Transfer of Tolerance to Collagen Type V Suppresses T-Helper-Cell-17 Lymphocyte-Mediated Acute Lung Transplant Rejection

Braun, Ruedi K.; Molitor-Dart, Melanie L.; Wigfield, C.H.; Xiang, Zhuzai; Fain, Sean B.; Jankowska‐Gan, Ewa; Seroogy, Christine M.; Burlingham, William J.; Wilkes, David S.; Brand, David; Torrealba, José; Love, Robert B.

doi:10.1097/tp.0b013e3181bcde7b

Cited by 52 publications

(36 citation statements)

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“…We and others (8,(12)(13)(14) previously reported that autoimmune responses to col(V) are linked to the pathogenesis of lung fibrosis. We also have previously reported IL-17-dependent anti-col(V) cellular immune responses in patients with OB with lung transplants (as measured by the trans-vivo delayed-type hypersensitivity assay); we attributed this response to be possibly due to the overabundance of induced ␣1(V) chains noted in the OB lesions (14).…”

Section: Il-17 Mediates Specific Rna and Protein Overexpression For Tmentioning

confidence: 99%

“…Prior reports demonstrated that induction of tolerance to col(V) protects against OB mediated by col(V)-specific reactive Th17 cells, but the col(V) distribution in the clinical OB lesions has not been illustrated (13,53). Therefore, immunohistochemistry was utilized to determine the localization of col(V) in clinical OB.…”

Section: Col(v) Is Highly Expressed In Clinical Ob Lesions and In A Mmentioning

confidence: 99%

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IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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erative bronchiolitis (OB), a fibrotic airway lesion, is the leading cause of death after lung transplantation. Type V collagen [col(V)] overexpression and IL-17-mediated anti-col(V) immunity are key contributors to OB pathogenesis. Here, we report a previously undefined role of IL-17 in inducing col(V) overexpression, leading to epithelial mesenchymal transition (EMT) and subsequent OB. We observed IL-17-mediated induction of col(V) ␣1 chains [␣1 (V)] in normal airway epithelial cells in vitro and detected ␣1 (V)-specific antibodies in bronchoalveolar lavage fluid of lung transplant patients. Overexpression of IL-17 and col(V) was detected in OB lesions in patient lung biopsies and in a murine OB model. IL-17 is shown to induce EMT, TGF-␤ mRNA expression, and SMAD3 activation, whereas downregulating SMAD7 expression in vitro. Pharmacological inhibition of TGF-␤RI tyrosine kinase, p38 MAPK, or focal adhesion kinase prevented col(V) overexpression and EMT. In murine orthotopic lung transplants, neutralizing IL-17 significantly decreased TGF-␤ mRNA and protein expression and prevented epithelial repair/ OB. Our findings highlight a feed-forward loop between IL-17 and TGF-␤, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation. autoimmunity; p38 MAPK; focal adhesion kinase; small-airway epithelial cells; RLE-6TN; mouse transplant model; epithelial-mesenchymal transition OBLITERATIVE BRONCHIOLITIS (OB) is characterized by extensive peribronchiolar fibrosis with plugs of granulation tissues (fibroblasts and collagen) that occlude small airways. OB is the key reason that the 5-yr survival of lung transplant recipients is only 50%, the worst of all major solid organ transplants (42,48).Aberrant epithelial repair is a key event in the transplanted lung (1, 9) in which bronchioles lose resident epithelial cells and become occluded by granulation tissue. Abnormal epithelial repair eventually causes an epithelial-to-mesenchymal transition (EMT), a functional and phenotypic change of epithelial cells into spindle-shaped, migratory (43) and matrix-component-secreting mesenchymal cells (10, 41), and a process associated with lung fibrosis (15,27). However, the direct connection between EMT and the in vivo phenomena of fibrosis and fibro-obliterative disease remains controversial.We and others previously reported that OB is associated with dysregulation of two types of collagen: 1) marked increase in type V collagen [col(V)], a quantitatively minor lung collagen (8,14,40), and 2) a decrease in the major lung collagen type I [col(I)] (2, 53). We have shown that prospective monitoring of patients with human lung transplant revealed a critical role of col(V)-specific cellular immunity in OB pathogenesis (14,40). Although overexpression of col(V), an otherwise quantitatively minor collagen, is involved in OB pathology, mechanisms leading to col(V) overexpression are unknown. Thus a mechanistic understanding of the triggers of col(V)...

