Daniel R Calabrese1, Tiffany Chong1, Angelia Wang1, Jonathan P Singer1, Marc Gottschall2, Steven R Hays1, Jeffrey A Golden1, Jasleen Kukreja3, Lewis L Lanier4, Qizhi Tang3, John R Greenland1,5. 1. Department of Medicine, University of California, San Francisco, CA. 2. Department of Clinical Lab Immunology, University of California, San Francisco, CA. 3. Department of Surgery, University of California, San Francisco, CA. 4. Department of Microbiology and Immunology and the Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA. 5. Medical Service, Veterans Affairs Health Care System, San Francisco, CA.
Abstract
BACKGROUND: Cytomegalovirus (CMV) infection is a risk factor for chronic lung allograft dysfunction (CLAD), which limits survival in lung allograft recipients. Natural killer (NK) cells that express the NKG2C receptor mediate CMV-specific immune responses. We hypothesized that NKG2C NK cells responding to CMV in the lung allograft would reduce CMV-related inflammation and would improve CLAD-free survival. METHODS: We prospectively followed 130 subjects who underwent lung transplantation from 2012 to 2016. Bronchoalveolar lavage (BAL) NK cells were immunophenotyped for NKG2C, maturation, and proliferation markers. CMV viral load, serologies, serial spirometry, and mortality were recorded from medical records. Natural killer cell subset association with CMV endpoints were made using generalized estimating equation-adjusted linear models. BAL NKG2C NK cell association with CLAD-free survival was assessed by Cox proportional hazards modeling. RESULTS: NKG2C NK cells were more mature and proliferative than NKG2C NK cells and represented a median of 7.8% of BAL NK cells. The NKG2C NK cell proportion increased prior to the first detection of viremia and was nearly tripled in subjects with high level viremia (>1000 copies/mL) compared with no detected viremia. Subjects with increased BAL NKG2C NK cells, relative to the median, had a significantly increased risk for CLAD or death (hazard ratio, 4.2; 95% confidence interval, 1.2-13.3). CONCLUSIONS: The BAL NKG2C NK cell proportion may be a relevant biomarker for assessing risk of CMV viremia and quantifying potential CMV-related graft injury that can lead to CLAD or death.
BACKGROUND:Cytomegalovirus (CMV) infection is a risk factor for chronic lung allograft dysfunction (CLAD), which limits survival in lung allograft recipients. Natural killer (NK) cells that express the NKG2C receptor mediate CMV-specific immune responses. We hypothesized that NKG2C NK cells responding to CMV in the lung allograft would reduce CMV-related inflammation and would improve CLAD-free survival. METHODS: We prospectively followed 130 subjects who underwent lung transplantation from 2012 to 2016. Bronchoalveolar lavage (BAL) NK cells were immunophenotyped for NKG2C, maturation, and proliferation markers. CMV viral load, serologies, serial spirometry, and mortality were recorded from medical records. Natural killer cell subset association with CMV endpoints were made using generalized estimating equation-adjusted linear models. BAL NKG2C NK cell association with CLAD-free survival was assessed by Cox proportional hazards modeling. RESULTS:NKG2C NK cells were more mature and proliferative than NKG2C NK cells and represented a median of 7.8% of BAL NK cells. The NKG2C NK cell proportion increased prior to the first detection of viremia and was nearly tripled in subjects with high level viremia (>1000 copies/mL) compared with no detected viremia. Subjects with increased BAL NKG2C NK cells, relative to the median, had a significantly increased risk for CLAD or death (hazard ratio, 4.2; 95% confidence interval, 1.2-13.3). CONCLUSIONS: The BAL NKG2C NK cell proportion may be a relevant biomarker for assessing risk of CMV viremia and quantifying potential CMV-related graft injury that can lead to CLAD or death.
Authors: Daniel R Calabrese; Ping Wang; Tiffany Chong; Jonathan Hoover; Jonathan P Singer; Dara Torgerson; Steven R Hays; Jeffrey A Golden; Jasleen Kukreja; Daniel Dugger; Jason D Christie; John R Greenland Journal: JCI Insight Date: 2019-11-14
Authors: Nancy Y Greenland; Fred Deiter; Daniel R Calabrese; Steven R Hays; Jasleen Kukreja; Lorriana E Leard; Nicholas A Kolaitis; Jeffrey A Golden; Jonathan P Singer; John R Greenland Journal: Clin Transplant Date: 2022-03-12 Impact factor: 3.456
Authors: Daniel R Calabrese; Emily Aminian; Benat Mallavia; Fengchun Liu; Simon J Cleary; Oscar A Aguilar; Ping Wang; Jonathan P Singer; Steven R Hays; Jeffrey A Golden; Jasleen Kukreja; Daniel Dugger; Mary Nakamura; Lewis L Lanier; Mark R Looney; John R Greenland Journal: J Clin Invest Date: 2021-02-01 Impact factor: 14.808
Authors: Hannes Vietzen; Bernd Döhler; Thuong Hien Tran; Caner Süsal; Philip F Halloran; Farsad Eskandary; Carsten T Herz; Katharina A Mayer; Nicolas Kozakowski; Markus Wahrmann; Sarah Ely; Susanne Haindl; Elisabeth Puchhammer-Stöckl; Georg A Böhmig Journal: Front Immunol Date: 2022-03-24 Impact factor: 7.561
Authors: Simon J Cleary; Nicholas Kwaan; Jennifer J Tian; Daniel R Calabrese; Beñat Mallavia; Mélia Magnen; John R Greenland; Anatoly Urisman; Jonathan P Singer; Steven R Hays; Jasleen Kukreja; Ariel M Hay; Heather L Howie; Pearl Toy; Clifford A Lowell; Craig N Morrell; James C Zimring; Mark R Looney Journal: J Clin Invest Date: 2020-11-02 Impact factor: 14.808