Initial In Vitro Investigation of the Human Immune Response to Corneal Cells from Genetically Engineered Pigs
| Autor: | Hidetaka Hara, Danny S. Roh, Jordan Piluek, Suyapa Ball, Yoshiaki Mizuguchi, David K. C. Cooper, Naoko Koike, Kumiko Isse, Carol Phelps, Cassandra Long, James L. Funderburgh, David Ayares, Nirmala SundarRaj |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cytotoxicity
Immunologic genetic structures Cell Transplantation Swine medicine.medical_treatment T cell Population Transplantation Heterologous Biology In Vitro Techniques Disaccharides Animals Genetically Modified Cornea Corneal Transplantation Membrane Cofactor Protein Epitopes Interferon-gamma Immune system medicine Cytotoxic T cell Animals Humans education Corneal transplantation Aorta Cells Cultured education.field_of_study Immunity Cellular Endothelium Corneal Histocompatibility Antigens Class I Histocompatibility Antigens Class II Endothelial Cells Eye bank Dendritic cell Articles Flow Cytometry Galactosyltransferases eye diseases Immunity Humoral Transplantation medicine.anatomical_structure Immunoglobulin M Immunoglobulin G Immunology B7-1 Antigen sense organs B7-2 Antigen |
| Popis: | Although corneal transplantation is readily available in the United States and certain other regions of the developed world, the worldwide need for human donor corneas far exceeds the supply.1 The shortage is particularly severe in Asia.1,2 Furthermore, in some countries (e.g., South Africa), the shortage has been exacerbated by the high incidence of infection with the human immunodeficiency virus in the population, making donation unsafe.3 Even in the developed world, the increasing popularity of refractive surgery is likely to reduce the supply of human corneas4,5; current Eye Bank Association of America standards do not allow the use of corneas that have been subjected to surgery for full-thickness corneal transplantation (penetrating keratoplasty). Pig corneas could provide an alternative source, because the anatomic and biomechanical properties of human and pig corneas are similar.1 The immune-privileged environment of the cornea appears to provide corneal xenogeneic grafts with some degree of protection.6,7 Indeed, corneas transplanted from wild-type (WT, i.e., unmodified) pigs into monkeys have been reported to survive for several months (>3 months) if corticosteroid is applied locally.8 Immune-mediated destruction of corneal allografts and xenografts is primarily CD4+ T-cell-mediated and targets the corneal endothelial cell (CEC),9–13 although keratocytes have also been suggested as important targets of corneal graft rejection.14,15 CD8+ T cells and NK T cells may play a role in rejection when CD4+ T cells are absent or their function is impaired.16 The immune response to corneal xenografts appears to occur almost exclusively by the indirect pathway.17 There is a resident myeloid corneal dendritic cell population that is normally MHC class II–negative, but can readily upregulate class II expression during inflammation.18 Thus, it is likely that a population of passenger leukocytes in xenogeneic corneas is involved in direct xenoantigen presentation to host T cells as well as in the alloimmune response,19 especially if a corneal graft is placed into a high-risk patient (e.g., with a neovascularized and/or inflamed host corneal bed). The role of cytotoxic anti-donor antibodies in corneal graft rejection remains a matter of discussion.20–23 Clinical studies suggest that, in some instances, antibodies may contribute to corneal allograft failure if a high-risk recipient has been sensitized to donor alloantigens24 or if the donor-recipient combination is ABO-incompatible.23,25 Similarly, sensitization to xenoantigens has been detrimental to graft survival in rodent models of xenotransplantation.13,26,27 This effect is, at least in part, a byproduct of the T cell- and macrophage-mediated response generated to the graft. With the current speed of advances in the genetic engineering of pigs,28,29 it is increasingly likely that these immune responses will be overcome by the transplantation of corneas from genetically engineered pigs. The primary purpose of the present study was to compare in vitro human humoral and cellular immune responses to pig CECs (pCECs) with those to pig aortic endothelial cells (pAECs), which are the target in vascularized solid organ xenografts, and to explore whether the effect of these immune responses is reduced when CECs from genetically engineered pigs are tested. This study is the first in which CECs from such pigs have been investigated. Our results demonstrated that the human humoral and cellular immune responses to genetically engineered pCECs were greatly reduced compared with those to WT pCECs, but were not comparable to those of human CECs (hCECs). |
| Databáze: | OpenAIRE |
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