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Pathophysiological Mechanisms in Ocular Graft-versus-Host Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (26 February 2021) | Viewed by 18153

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Special Issue Editors

Prof. Dr. Philipp Steven

E-Mail Website
Guest Editor

Department of Ophthalmology, Division for Dry-Eye and Ocular GvHD, Medical Faculty, University of Cologne, 50937 Cologne, Germany
Interests: ocular GvHD, Dry Eye Disease, Non-invasive Ocular Surface Imaging, Drug-development

Prof. Dr. Victor L. Perez

E-Mail Website
Guest Editor

Foster Center for Ocular Immunology at Duke Eye Center, USA
Interests: ocular GVHD, Immune Mediated Eye Diseases, Dry Eye Syndrome, Tear Flow Cytometry and Diagnostic, basic immune mechanisms ocular GVHD, Donor reactive T cells, immune therapy; keywords

Special Issue Information

Dear Colleagues,

Ocular graft-versus-host disease is a rapidly progressing multifactorial inflammatory disease of the entire eye and its adnexae. Approximately 50% of patients undergoing allogeneic hematopoietic stem cell transplantation suffer from acute and/or chronic ocular GvHD. Although foreseeable in its onset, there are limitations in diagnostic and therapeutic options based on a lack of knowledge in the understanding of its pathophysiology. As ocular GvHD is a “rare disease”, currently there is little interest in specific drug development and clinical trial implementation. Furthermore, mandatory treatment guidelines differ from region to region or are lacking entirely.

This Special Issue, titled “Pathophysiology of Ocular Graft-versus-Host Disease” is dedicated to providing an overview on current research efforts that focus on the understanding of ocular GvHD pathomechanisms. We hereby would like to invite you to submit original research papers and reviews on, but not limited to, new findings on immunomechanisms, molecular key players, pathomechanisms, risk factors, biomarkers, and therapeutic targets. This will include experimental cell or organ cultures models, animal studies. Phase I clinical trials or retrospective studies highlighting or proposing new molecular mechanisms are also welcome.

Prof. Dr. Philipp Steven
Prof. Dr. Victor L. Perez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Ocular GvHD
Immunopathogenesis
Animal models
Angiogenesis
Risk factors
Biomarkers
Immune therapies
Dermatological and GI Tract GVHD

Published Papers (6 papers)

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Research

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14 pages, 2189 KiB

Open AccessArticle

Analyses and Correlation of Pathologic and Ocular Cutaneous Changes in Murine Graft versus Host Disease

by Robert B. Levy, Hazem M. Mousa, Casey O. Lightbourn, Eric J. Shiuey, David Latoni, Stephanie Duffort, Ryan Flynn, Jing Du, Henry Barreras, Michael Zaiken, Katelyn Paz, Bruce R. Blazar and Victor L. Perez

Int. J. Mol. Sci. 2022, 23(1), 184; https://doi.org/10.3390/ijms23010184 - 24 Dec 2021

Cited by 4 | Viewed by 2805

Abstract

Graft versus host disease (GVHD) is initiated by donor allo-reactive T cells activated against recipient antigens. Chronic GVHD (cGVHD) is characterized by immune responses that may resemble autoimmune features present in the scleroderma and Sjogren’s syndrome. Unfortunately, ocular involvement occurs in approximately 60–90% of patients with cGVHD following allo-hematopoietic stem cell transplants (aHSCT). Ocular GVHD (oGVHD) may affect vision due to ocular adnexa damage leading to dry eye and keratopathy. Several other compartments including the skin are major targets of GVHD effector pathways. Using mouse aHSCT models, the objective was to characterize cGVHD associated alterations in the eye and skin to assess for correlations between these two organs. The examination of multiple models of MHC-matched and MHC-mismatched aHSCT identified a correlation between ocular and cutaneous involvement accompanying cGVHD. Studies detected a “positive” correlation, i.e., when cGVHD-induced ocular alterations were observed, cutaneous compartment alterations were also observed. When no or minimal ocular signs were detected, no or minimal skin changes were observed. In total, these findings suggest underlying cGVHD-inducing pathological immune mechanisms may be shared between the eye and skin. Based on the present observations, we posit that when skin involvement is present in aHSCT patients with cGVHD, the evaluation of the ocular surface by an ophthalmologist could potentially be of value. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms in Ocular Graft-versus-Host Disease)

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15 pages, 5199 KiB

Open AccessArticle

Ocular Graft-versus-Host Disease in a Chemotherapy-Based Minor-Mismatch Mouse Model Features Corneal (Lymph-) Angiogenesis

by Uta Gehlsen, Daniela Stary, Martina Maass, Katarina Riesner, Gwen Musial, Michael E. Stern, Olaf Penack and Philipp Steven

Int. J. Mol. Sci. 2021, 22(12), 6191; https://doi.org/10.3390/ijms22126191 - 08 Jun 2021

Cited by 8 | Viewed by 2349

Abstract

Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic “window of opportunity” is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms in Ocular Graft-versus-Host Disease)

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16 pages, 69660 KiB

Open AccessArticle

MSCs Become Collagen-Type I Producing Cells with Different Phenotype in Allogeneic and Syngeneic Bone Marrow Transplantation

by Robert Maximilian Rusch, Yoko Ogawa, Shinri Sato, Satoru Morikawa, Emi Inagaki, Eisuke Shimizu, Kazuo Tsubota and Shigeto Shimmura

Int. J. Mol. Sci. 2021, 22(9), 4895; https://doi.org/10.3390/ijms22094895 - 05 May 2021

