908.
38. Perruccio K, Tosti A, Burchielli E, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood, 2005, 106(13): 4397-4406.
39. Bouch S, Litvack ML, Litman K, et al. Therapeutic stem cell-derived alveolar-like macrophages display bactericidal effects and resolve Pseudomonas aeruginosa-induced lung injury. J Cell Mol Med, 2022, 26(10): 3046-3059.
40. Ackermann M, Kempf H, Hetzel M, et al. Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections. Nat Commun, 2018, 9(1): 5088.
41. Volk HD, Reinke P, Krausch D, et al. Monocyte deactivation--rationale for a new therapeutic strategy in sepsis. Intensive Care Med, 1996, 22(Suppl 4): S474-S481.
42. Kox WJ, Volk T, Kox SN, et al. Immunomodulatory therapies in sepsis. Intensive Care Med, 2000, 26(Suppl 1): S124-S128.
43. Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet, 2011, 377(9782): 2023-2030.
44. Martin-Loeches I, Torres A, Nagavci B, et al. ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia. Eur Respir J, 2023, 61(4): 2200735.
45. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med, 2021, 384(16): 1491-1502.
46. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med, 2021, 9(12): 1407-1418.

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