Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome

doi:10.1016/S0198-8859(03)00038-7

Human Immunology

Volume 64, Issue 5, May 2003, Pages 521-529

https://doi.org/10.1016/S0198-8859(03)00038-7 Get rights and content

Abstract

Development of anti-HLA class I antibodies is associated with bronchiolitis obliterans syndrome (BOS) after lung transplantation. BOS is characterized histologically by significant fibrosis and airway epithelial cell (AEC) apoptosis. Thus, this study was designed to determine whether anti-HLA class I antibodies can activate AECs to produce growth factors and to undergo apoptosis. KCC-266 AECs were activated with the W6/32 anti-HLA class I monoclonal antibody. Proliferation and apoptosis levels were determined after 24, 48, and 72 hours. The induction of fibroblast and bronchial smooth muscle cell proliferation by anti-HLA class I activated AECs was assessed in the presence of neutralizing antibodies against various growth factors. The anti-HLA class I induced AEC proliferation after 24 hours followed by significant induction of apoptosis after 48 hours. Anti-HLA class I activated AECs produced soluble growth factors that stimulated fibroblasts but not bronchial smooth muscle cells. The stimulation of fibroblast proliferation was inhibited by antibodies against platelet-derived growth factor, heparin-binding epidermal growth factor, insulin-like growth factor 1, and basic fibroblast growth factor. The results from this study suggest that anti-HLA class I alloantibodies may play an important role in the pathogenesis of BOS by inducing proliferation, growth factor production, and apoptotic cell death in AECs.

Section snippets

Abbreviations

AEC

airway epithelial cell

BOS

bronchiolitis obliterans syndrome

BSMC

bronchial smooth muscle cell

EGF

epidermal growth factor

HB-EGF

heparin-binding epidermal growth factor

bFGF

basic fibroblast growth factor

GM-CSF

granulocyte-monocyte colony-stimulating factor

IGF

insulin-like growth factor

mAb

monoclonal antibody

PDGF

platelet-derived growth factor

TGF-β

transforming growth factor-β

Cell lines

The KCC-266 AEC line was developed in our laboratory from a lung airway biopsy, immortalized by transfection with the pRSV-Tag plasmid, and cultured in plates precoated with bovine serum albumin, collagen, and fibronectin in LHC-9 medium as previously described [41]. The MRC-5 lung fibroblast cell line was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured in RPMI-1640 medium (Gibco BRL, Grand Island, NY, USA) supplemented with fetal bovine serum (15%;

Induction of AEC proliferation by Anti-HLA class I antibodies

We have previously reported that anti-HLA class I antibodies induce tyrosine phosphorylation and proliferation in the A549 lung adenocarcinoma cell line [32]. To determine whether anti-HLA class I antibodies could induce a similar response in a noncancerous AEC line, we incubated KCC-266 AECs in the presence of varying concentrations of the W6/32 mAb (2.5, 5, 10, and 20 μg/ml) for 24 hours. As illustrated in Figure 1, only AECs incubated in the presence of 5 μg/ml of the W6/32 mAb displayed a

Discussion

Previous studies have reported that the development of anti-HLA antibodies after transplantation is associated with chronic rejection in heart and kidney allografts 29, 30. In addition, studies from our laboratory have demonstrated a significant correlation between the development of anti-HLA class I antibodies and the development of BOS after lung transplantation [3]. Furthermore, passive transfer of antidonor MHC class I antibodies has been reported to accelerate the development of cardiac

Acknowledgements

This work was supported by Grants No. HL56643 and HL66452 from the National Institutes of Health. The authors would like to thank Ms. Billie J. Glasscock for secretarial assistance.

