Patterns of Corneal Graft Rejection in the Rabbit and Reversal of Rejection With Monoclonal Antibodies

Williams, Keryn A.; Standfield, Scott; Wing, Sarah; Barras, Christopher W.; Mills, Richard A.; Comacchio, Rafaella M.; Coster, Douglas J.

doi:10.1097/00007890-199207000-00006

Cited by 28 publications

(12 citation statements)

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“…In recipients of corneal allografts, irreversible rejection is the most frequent cause of transplant failure, accounting for 42% of failed grafts in the largest reported cohort [1]. The fact that human corneal grafts are not biopsied or replaced at the time of rejection episodes means that most of the available information on pathology of corneal graft rejection has been obtained from experimental models, of which rabbit [2][3][4] and rat [5,6] models have been most widely studied. In untreated rejecting rabbit allografts, the cellular infiltrate within the graft is heterogeneous, containing macrophages, lymphocytes, plasma cells and neutrophils [3,7].…”

Section: Introductionmentioning

confidence: 99%

“…In untreated rejecting rabbit allografts, the cellular infiltrate within the graft is heterogeneous, containing macrophages, lymphocytes, plasma cells and neutrophils [3,7]. A recent immunohistochemical study by Williams et al demonstrated that half of the leucocytes were T lymphocytes, two-thirds bore MHC class II markers and one-fifth carried myeloid cell markers [4]. In rat cornea, which more closely resembles human cornea in terms of MHC molecule expression [8], allograft rejection is also T cell-mediated, although there is conflicting information from various rat transplantation models and various donor-recipient strain combinations on the relative importance of different cell subsets and MHC antigen disparities [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of cells infiltrating the graft and aqueous humour in rat corneal allograft rejection

Larkin¹,

Calder²,

Lightman³

1997

Clinical and Experimental Immunology

101

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SUMMARYIn a rat model of corneal transplantation, Fischer 344 (RT1 lv1 ) rats received orthotopic corneal isografts or Wistar-Furth (RT1 u ) donor allografts. Rejection was observed in 25 of 26 allograft recipients, at a median time of 18 days, with all isografts surviving > 100 days. Flow cytometric analysis of aqueous humour identified cellular infiltration of the aqueous at the time of allograft rejection, in contrast to the acellular aqueous found in isografts at corresponding times following transplantation. A higher proportion of CD8 + than CD4 + cells was found at days 1-3 following rejection, whereas there was a higher proportion of CD4 + cells at days 5-8. No changes in peripheral blood T cell subsets were found at the time of rejection. Immunohistochemical analysis of cells infiltrating recipient iris and grafted cornea undertaken at days 1-2, 4 and 7-10 following onset of rejection, demonstrated inflammatory cells in the graft epithelium, stroma and aggregated on the endothelium. Large numbers of macrophages, T cells (CD4 + > CD8 + at all time points), natural killer (NK) cells and neutrophils were detected in graft tissue at days 1-2 and 4, diminishing after that time. Most infiltrating cells expressed MHC class II antigen, and a smaller number expressed IL-2R. Expression of the co-stimulatory marker B7 was identified in a few cells at day 4 in the region of the graft-host wound. The immune response in graft rejection was characterized at day 4 also by expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells of iris and corneal vessels, demonstration of interferon-gamma on mononuclear cells in the peripheral (recipient) cornea, and tumour necrosis factor-alpha on aggregated mononuclear cells on the graft, but not recipient, endothelium. Only sparse cellular infiltrates were found in isograft controls, with inflammation located at the graft-host wound. These findings suggest that inflammatory cells reach a corneal allograft by two routes-from vessels in the peripheral recipient cornea, and from vessels in the recipient iris via the aqueous humour. Different aqueous and intragraft T cell subset proportions were seen early in rejection, although a preponderance of CD4 + cells was found in both aqueous and graft at later times.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and characterization of cells infiltrating the graft and aqueous humour in rat corneal allograft rejection

Larkin¹,

Calder²,

Lightman³

1997

Clinical and Experimental Immunology

101

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“…Corneal graft rejection appears histologically to be an inflammatory process with characteristics typical of a delayed type hypersensitivity response: the infiltrate is mixed, but is composed predominantly of T cells. [39][40][41] In the non-inflammatory programmed cell death that occurs as part of normal development, apoptotic nuclei are quickly cleared by phagocytosis. 42 TUNEL positive cells may accumulate in rejecting corneal grafts because there are insufficient phagocytic cells present in the grafts to clear the substantial number of dead and dying T cells.…”

Section: Discussionmentioning

confidence: 99%

Corneal graft rejection occurs despite Fas ligand expression and apoptosis of infiltrating cells

Williams

Standfield²,

Smith³

et al. 2005

British Journal of Ophthalmology

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Background/aims: Constitutive expression of Fas ligand (CD95L) protects the eye against cell mediated immune responses by inducing apoptosis in infiltrating Fas bearing T cells. This study was designed to examine Fas ligand expression on acutely rejecting rat corneal grafts and to investigate the kinetics of induction of apoptosis in infiltrating leucocytes. Methods: Orthotopic penetrating corneal transplantation was performed between genetically disparate inbred rats. Fas ligand expression and the phenotype of infiltrating leucocytes were examined by immunohistochemistry. Apoptotic nuclei were visualised in sections of normal rat cornea, rejecting allografts, and time matched isografts by terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labelling (TUNEL) and quantified by video image analysis. Staining with Hoechst dye 33258 was used to confirm the presence of apoptotic nuclei. Results: Fas ligand was expressed on corneal endothelial and epithelial cells during acute corneal graft rejection. At all time points examined, including as early as the fifth postoperative day, the cells infiltrating both corneal isografts and allografts were TUNEL positive. By the 15th postoperative day, over 90% of all nuclei, many of which were T cells, were apoptotic. Conclusion: Expression of Fas ligand is not downregulated on the cornea during allograft rejection and infiltrating leucocytes in both isografts and allografts die rapidly in situ. Despite the death of the cells believed to be responsible for rejection, isografts survive indefinitely whereas allografts are irreparably damaged.

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“…An effective local treatment regimen might be preferable, but whole antibodies penetrate poorly into the normal eye when administered topically and must be injected intraocularly to achieve therapeutic doses. Injection of immunoglobulins (Ig) into the anterior chamber of the eye of experimental animals tends to elicit unwanted inflammatory reactions 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Injection of immunoglobulins (Ig) into the anterior chamber of the eye of experimental animals tends to elicit unwanted inflammatory reactions. 3 Amongst the plethora of costimulatory molecules, the function of which might be modulated by treatment with antibody, the CD28-B7 axis 2 has attracted considerable interest in experimental corneal transplantation. Soluble constructs of CTLA4 bind to B7 molecules (CD80 and CD86), thereby preventing their interaction with CD28 and blocking effective costimulation.…”

Section: Introductionmentioning

confidence: 99%

Local or short‐term systemic costimulatory molecule blockade prolongs rat corneal allograft survival

Thiel

Steiger

O’Connell

et al. 2005

Clinical Exper Ophthalmology

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Patterns of Corneal Graft Rejection in the Rabbit and Reversal of Rejection With Monoclonal Antibodies

Cited by 28 publications

References 0 publications

Identification and characterization of cells infiltrating the graft and aqueous humour in rat corneal allograft rejection

Identification and characterization of cells infiltrating the graft and aqueous humour in rat corneal allograft rejection

Corneal graft rejection occurs despite Fas ligand expression and apoptosis of infiltrating cells

Local or short‐term systemic costimulatory molecule blockade prolongs rat corneal allograft survival

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