Stromal Activation and Formation of Lymphoid-Like Stroma in Chronic Lung Allograft Dysfunction

Sato, Masaaki; Hirayama, S.; Matsuda, Yasushi; Wagnetz, Dirk; Hwang, David; Guan, Z.; Liu, Mingyao; Keshavjee, Shaf

doi:10.1097/tp.0b013e31821b2f7a

Cited by 41 publications

(24 citation statements)

References 26 publications

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“…9 Regardless of the causal inflammatory stimuli, the vicious cycle of immuneresponsive cells and activated stromal resident cells through cytokines, chemokines and adhesion molecules 10 may lead to irreversible tissue organization and fibrosisnamely, irreversible graft dysfunction. If so, an appropriate therapeutic target of RAS or CLAD in general should not simply be the cause (i.e., rejection or infection) but instead the final common pathway (i.e., uncontrollable inflammation and subsequent fibrosis).…”

Section: Discussionmentioning

confidence: 99%

Progression pattern of restrictive allograft syndrome after lung transplantation

Sato

Hwang

Waddell

et al. 2013

The Journal of Heart and Lung Transplantation

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Section: Discussionmentioning

confidence: 99%

Progression pattern of restrictive allograft syndrome after lung transplantation

Sato

Hwang

Waddell

et al. 2013

The Journal of Heart and Lung Transplantation

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“…Inflammatory cells may substitute for LTi cells in ectopic lymphoneogenesis, but there is increasing evidence that stromal tissue cells also display LTo‐like properties39, 40, 41. In rheumatoid arthritis, synovial fibroblasts contribute to ELF formation through the secretion of homeostatic chemokines such as CXCL13, CCL21 and CXCL12 5, 23, 42, 43, 44.…”

Section: Cellular Initiators Of Ectopic Lymphoneogenesismentioning

confidence: 99%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.

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“…Lymphoid neogenesis, the de novo formation of ectopic germinal centers observed in chronic inflammation associated with autoimmune disorders and chronic infections (16), has been described by us as associated with CLAD (17,18), likely by perpetuating the inflammatory processes initiated by alloimmune and nonalloimmune stimuli. Although the antiinflammatory properties of azithromycin have been reported to slow the progression of CLAD in a subset of patients (19), no effective therapy exists other than retransplantation.…”

Section: Introductionmentioning

confidence: 99%

Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation

Matsuda

Wang

Oishi

et al. 2016

American Journal of Transplantation

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Chronic lung allograft dysfunction, the major cause of death following lung transplantation, usually manifests as irreversible airflow obstruction associated with obliterative bronchiolitis (OB), a lesion characterized by chronic inflammation, lymphoid neogenesis, fibroproliferation and small airway obliteration. Spleen tyrosine kinase (Syk), a tyrosine kinase that regulates B cell function and innate immunity, has been implicated in the pathogenesis of chronic inflammation and tissue repair. This study evaluated the role of Syk in development of OB, using an intrapulmonary tracheal transplant model of OB with the conditional Syk-knockout Syk flox/flox // rosa26-CreER T2 mice and a Syk-selective inhibitor, GSK2230413. BALB/c trachea allografts were transplanted into Syk-knockout (Syk del/del ) mice or wild-type C57BL/6 recipients treated with GSK2230413. At day 28, histological analysis revealed that in the Syk del/del and GSK2230413-treated C57BL/6 recipients, the graft lumen remained open compared with allografts transplanted into Syk-expressing (Syk flox/flox ) and placebo controltreated C57BL/6 recipients. Immunofluorescence showed lymphoid neogenesis with distinct B and T cell zones in control mice. In contrast, lymphoid neogenesis was absent and few B or T cells were found in Syk del/del and GSK2230413-treated mice. These observations suggest that inhibition of Syk may be a potential therapeutic strategy for the management of OB following lung transplantation.Abbreviations: BOS, bronchiolitis obliterans syndrome; CLAD, chronic lung allograft dysfunction; IPTT, intrapulmonary tracheal transplant; MC, methylcellulose; OB, obliterative bronchiolitis; PBS, phosphate-buffered saline; PNAd, peripheral node addressin; Syk, spleen tyrosine kinase

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Stromal Activation and Formation of Lymphoid-Like Stroma in Chronic Lung Allograft Dysfunction

Abstract: Lymphoid neogenesis associated with CLAD accompanies activation of stromal resident cells and formation of lymphoid-like stroma. Induction of PNAd+ HEV-like vessels occurs before the manifestation of CLAD.

Cited by 41 publications

References 26 publications

Progression pattern of restrictive allograft syndrome after lung transplantation

Progression pattern of restrictive allograft syndrome after lung transplantation

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation

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