Potential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation

doi:10.1016/0003-4975(90)90248-5

The Annals of Thoracic Surgery

Volume 49, Issue 3, March 1990, Pages 424-428

https://doi.org/10.1016/0003-4975(90)90248-5 Get rights and content

Abstract

Dendritic cells are essential for the activation of the type IV immunological reactions that are intrinsic to rejection of transplanted organs. We evaluated the number of dendritic cells in the recipient and donor portions of the trachea and donor bronchi of 6 heart-lung transplant recipients, 3 of whom had evidence of bronchiolitis obliterans, a presumed manifestation of chronic rejection of the lung. As compared with recipients without bronchiolitis obliterans, patients with it showed a significant increase in the number of S100-protein-positive dendritic cells in the tracheal and bronchial epithelium and submucosa of the donor organs. This finding of increased accessary cells in the transplanted mucosa provides support for the belief that bronchiolitis obliterans is an immunologically mediated form of chronic rejection.

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Cited by (54)

Lung Transplantation Has a Strong Impact on the Distribution and Phenotype of Monocyte Subsets
2020, Transplantation Proceedings
Lung transplantation (LTx) is a last treatment option for patients with an end-stage pulmonary disease. Chronic lung allograft dysfunction, which generally manifests as bronchiolitis obliterans syndrome (BOS), is a major long-term survival limitation. During injury, inflammation and BOS monocytes are recruited. We determined whether changes in count, subset distribution, and functionality by surface marker expression coincided with BOS development.
Fresh whole-blood samples were analyzed from 44 LTx patients, including 17 patients diagnosed with BOS, and compared with 10 age-matched healthy controls and 9 sarcoidosis patients as positive controls. Monocytes were quantified and analyzed using flow cytometry. Based on surface marker expression, classical, intermediate, and nonclassical subsets were determined, and functional phenotypes were investigated.
The absolute count of monocytes was decreased in LTx and slightly increased in BOS patients. The relative count shifted toward classical monocytes at the expense of nonclassical monocytes in LTx and BOS. Surface marker expression was highest on intermediate monocytes. The expression of both CD36 and CD163 was significantly increased in the LTx and BOS cohort. The difference between the BOS cohort and the LTx cohort was only subtle, with a significant decrease in HLA-DR expression on nonclassical monocytes in BOS.
Monocyte subsets and surface marker expression changed significantly in transplantation patients, while BOS-specific changes were understated. More research is needed to determine whether and how monocytes influence the disease process and how current immunosuppressants affect their normal function in vivo.
Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model
2016, Transplant Immunology
Citation Excerpt :
However, DC were not significantly reduced within tracheal allografts after ICA pretreatment, indicating, that DC may not play a major role in this experimental model. These findings are also reflected in the literature [49]: while Yousem et al. [50] found elevated levels of DC in patients with OB [50], Milne et al. could not find a relevant amount of DC leading to OB [51]. Recent findings have shown that hypoxia alone is not sufficient to activate murine DC [52].
Obliterative bronchiolitis (OB) is the major limiting factor for long-term survival after lung transplantation. As previously shown, donor treatment with a PHD-inhibitor activating hypoxia-inducible transcription factors (HIFs) prevents graft injury both in an allogenic kidney and aortic allograft transplant model. The aim of this study was to investigate the effect of HIF activation with a PHD-inhibitor on the development of OB.
Fully MHC-mismatched C57BL/6 (H-2^b) donor tracheas were orthotopically transplanted into CBA/J (H-2^k) recipients. Donor animals received a single dose of PHD-inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) (40 mg/kg i.p.) or vehicle control 4 h before transplantation. Transplanted tracheas were harvested 14 or 30 days after transplantation and were analyzed by histology, by immunofluorescence and by rtPCR for mRNA expression.
Donor pre-conditioning with ICA resulted in HIF accumulation and induction of HIF target genes: HO-1, VEGF, MIF, TGFβ, and EpoR, which persisted during different times of ischemia. Grafts of vehicle treated controls showed substantially more luminal obliteration on postoperative day 30 in contrast to groups pre-treated with ICA [luminal obliteration 29.2 ± 5% (ICA) vs. 36.7 ± 8% (control), p < 0.01]. We found significantly lower expression of TNFα, PDGFß, MCP-1, E-selectin, and ICAM-1 14 days after ICA premedication. In addition ICA pre-treated groups revealed decreased T-cell and macrophage infiltration in tracheal grafts on days 30 after transplantation (p < 0.05).
Pre-treatment with ICA effectively reduced obliterative bronchiolitis. Our data suggest that activation of hypoxia-inducible transcription factors (HIFs) and thereby adaptation to low oxygen prevents the development of OB and allograft injury. Pharmaceutical inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves further clinical evaluation.
Profiling of peripheral blood mononuclear cells does not accurately predict the bronchiolitis obliterans syndrome after lung transplantation
2015, Transplant Immunology
Citation Excerpt :
Prior to BOS development infiltration of immune cells into the allograft has been shown. Accumulation of dendritic cells has been reported as well as submucosal lymphocyte and plasma cell infiltrates [6–8]. These submucosal lymphocyte infiltrates consisted mainly of T cells, both CD4 + and CD8 + T cells, but also NK cells have sometimes been identified [8–11].
After lung transplantation (LTx), circulating mononuclear cell composition and their subsets may be predictive for the bronchiolitis obliterans syndrome (BOS). We investigated the cellular composition in patients developing BOS, or not, by analyzing peripheral blood taken at multiple time points after transplantation. PBMCs of 11 BOS and 39 non-BOS patients were analyzed by FACS for monocytes, dendritic cells, NK-, NKT-, B- and T cells as well as B- and T cell subsets. Analysis of blood samples taken monthly during the first year post-LTx showed that circulating NK, NKT and dendritic cell percentages were not indicative of BOS development, whereas increases in T cells, monocytes and lowered fractions of B cells were related to BOS development. B- and T cell subset analysis at month 5 post-LTx indicated that IgM+IgD − memory B cells and central memory CD8 + T cells were decreased, whereas NKT cells were increased in BOS patients compared to non-BOS patients. Prior to BOS diagnosis, the composition of specific mononuclear cells on a group level differs from patients remaining BOS free. However, given the overlap in percentages of cellular frequencies between the patient groups investigated, this analysis does not allow prediction or risk stratification for development of BOS in individual patients.
The lung as a target organ of graft-versus-host disease
2006, Seminars in Hematology
Despite significant advances in critical care and transplantation medicine, non-infectious lung injury remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT) both in the immediate post-transplant period and in the months to years that follow. Historically, approximately 50% of all pneumonias seen after HSCT have been secondary to infection. Although non-infectious lung injury occasionally occurs following autologous transplants, the allogeneic setting greatly exacerbates toxicity acutely and chronically. Pulmonary injury is associated with significant morbidity and mortality and responds poorly to standard therapies. Insights generated using animal models suggest that the immunologic mechanisms contributing to lung inflammation after HSCT may be similar to those responsible for graft-versus-host disease (GVHD).
Obliterative bronchiolitis or chronic lung allograft rejection: A basic science review
2005, Journal of Heart and Lung Transplantation
Bronchiolitis obliterans syndrome
2003, Chest Surgery Clinics of North America

