The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy

Huibers, Manon M. H.; Gareau, Alison J.; Vink, Aryan; Kruit, Rianne; Feringa, Hannah; Beerthuijzen, Johanna M.T.; Koning, E. Siera de; Peeters, Ton; Jonge, Nicolaas de; Weger, Roel A. de; Lee, Timothy D.G.

doi:10.1016/j.healun.2014.11.022

Cited by 39 publications

(41 citation statements)

References 30 publications

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“… who, analyzing postmortem heart allografts, found that pathology evidence of AMR was more often associated with specific phenotypes of coronary lesions, characterized by inflammation and myointimal hyperplasia, while it was not observed in patients with morphology of pure coronary atherosclerosis. Additional important observations supporting the role of allo‐ and autoimmunity in CAV development were consistently reported again by Huibers and by Chatterjee . With different methodologies and study design, both authors found perivascular B‐cell lineage infiltrates in CAV allograft explants.…”

Section: Discussionsupporting

confidence: 65%

Coronary artery disease in heart transplantation: new concepts for an old disease

et al. 2018

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Cardiac allograft vasculopathy (CAV) remains one of the main long-term complications after heart transplantation. We performed a systematic review focused on articles published in the previous 6 years to reappraise the novel evidences supporting risk factors, pathology, prevention, and treatment of CAV. We identified a search string for a literature search on PubMed. We excluded articles specifically focused on diagnosis/biomarkers/imaging only or complications of other diseases. We included 98 studies out of our search. Forty-eight articles describe risk factors for CAV, 13 pathology, 24 prevention, and 13 treatment for CAV. While confirming known concepts, we found supportive evidence that CAV pathophysiology may vary according to the time post-transplant and the prevalence of metabolic versus immune-mediated risk factors. Selective revascularization of focal lesions in patients with CAV may result in some clinical benefit, but CAV prevention, rather than treatment, by controlling risk factors and by using targeted immunosuppressive therapies is the most evidence-based approach to reduce disease progression.

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Section: Discussionsupporting

confidence: 65%

Coronary artery disease in heart transplantation: new concepts for an old disease

et al. 2018

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“…Several studies have shown that TLO support protective immunity against a variety of pathogens (46, 47, 58) or cause tissue damage in inflammatory and autoimmune diseases (15, 69–72). Interestingly, presence of TLO in solid tumors correlated with a favorable clinical outcome (18, 19).…”

Section: Discussionmentioning

confidence: 99%

A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression

et al. 2017

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ObjectiveMultiple solid cancers contain tertiary lymphoid organs (TLO). However, it is unclear whether they promote tumor rejection, facilitate tumor evasion, or simply whether they are a byproduct of chronic inflammation. We hypothesize that although chronic inflammation induces TLO formation, the tumor milieu can modulate TLO organization and functions in prostate cancer. Therefore, our study seeks to elucidate the cellular and molecular signatures in unique prostatectomy specimens from evanescent carcinoma patients to identify markers of cancer regression, which could be harnessed to modulate local immunosuppression or potentially enhance TLO function.MethodsWe used multicolor immunofluorescence to stain prostate tissues, collected at different stages of cancer progression (prostatic intraepithelial neoplasia, intermediate and advanced cancer) or from patients with evanescent prostate carcinoma. Tissues were stained with antibodies specific for pro-inflammatory molecules (cyclooxygenase 2, CXCL10, IL17), tumor-infiltrating immune cells (mature DC-LAMP+ dendritic cells, CD3+ T cells, CD3+Foxp3+ regulatory T cells (Treg), T bet+ Th1 cells, granzyme B+ cytotoxic cells), and stromal cell populations (lymphatic vessels, tumor neovessels, high endothelial venules (HEV), stromal cells), which promote prostate tumor growth or are critical components of tumor-associated TLO.ResultsGenerally, inflammatory cells are located at the margins of tumors. Unexpectedly, we found TLO within prostate tumors from patients at different stages of cancer and in unique samples from patients with spontaneous cancer remission. In evanescent prostate carcinomas, accumulation of Treg was compromised, while Tbet+ T cells and CD8 T cells were abundant in tumor-associated TLO. In addition, we found a global decrease in tumor neovascularization and the coverage by cells positive for cyclooxygenase 2 (COX2). Finally, consistent with tumor regression, prostate stem cell antigen was considerably reduced in TLO and tumor areas from evanescent carcinoma patients.ConclusionCollectively, our results suggest that COX2 and Treg are attractive therapeutic targets that can be harnessed to enhance TLO-driven tumor immunity against prostate cancer. Specially, the presence of HEV and lymphatics indicate that TLO can be used as a platform for delivery of cell-based and/or COX2 blocking therapies to improve control of tumor growth in prostate cancer.

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“…In a subsequent study, this group provided evidence that the local humoral response in the graft differed qualitatively from the systemic humoral response in the transplant recipients (24). Similarly, Huibers et al found ectopic lymphoid tissue in close proximity to cardiac allograft vasculopathy lesions in hearts from deceased heart transplant recipients (25). Notably, memory B cells and IgM-and IgG-producing plasma cells were present in these structures, raising the possibility that locally produced alloantibody contributed to damage of the coronary endothelium.…”

Section: Lymphoid Neogenesis In Allografts Promoting Rejectionmentioning

confidence: 93%

The Role of Lymphoid Neogenesis in Allografts

Hsiao

Gelman

et al. 2016

American Journal of Transplantation

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De novo induction of organized lymphoid aggregates at non-lymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, auto- or alloantigens, persist. The prevailing opinion in the field of transplantation is that lymphoid neogenesis within allografts is detrimental to the establishment of immune tolerance. These structures, commonly referred to as tertiary lymphoid organs (TLOs), are thought to contribute to graft rejection by generating and propagating local alloimmune responses. However, recent studies have shown that TLOs rich in regulatory Foxp3+ cells are present in long term accepting allografts. The notion that TLOs can contribute to the local downregulation of immune responses has been corroborated in other chronic inflammation models. These findings suggest that contrary to previous suggestions that the induction of TLOs in allografts is necessarily harmful, the induction of “tolerogenic” TLOs may prove advantageous. In this review, we discuss our current understanding of how TLOs are induced and how they regulate immune responses with a particular focus on alloimmunity.

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The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy

Cited by 39 publications

References 30 publications

Coronary artery disease in heart transplantation: new concepts for an old disease

Coronary artery disease in heart transplantation: new concepts for an old disease

A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression

The Role of Lymphoid Neogenesis in Allografts

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