References (48)

K. Kelly et al.
Obliterative bronchiolitis
Clin Chest Med
(1997)
S.I. Reznik et al.
Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome
Am J Transpl
(2001)
K.C. Lu et al.
Concomitant allorecognition of mismatched donor HLA class I- and II-derived peptides in pediatric lung transplant recipients with bronchiolitis obliterans syndrome
J Heart Lung Transplant
(2003)
J. Zhao et al.
Epithelium-specific adenoviral transfer of a dominant-negative mutant TGF-β type II receptor stimulates embryonic lung branching morphogenesis in culture and potentiates EGF and PDGF-AA
Mech Dev
(1998)
A.D. O’Brien et al.
Chemotaxis of alveolar macrophages in response to signals derived from alveolar epithelial cells
J Lab Clin Med
(1998)
L. Postiglione et al.
Expression of GM-CSF receptor and “in vitro” effects of GM-CSF on human fibroblasts
Life Sci
(1998)
L. Pukac et al.
Platelet-derived growth factor-BB, insulin-like growth factor-I, and phorbol ester activate different signaling pathways for stimulation of vascular smooth muscle cell migration
Exp Cell Res
(1998)
A. El-Gamel et al.
Transforming growth factor-beta (TGF-beta1) genotype and lung allograft fibrosis
J Heart Lung Transplant
(1999)
A. El-Gamel et al.
Transforming growth factor beta (TGF-β) and obliterative bronchiolitis following pulmonary transplantation
J Heart Lung Transplant
(1999)
S.I. Reznik et al.
Anti-HLA antibody binding to HLA class I molecules induces proliferation of airway epithelial cellsa potential mechanism for bronchiolitis obliterans syndrome
J Thorac Cardiovasc Surg
(2000)

L. Genestier et al.

Antibodies to HLA class I alpha 1 domain trigger apoptosis of CD40-activated human B lymphocytes

Blood

(1997)

L. Genestier et al.

Fas-independent apoptosis of activated T cells induced by antibodies to the HLA class I alpha 1 domain

Blood

(1997)

P.R. Hansen et al.

Apoptosis and formation of peroxynitrite in the lungs of patients with obliterative bronchiolitis

J Heart Lung Transplant

(2000)

S. Dissing et al.

T cell activation II. Activation of human T lymphoma cells by cross-linking of their MHC class I antigens

Cell Immunol

(1990)

N.Q. Hansen et al.

T cell activation

IV. Evidence for a functional linkage between MHC class I, interleukin-2 receptor and interleukin-4 receptor molecules. Cytokine

(1991)

S.G. Tullius et al.

Both alloantigen-dependent and independent factors influence chronic allograft rejection

Transplantation

(1995)

A. Jaramillo et al.

Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation

Transplantation

(1999)

A. Jaramillo et al.

Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantationa potential etiological factor for bronchiolitis obliterans syndrome

Transplantation

(2001)

K.S.R. SivaSai et al.

Indirect recognition of donor HLA class I peptides in lung transplantation recipients with bronchiolitis obliterans syndrome

Transplantation

(1999)

H. Kubota et al.

Importance of bronchus-associated lymphoid tissue and major histocompatibility complex class I and II antigen expression on bronchial epithelium in acute lung allograft rejection and lung infection in rats

Transpl Proc

(1994)

K.A. Mauck et al.

The bronchial epitheliumA potential allogenic target for chronic rejection after lung transplantation

J Heart Lung Transplant

(1996)

A.D. Cambrey et al.

Insulin-like growth factor I is a major fibroblast mitogen produced by primary cultures of human airway epithelial cells

Clinical Science

(1995)

D. Luo et al.

Effect of prostatic growth factor, basic fibroblast growth factor, epidermal growth factor, and steroids on the proliferation of human fetal prostatic fibroblasts

Prostate

(1996)

S. Ohgi et al.

Glucose modulates growth of gingival fibroblasts and periodontal ligament cellscorrelation with expression of basic fibroblast growth factor

J Periodont Res

(1996)