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Original articlePotential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation

Abstract

Antigen presentation: comments on its regulation and mechanism

J Immunol

Antigen presenting cells. Their identification and involvement in immunopathology

Clin Exp Immunol

Human dendritic cells, enrichment and characterization from peripheral blood

J Exp Med

The regulatory role of macrophages in antigenic stimulation. Part two: symbiotic relationship between lymphocytes and macrophages

Adv Immunol

Analogous functions of macrophages and Langerhans cells in the initiation of the immune response

J Invest Dermatol

Dendritic cells: features and functions

Immunol Rev

Cigarette smoking induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells

Am Rev Respir Dis

The wide-spread distribution of Langerhans cells in pathologic tissues

Hum Pathol

Pulmonary Langerhans cells in patients with fibrotic lung disorders

Lab Invest

Dendritic cells with antigen presenting capability reside in airway epithelium, lung parenchyma and visceral pleura

J Exp Med

Mononuclear cells in human lung parenchyma: characterization of a potent accessory cell not obtained by bronchoalveolar lavage

Am Rev Respir Dis

The accessory cell function of human alveolar macrophages in specific T cell proliferation

J Immunol

Accumulation of Langerhans cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking

Am Rev Respir Dis

T zone histiocytes in adenocarcinoma of the lung in relation to postoperative prognosis

Cancer

Original article
Potential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation