Association of Local Intrapulmonary Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I With the Progression of Chronic Rejection of Lung Allografts

Miyamoto, Ei; Motoyama, Hideki; Sato, Masaaki; Aoyama, Akihiro; Menju, Toshi; Shikuma, Kei; Sowa, Terumasa; Yoshizawa, Akihiko; Saito, Masao; Takahagi, A.; Tanaka, Satona; Takahashi, Mamoru; Ohata, Keiji; Kondo, Takeshi; Hijiya, Kyoko; Chen‐Yoshikawa, Toyofumi F.; Date, Hiroshi

doi:10.1097/tp.0000000000001665

Cited by 17 publications

(8 citation statements)

References 51 publications

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“…The lungs of BN rats were implanted into LEW rats orthotopically for major histocompatibility complex (MHC)-mismatched transplantation, the lungs of F344 rats were implanted into LEW rats for minor histocompatibility antigen-mismatched transplantation, and the lungs of LEW rats were implanted into LEW rats for syngeneic transplantation. Orthotopic lung transplantation was performed as previously reported (20), and is described in the data supplement.…”

Section: Orthotopic Lung Transplantationmentioning

confidence: 99%

“…Trametinib was reconstituted in DMSO (Wako Pure Chemical Industries), stored at 220 8 C, suspended in 0.5% methylcellulose (Sigma-Aldrich), and orally administered on 5 d/wk (17,18,21). Rats were subcutaneously administered 25 mg/kg CsA on 4 days in the first week and on 2 d/wk thereafter (20). After allogeneic transplantation, rats were treated with a single reagent for 28 days or switched to another reagent at Day 14.…”

Section: Treatment Protocolsmentioning

confidence: 99%

“…We previously established an orthotopic left lung transplantation model in rats (20). Here, we used this model to investigate whether trametinib suppresses acute or delayed graft rejection.…”

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confidence: 99%

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Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

Takahagi¹,

Shindo

Chen‐Yoshikawa³

et al. 2019

Am J Respir Cell Mol Biol

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Delayed immunological rejection after human lung transplantation causes chronic lung allograft dysfunction, which is associated with high mortality. Delayed rejection may be attributable to indirect alloantigen presentation by host antigen-presenting cells; however, its pathophysiology is not fully understood. The mitogen-activated protein kinase pathway is activated in T cells upon stimulation, and we previously showed that the MEK inhibitor, trametinib, suppresses graft-versus-host disease after murine bone marrow transplantation. We investigated whether trametinib suppresses graft rejection after two types of rat lung transplantation and analyzed its immunological mode of action. Major histocompatibility complex-mismatched transplantation from brown Norway rats into Lewis rats and minor histocompatibility antigen-mismatched transplantation from Fischer 344 rats into Lewis rats were performed. Cyclosporine (CsA) and/or trametinib were administered alone or consecutively. Acute and delayed rejection, lymphocyte infiltration, and pulmonary function were evaluated. Administration of trametinib after CsA suppressed delayed rejection, reduced inflammatory cell infiltration and fibrosis within the graft, and preserved pulmonary functions at Day 28. Trametinib suppressed functional differentiation of T and B cells in the periphery but preserved thymic T cell differentiation. Donor B cells within the graft disappeared by Day 14, indicating that delayed graft rejection at Day 28 was mainly due to indirect presentation by host antigen-presenting cells. Finally, trametinib administration without CsA preconditioning suppressed rejection after minor histocompatibility antigen-mismatched transplantation. Trametinib attenuates delayed rejection upon major histocompatibility complex-mismatched transplantation by suppressing indirect presentation and is a promising candidate to treat chronic lung allograft dysfunction in humans.

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Section: Orthotopic Lung Transplantationmentioning

confidence: 99%

Section: Treatment Protocolsmentioning

confidence: 99%

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Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

Takahagi¹,

Shindo

Chen‐Yoshikawa³

et al. 2019

Am J Respir Cell Mol Biol

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“…In patients with RAS, the level of anti-HLA antibody as DSA in grafts was higher than in BOS, which indicated a strong relationship with fibrosis[ 61 ]. Furthermore, our laboratory reported that local anti-donor antibody production occurred in tertiary lymphoid structures of the donor lung in a rat lung transplant model[ 62 ]. Thus, the humoral immune response may occur locally in rejected lung allografts as well as in the spleen, a secondary lymphoid tissue.…”

Section: Interaction Of Immune Cellsmentioning

confidence: 99%

Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome

Yoshiyasu

Sato

2020

WJT

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Chronic lung allograft dysfunction (CLAD) following lung transplantation limits long-term survival considerably. The main reason for this is a lack of knowledge regarding the pathological condition and the establishment of treatment. The consensus statement from the International Society for Heart and Lung Transplantation on CLAD in 2019 classified CLAD into two main phenotypes: Bronchiolitis obliterans syndrome and restrictive allograft syndrome. Along with this clear classification, further exploration of the mechanisms and the development of appropriate prevention and treatment strategies for each phenotype are desired. In this review, we summarize the new definition of CLAD and update and summarize the existing knowledge on the underlying mechanisms of bronchiolitis obliterans syndrome and restrictive allograft syndrome, which have been elucidated from clinicopathological observations and animal experiments worldwide.

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“…Bronchiolitis obliterans syndrome (BOS), a major form of chronic lung allograft dysfunction, has the greatest impact on the long-term survival of lung transplant patients [1,2]. Various pathologies have been associated with BOS, including innate immune system activation, acute cellular rejection, autoimmunity, and antibody-mediated rejection (AMR) via donor specific antibodies [3][4][5][6][7]. Current therapeutic options, such as macrolide antibiotic treatment and immunosuppressants, have been shown to stabilize pulmonary function [2,8,9].…”

Section: Introductionmentioning

confidence: 99%

Differential gene analysis during the development of obliterative bronchiolitis in a murine orthotopic lung transplantation model: A comprehensive transcriptome-based analysis

et al. 2020

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Background Obliterative bronchiolitis (OB) is a known issue during minor histocompatibility antigen (mHA) disparity during lung transplantation. This study evaluated gene expression in a murine orthotropic lung transplantation model using microarray analysis. Methods Left lungs from C57BL/10(H-2 b) donor mice were transplanted into mHA-mismatched C57BL/6(H-2 b) recipient mice. Three groups (OB, non-OB, and sham controls) were confirmed pathologically and analyzed. Gene expression changes in the lung grafts were determined by microarray and immunohistochemical staining, and genes were verified by quantitative PCR in the lungs and mediastinal lymph nodes (LNs). Results A total of 1343 genes were upregulated in the OB lungs compared to the sham group. Significant upregulation was observed for genes related to innate, e.g. Tlr2 and CCL3 and adaptive immunity, e.g. H2-ab1 and Il-21. Positive labeling for MHC class II antigen was observed in the bronchial epithelium of OB accompanied with B cells. We found increased Tlr2, Ccl3, H2-ab1, Il-21, Ighg3, Ifng, and Pdcd1 mRNA expression in the OB lung, and increased Il-21, Ighg3, and Pdcd1 expression in the OB LNs.

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Association of Local Intrapulmonary Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I With the Progression of Chronic Rejection of Lung Allografts

Abstract: DSA can be locally produced in chronically rejected lung allografts, along with intragraft immunocompetent cells. Clinical testing of DSA in serum samples alone may underestimate lung allograft dysfunction.

Cited by 17 publications

References 51 publications

Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome

Differential gene analysis during the development of obliterative bronchiolitis in a murine orthotopic lung transplantation model: A comprehensive transcriptome-based analysis

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