IFN-γ and Contact-Dependent Cytotoxicity Are Rate-Limiting for NK Cells in a Model of Antibody-Mediated Chronic Rejection.
1Medicine, University of Colorado, Denver, Aurora, CO
2Surgery, University of Colorado, Denver, Aurora, CO.
Meeting: 2016 American Transplant Congress
Abstract number: A7
Keywords: Fas (CD95), Interferon (IFN), Perforin, Rejection
Session Name: Poster Session A: B cells & AMR, Alloreactivity, Immune Regulation & Regulatory T Cells, T Cell Biology and Alloreactivity, Immunesuppression
Session Type: Poster Session
Date: Saturday, June 11, 2016
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Halls C&D
BACKGROUND. Natural killer (NK) cells are key components of the innate immune that contribute to acute and chronic graft rejection. After engagement with antibody, NK cells can facilitate injury through a number of downstream responses. Specifically, they mediate cellular toxicity through perforin and/or Fas/FasL and generate pro-inflammatory mediators (e.g. IFN-γ). Importantly, donor-specific antibodies (DSA) in concert with NK cells can be sufficient to inflict chronic allograft vasculopathy independently of T and B cells. Thus, our study aimed to investigate the underlying cellular mechanism(s) required in this process.
METHODS. We utilized a murine model of cardiac transplantation with C3H/HeJ (C3H) donors grafted to C57BL/6 (B6) rag-/-γc-/- recipients; recipients had no functional T, B, or NK cells. B6 NK cells of differing phenotypes (wild-type, IFN-γ-/-, perforin-/-) were adoptively transferred on post-operative day 1. To test the requirement for the Fas/FasL pathway, Fas-deficient C3H lpr allografts were transplanted into B6 rag-/-γc-/- recipients followed by transfer with wild-type NK cells. Combined Fas/FasL and perforin deficiency was tested using C3H lpr allografts in conjunction with perforin-/- NK cells. All recipients received monoclonal DSA (anti-H2Kk) and allografts were recovered / examined after 30 days.
RESULTS. Initial studies verified that neither DSA nor NK cells alone could cause significant vascular injury. However, recipient mice (n=6) that received adoptively transferred wild-type NK cells in addition to DSA showed marked neointimal changes consistent with chronic allograft vasculopathy. Interestingly, recipient mice that received IFN-γ-/- NK cells showed complete amelioration of these lesions (n=8, p=0.0007). Deficiencies in either perforin or Fas/FasL alone did not appreciably alter this disease process, but simultaneous disruption of these two pathways also resulted in attenuation of the vascular changes (p=0.004). Importantly, the adoptively transferred NK cells persisted at comparable levels in recipients at time of allograft recovery.
CONCLUSION. NK cell production of IFN-γ is necessary for this antibody-dependent form of chronic allograft vasculopathy. However, perforin and Fas/FasL comprise additional rate-limiting effector pathways for this process, outlining an important role for cell-mediated cytotoxicity in this form of rejection.
CITATION INFORMATION: Lin C, Plenter R, Gill R. IFN-γ and Contact-Dependent Cytotoxicity Are Rate-Limiting for NK Cells in a Model of Antibody-Mediated Chronic Rejection. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Lin C, Plenter R, Gill R. IFN-γ and Contact-Dependent Cytotoxicity Are Rate-Limiting for NK Cells in a Model of Antibody-Mediated Chronic Rejection. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/ifn-and-contact-dependent-cytotoxicity-are-rate-limiting-for-nk-cells-in-a-model-of-antibody-mediated-chronic-rejection/. Accessed March 26, 2023.
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