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Citation Excerpt :
This study was approved by the human studies institutional review board of St Joseph's Hospital and Medical Center IRB committee (approval number PHXB-16-0027-10-18; date February 27, 2018). The KCC-266 airway epithelial cell line (AEC) was developed in our laboratory from a lung airway biopsy, immortalized by transfection with the pRSV-Tag plasmid, and cultured in RPMI-1640 medium supplemented with bovine serum albumin (2%), L-glutamine (2 mM), nonessential amino acids (100 μM), HEPES (25 mM), sodium pyruvate (1 mM), penicillin (100 U/mL), and streptomycin (0.1 mg/mL) as previously described.17 The AECs (1 × 106 cells) were cultured for 24 hours in the presence of the anti-HLA (Hi PRA, 1:50 dilution), and Abs to lung SAgs (Col-V and Kα1T) at 20 μg/mL.
Lung transplantation is therapeutic for end-stage lung disease, but survival is limited due to bronchiolitis obliterans syndrome and restrictive chronic lung allograft dysfunction. We sought a common denominator in lung transplant recipients, analyzing risk factors that trigger immune responses that lead to bronchiolitis obliterans syndrome.
We collected blood from patients who underwent lung transplant at our institution. Exosomes were isolated from the sera of recipients with risk factors for chronic rejection and from stable recipients. Exosomes were analyzed with western blot, using antibodies to lung self-antigens K alpha 1 tubulin and collagen-V, costimulatory molecules (costimulatory molecule 80, costimulatory molecule 86), transcription factors (nuclear factor kappa-light-chain-enhancer of activated B cells, hypoxia-inducible factor 1α, Class II Major Histocompatibility Complex Transactivator), and 20S proteasome.
Of the 90 patients included, we identified 5 with grade 3 primary graft dysfunction, 5 without, 15 with respiratory viral infection, 10 with acute rejection, 10 with donor-specific antibodies (DSA), 5 without DSA, and 10 who were stable for exosome isolation. Recipients with grade 3 primary graft dysfunction, respiratory viral infection, acute rejection, and DSA had exosomes containing self-antigens; exosomes from stable recipients did not. Exosomes from recipients with grade 3 primary graft dysfunction, acute rejection, and DSA also demonstrated costimulatory molecule 80, costimulatory molecule 86, major histocompatibility complex class II, transcription factor, and 20S proteasome.
Transplanted lungs with grade 3 primary graft dysfunction, symptomatic respiratory viral infection, acute rejection, and immune responses induce exosomes that contain self-antigens, costimulatory molecules, major histocompatibility complex class II, transcription factors, and 20S proteasome. Release of circulating exosomes post-transplant from the aforementioned stress-inducing insults augment immunity and may play an important role in the pathogenesis of bronchiolitis obliterans syndrome.
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Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome

Abstract

Section snippets

Abbreviations

Cell lines

Induction of AEC proliferation by Anti-HLA class I antibodies

Discussion

Acknowledgements

Clin Chest Med

Am J Transpl

J Heart Lung Transplant

Mech Dev

J Lab Clin Med

Life Sci

Exp Cell Res

J Heart Lung Transplant

J Heart Lung Transplant

J Thorac Cardiovasc Surg

Blood

Blood

J Heart Lung Transplant

Cell Immunol

IV. Evidence for a functional linkage between MHC class I, interleukin-2 receptor and interleukin-4 receptor molecules. Cytokine

Both alloantigen-dependent and independent factors influence chronic allograft rejection

Transplantation

Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation

Transplantation

Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantationa potential etiological factor for bronchiolitis obliterans syndrome

Transplantation

Indirect recognition of donor HLA class I peptides in lung transplantation recipients with bronchiolitis obliterans syndrome

Transplantation

Importance of bronchus-associated lymphoid tissue and major histocompatibility complex class I and II antigen expression on bronchial epithelium in acute lung allograft rejection and lung infection in rats

Transpl Proc

The bronchial epitheliumA potential allogenic target for chronic rejection after lung transplantation

J Heart Lung Transplant

Insulin-like growth factor I is a major fibroblast mitogen produced by primary cultures of human airway epithelial cells

Clinical Science

Effect of prostatic growth factor, basic fibroblast growth factor, epidermal growth factor, and steroids on the proliferation of human fetal prostatic fibroblasts

Prostate

Glucose modulates growth of gingival fibroblasts and periodontal ligament cellscorrelation with expression of basic fibroblast growth factor

J Periodont Res