Gene Therapy for Modulation of T-Cell-Mediated Immune Response Provoked by Corneal Transplantation

Pastak, Marko; Kleff, Veronika; Saban, Daniel R.; Czugala, Marta; Steuhl, Klaus‐Peter; Ergün, Süleyman; Singer, Bernhard B.; Fuchsluger, Thomas Armin

doi:10.1089/hum.2017.044

Cited by 10 publications

(7 citation statements)

References 44 publications

(46 reference statements)

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“…Our study is the first to compare multiple aspects of corneal rejection between M1- and M2-dominated immune response models, namely C57BL/6J and BALB/c mice. These mouse strains are two of the most widely used models for rejection studies [7-9, 12, 24, 25, 27, 44, 45]. The results of our study indicate that these studies deserve cautious interpretation.…”

Section: Discussionmentioning

confidence: 65%

“…Most of the research in corneal transplantation and in conducting research on pharmacological interventions is performed using mouse models, with C57BL/6 and BALB/c mice most frequently used as recipients [6][7][8][9]. In murine keratoplasty, a 2.0-2.5-mm graft is obtained from the donor animal and sutured into the recipient animal by interrupted sutures.…”

Section: Introductionmentioning

confidence: 99%

“…Mouse models used to investigate corneal transplantation[7,12,[20][21][22][23][24][25][26][27][28] Definition of the clinical score…”

mentioning

confidence: 99%

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Different Innate Immune Responses in BALB/c and C57BL/6 Strains following Corneal Transplantation

et al. 2020

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Purpose: To investigate immunological differences and the role of CD38+/F4/80 + M1 macrophages in C57BL/6J- and BALB/c-recipient mouse corneal transplantation models. Methods: Allogeneic transplantation was performed crosswise in BALB/c mice and C57BL/6J mice; syngeneic transplantation was performed in both strains. Anterior chamber depth (ACD) was measured before and central corneal thickness (CCT) was measured both before and after transplantation. In vivo graft rejection was monitored using anterior eye segment optical coherence tomography (ASOCT) evaluating the CCT and grading of corneal oedema using a well-established clinical score (CS). Histology of corneal grafts was performed 18 or 21 days after surgery. Immunohistochemistry with anti-F4/80 antibody and anti-CD38 antibody was used for detecting M1 macrophages within the grafts. Results: High CS and CCT values after allogeneic transplantation persisted in both BALB/c (n = 18) and C57BL/6J recipients (n = 20). After syngeneic transplantation, CS and CCT values increased in both models in the early phase after surgery due to the surgical trauma. Surprisingly, in the syngeneic C57BL/6J model, high CCT values persisted. Furthermore, anterior synechiae developed in C57BL/6 recipients after both syngeneic and allogeneic transplantation, whereas BALB/c recipients showed almost no synechiae – even though C57/BL6J animals tended to have a deeper anterior chamber (281 ± 11 pixels [mean ± SD]) compared with BALB/c animals of the same age (270 ± 9 pixels [mean ± SD]). Immunohistochemistry revealed numerous CD38+/F4/80 + M1 macrophages in grafts of C57BL/6J recipients following both syngeneic and allogeneic transplantation. However, in BALB/c-recipient mice only sparse M1 macrophages were detectable (CD38 + M1 macrophages relative to all F4/80 + cells: 75 vs. 17% [after allogeneic transplantation] and 66 vs. 17% [after syngeneic transplantation]; p < 0.05). Conclusions: Allogeneic corneal transplants are rejected in BALB/c as well as C57BL/6J mice, but tissue alterations with anterior synechiae are more pronounced in C57BL/6J recipients. Following syngeneic transplantation, C57BL/6J-recipient animals show a persistent graft swelling with increased numbers of CD38+/F4/80 + M1 macrophages in grafted tissue, in contrast to the common model using BALB/c-recipient mice. Our data strongly suggest that strain-dependent differences convey different innate immune responses in BALB/c and C57BL/6J strains. Accordingly, in murine keratoplasty experiments, the mouse line of both donor and recipient animals must be carefully considered. C57BL/6J-recipient mice might be particularly suited to study corneal graft rejection in a clinical setting considered “high risk.”

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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Different Innate Immune Responses in BALB/c and C57BL/6 Strains following Corneal Transplantation

et al. 2020

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“…Although its mechanism remains unclear, studies have confirmed that immune rejection is highly dependent on the directional migration and homing of immune cells to lymphoid tissue or inflammatory sites, including lymphocytes, macrophages, and natural killer (NK) cells, and is regulated by adhesion molecules and chemokines (38). Clinical and experimental data has shown that the destructive attack of immune cells, especially CD 4 + T cells, on the grafts is an important reason for the failure of corneal transplantation due to graft rejection (32,39,40).…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence has shown that T cell responses and Th17 cells are involved in corneal allograft survival (12,32). However, whether the proportion of Th17 cells changes after corneal transplantation, as well as its regulatory mechanism, still need to be further studied.…”

Section: Rejection Of Corneal Allograftmentioning

confidence: 99%

Loss of miR-673-5p expression in the cornea promotes rat corneal allograft rejection by promoting Th17 cell differentiation mediated by JAK2/STAT3

Cao¹,

Li²,

Li³

et al. 2021

Ann Transl Med

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Background: Cluster of differentiation 4 positive (CD 4 + ) T cells play an important role in corneal graft rejection, especially the dynamic balance between regulatory T cells and helper T cells. This study aims to explore the upstream and downstream regulatory mechanisms of Th17 cell differentiation-mediated corneal allograft rejection. Methods: By establishing rat corneal allograft transplantation model, transcriptome analysis was carried out to screen the differentially expressed genes related to T helper 17 (Th17) cell differentiation, and then cell experiments were used to verify the effect of miR-673-5p/Janus Kinase 2 (JAK2) signal on naïve CD 4 + T cell differentiation and the proliferation, migration, and tube formation ability of human umbilical vein endothelial cells (HUVECs). Finally, the role of miR-673-5p/JAK2 signal in corneal allograft rejection was verified by animal model in vivo.Results: The results showed that JAK2/STAT3 signaling activation-mediated Th17 cell differentiation was significantly up-regulated during corneal allograft rejection, and miR-673-5p expression was down-regulated after corneal allograft rejection. Low expression of miR-673-5p promoted Th17 cell differentiation by up-regulating JAK2, and then promoted placental growth factor (PLGF)mediated corneal neovascularization (CNV). Conclusions:The results of this study suggested that low expression of miR-673-5p is a promoter of corneal allograft rejection. Overexpression of miR-673-5p can improve the survival rate of corneal allografts by inhibiting the differentiation and maturation of Th17 cells mediated by JAK2/STAT3 signaling.

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Gentherapie in der Augenheilkunde

et al. 2023

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Gene Therapy for Modulation of T-Cell-Mediated Immune Response Provoked by Corneal Transplantation

Cited by 10 publications

References 44 publications

Different Innate Immune Responses in BALB/c and C57BL/6 Strains following Corneal Transplantation

Different Innate Immune Responses in BALB/c and C57BL/6 Strains following Corneal Transplantation

Loss of miR-673-5p expression in the cornea promotes rat corneal allograft rejection by promoting Th17 cell differentiation mediated by JAK2/STAT3

Gentherapie in der Augenheilkunde

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