Cited by 2 | Viewed by 2031

Abstract

Mesenchymal stem cells (MSCs) have been widely used in therapeutic applications for many decades. However, more and more evidence suggests that factors such as the site of origin and pre-implantation treatment have a crucial impact on the result. This study investigates the role of freshly isolated MSCs in the lacrimal gland after allogeneic transplantation. For this purpose, MSCs from transgenic GFP mice were isolated and transplanted into allogeneic and syngeneic recipients. While the syngeneic MSCs maintained a spherical shape, allogeneic MSCs engrafted into the tissue as spindle-shaped cells in the interstitial stroma. Furthermore, the MSCs produced collagen type I in more than 85% to 95% of the detected GFP⁺ MSCs in the recipients of both models, supposedly contributing to pathogenic fibrosis in allogeneic recipients compared to syngeneic models. These findings indicate that allogeneic MSCs act completely differently from syngeneic MSCs, highlighting the importance of understanding the exact mechanisms behind MSCs. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms in Ocular Graft-versus-Host Disease)

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16 pages, 5534 KiB

Open AccessArticle

Positive Effects of Oral Antibiotic Administration in Murine Chronic Graft-Versus-Host Disease

by Shinri Sato, Eisuke Shimizu, Jingliang He, Mamoru Ogawa, Kazuki Asai, Hiroyuki Yazu, Robert Rusch, Mio Yamane, Fan Yang, Shinji Fukuda, Yutaka Kawakami, Kazuo Tsubota and Yoko Ogawa

Int. J. Mol. Sci. 2021, 22(7), 3745; https://doi.org/10.3390/ijms22073745 - 03 Apr 2021

Cited by 8 | Viewed by 3506

Abstract

Chronic graft-versus-host disease (cGVHD) is one of the most frequent complications experienced after allogeneic hematopoietic stem cell transplantation. Reportedly, dysbiosis and severe damage to the microbiome are also closely associated with GVHD. Herein, we aimed to elucidate the positive and negative effects of the administration of various antibiotics in a murine model of cGVHD. For allogeneic bone marrow transplantation (allo-BMT), bone marrow from B10.D2 mice were transplanted in BALB/c mice to induce cGVHD. The cGVHD mice were orally administered ampicillin, gentamicin (GM), fradiomycin, vancomycin, or the solvent vehicle (control group). Among the antibiotic-treated mice, the systemic cGVHD phenotypes and ocular cGVHD manifestations were suppressed significantly in GM-treated mice compared to that in control mice. Inflammatory cell infiltration and fibrosis in cGVHD-targeted organs were significantly attenuated in GM-treated mice. Although regulatory T cells were retained at greater levels in GM-treated mice, there were significantly fewer Th17 cells and interleukin (IL)-6-producing macrophages in cGVHD-targeted organs in these mice. Collectively, our results revealed that orally administered GM may exert positive effects in a cGVHD mouse model. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms in Ocular Graft-versus-Host Disease)

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Review

Jump to: Research

20 pages, 933 KiB

Open AccessReview

Cascade of Inflammatory, Fibrotic Processes, and Stress-Induced Senescence in Chronic GVHD-Related Dry Eye Disease

by Yoko Ogawa, Yutaka Kawakami and Kazuo Tsubota

Int. J. Mol. Sci. 2021, 22(11), 6114; https://doi.org/10.3390/ijms22116114 - 06 Jun 2021

Cited by 24 | Viewed by 4251

Abstract

Ocular graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Ocular GVHD affects recipients’ visual function and quality of life. Recent advanced research in this area has gradually attracted attention from a wide range of physicians and ophthalmologists. This review highlights the mechanism of immune processes and the molecular mechanism, including several inflammation cascades, pathogenic fibrosis, and stress-induced senescence related to ocular GVHD, in basic spectrum topics in this area. How the disease develops and what kinds of cells participate in ocular GVHD are discussed. Although the classical immune process is a main pathological pathway in this disease, senescence-associated changes in immune cells and stem cells may also drive this disease. The DNA damage response, p16/p21, and the expression of markers associated with the senescence-associated secretory phenotype (SASP) are seen in ocular tissue in GVHD. Macrophages, T cells, and mesenchymal cells from donors or recipients that increasingly infiltrate the ocular surface serve as the source of increased secretion of IL-6, which is a major SASP driver. Agents capable of reversing the changes, including senolytic reagents or those that can suppress the SASP seen in GVHD, provide new potential targets for the treatment of GVHD. Creating innovative therapies for ocular GVHD is necessary to treat this intractable ocular disease. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms in Ocular Graft-versus-Host Disease)

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11 pages, 671 KiB

Open AccessReview

Meibomian Gland Dysfunction in Ocular Graft vs. Host Disease: A Need for Pre-Clinical Models and Deeper Insights

by Eugene Appenteng Osae and Philipp Steven

Int. J. Mol. Sci. 2021, 22(7), 3516; https://doi.org/10.3390/ijms22073516 - 29 Mar 2021

Cited by 9 | Viewed by 2362

Abstract

Despite decades of experience with hematopoietic stem cell transplantation, we are still faced with the delicate equipoise of achieving stable ocular health post-transplantation. This is because ocular graft-versus-host disease (oGvHD) following hematopoietic stem cell transplantation frequently occurs (≥50%) among transplant patients. To date, our understanding of the pathophysiology of oGvHD especially the involvement of the meibomian gland is still limited as a result of a lack of suitable preclinical models among other. Herein, the current state of the etiology and, pathophysiology of oGvHD based on existing pre-clinical models are reviewed. The need for additional pre-clinical models and knowledge about the involvement of the meibomian glands in oGvHD are emphasized. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms in Ocular Graft-versus-Host Disease)

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