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Section: Il-17 Mediates Specific Rna and Protein Overexpression For Tmentioning

confidence: 99%

Section: Col(v) Is Highly Expressed In Clinical Ob Lesions and In A Mmentioning

confidence: 99%

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Advances in understanding the effects of allograft cellular senescence (accelerated ageing) on allograft function and BOS risk are needed, and a better understanding of the role of interleukin-17 [150][151][152][153][154][155][156], autoimmune pathways, regulatory lymphocyte populations [157][158][159][160][161][162][163] and neutrophil responses, as well as mechanisms by which the hypothetical phenomenon of epithelial-mesenchymal transition (which remains hypothetical and has not been well validated in humans) [164][165][166][167] leads to airway fibrosis, may lead to novel therapies to prevent and treat BOS. Improved animal models of OB are needed and are likely to be useful in improving our understanding of the role of these and other phenomena in the initiation, progression, prevention and treatment of OB following lung transplantation.…”

Section: Key Unanswered Questions and Specific Research Needsmentioning

confidence: 99%

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

et al. 2014

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Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS.A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations.The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of posttransplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS.The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Executive summaryMany lung transplant recipients develop delayed allograft dysfunction that has been traditionally referred to as bronchiolitis obliterans syndrome (BOS), which is thought to be caused by inflammation, destruction and fibrosis of small airways in the lung allograft that leads to obliterative bronchiolitis (OB). Because a definitive diagnosis of OB is difficult to make without a surgical lung biopsy, a decrease in the forced expiratory volume in 1 s (FEV1) has been used as a surrogate marker to identify patients who develop a syndrome of significant and persistent loss of lung allograft function with onset three or more months following transplantation. However, it is now recognised that numerous factors apart from OB can lead to a delayed onset, significant decline in lung function, and these causes of delayed onset graft dysfunction must be carefully excluded when a diagnosis of BOS is made. In general, BOS responds poorly to therapeutic interventions but may stabilise, and some patients may have a significant improvement in FEV1 with certain ther...

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“…Conventionally, Th1 cells and cytotoxic CD8 þ T cells induced by alloantigen stimuli were thought to be important in allograft rejection. However, recent studies provided evidence suggesting a role for IL-17 in acute allograft rejection, 14 and blockade of IL-17 action by an IL-17R/IgG-Fc fusion protein prolonged cardiac allograft survival. 15 Patients undergone acute renal or lung allograft rejection were also found to be associated with increased IL-17 in the serum or bronchoalveolar lavage.…”

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confidence: 99%

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

Duan

Wang

Chen

et al. 2011

Laboratory Investigation

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Previously, we reported that extracellular high-mobility group box 1 (HMGB1) functions as an innate alarmin implicated in cardiac allograft acute rejection. We now present evidence suggesting that HMGB1 is pivotal in inducing interleukin-17 (IL-17)-producing alloreactive T cells by stimulating dendritic cells secretion of IL-6. Those IL-17 þ T cells are likely to be the major effector cells responsible for the early stage of cardiac allograft rejection through mediating an influx of neutrophils into allografts, and therefore, blockade of IL-17A significantly prolonged murine cardiac allograft survival. In contrast to the classical model for a dominant role of IFN-g þ -Th1 cells have in acute allograft rejection, our data suggest that IFN-g þ -Th1 cells are responsible for the late stage of graft destruction by inducing monocyte infiltration when IL-17 þ T-cell response recedes. Blockade of HMGB1 significantly decreased splenic alloreactive Th17 cells and IFN-g-producing CD8 þ T cells in the recipients, leading to less infiltration of neutrophils along with lower IL-6 and IL-17 expression levels in the grafts as well as prolongation of cardiac allograft survival. Together, these data support a novel model in which HMGB1 induces IL-17-producing alloreactive T cells to mediate early stage of allograft rejection, whereas IFN-g-producing alloreactive Th1 cells provoke graft destruction after Th17 response recedes.

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Transfer of Tolerance to Collagen Type V Suppresses T-Helper-Cell-17 Lymphocyte-Mediated Acute Lung Transplant Rejection

Cited by 52 publications

References 52 publications

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

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