Effects of Cellular Sensitization and Donor Age on Acute Rejection and Graft Function After Deceased-Donor Kidney Transplantation
| Autor: | Kenneth J. Woodside, Emilio D. Poggio, Aparna Padiyar, James A. Schulak, Joshua J. Augustine, Naragaju Sarabu, Donald E. Hricik, Peter S. Heeger, Edmund Q. Sanchez |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Adult
Graft Rejection Male Enzyme-Linked Immunospot Assay Human leukocyte antigen Article Interferon-gamma Antigen Fibrosis Humans Medicine Sensitization Kidney transplantation Aged Transplantation biology business.industry ELISPOT Age Factors Middle Aged medicine.disease Kidney Transplantation Tissue Donors Logistic Models medicine.anatomical_structure Acute Disease Immunology biology.protein Female Antibody business Glomerular Filtration Rate |
| Zdroj: | Transplantation. 95:1254-1258 |
| ISSN: | 0041-1337 |
| Popis: | Donor age is one of the most important factors that negatively impact the outcomes of kidney allografts from deceased donors (1, 2). However, the mechanisms accounting for this observation remain poorly understood. Senescent organs have limited ability to recover after ischemia-reperfusion (IR) injury and, as a consequence, are more likely to develop irreversible fibrosis (3, 4). There is also emerging evidence that organs from elderly donors are more immunogenic than those from younger donors (5–8). Primed or memory antidonor T cells are commonly detected in human transplantation candidates, likely reflecting heterologous immunity that results, in part, from cross reactivity with environmental antigens (9, 10). Studies in animal models have shown that memory T cells rapidly interact with the donor endothelium of a vascularized allograft, initiating a cascade of inflammatory events that facilitate organ injury and prevent tolerance (11, 12). We and others have translated these findings to humans by demonstrating that the pretransplantation frequency of donor reactive interferon gamma (IFNγ)–producing T cells in the peripheral circulation, measured by an enzyme-linked immunosorbent spot (ELISPOT) assay, is a direct correlate of posttransplantation acute rejection (AR) and reduced glomerular filtration rate (GFR) after kidney transplantation (13–16). Pretransplantation sensitization, traditionally defined by the detection of antibodies against human leukocyte antigens (HLAs), is associated with inferior graft survival based primarily on its association with AR, itself a risk factor for premature graft failure (17, 18). In contrast to conventional crossmatches that serve as measures of pretransplantation humoral sensitization (usually against HLAs), the donor reactive IFNγELISPOT assay serves as a measure of pretransplantation cellular sensitization, measuring cellular responses to antigens that may or may not be HLAs. We hypothesized that the enhanced immunogenicity of organs from older donors would facilitate immune recognition by primed donor reactive T cells. Together with the reduced ability of senescent organs to heal and, thereby, to develop fibrosis, donor reactive T cells are likely to synergize negatively with advanced donor age, increasing the risk of AR and declining kidney function after transplantation. To test this hypothesis, we analyzed outcomes in a cohort of human transplant recipients by correlating the frequencies of donor reactive IFNγ-producing peripheral blood lymphocytes with donor age, AR, and GFR. The results indicate a strong interaction between donor age and primed donor reactive T cells and suggest that patients with high pretransplantation frequencies of donor reactive IFNγ-producing peripheral blood lymphocytes are at high risk for poor outcomes if they receive grafts from older donors. |
| Databáze: | OpenAIRE |
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