{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:30:25Z","timestamp":1791311425783,"version":"4.3.1"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2001,12,1]],"date-time":"2001-12-01T00:00:00Z","timestamp":1007164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chronic allograft nephropathy (CAN) is the principal cause of late renal allograft failure. This complex process is multifactorial in origin, and there is good evidence for immune-mediated effects. The immune contribution to this process is directed by CD4+ T cells, which can be activated by either direct or indirect pathways of allorecognition. For the first time, these pathways have been simultaneously compared in a cohort of 22 longstanding renal allograft recipients (13 with good function and nine with CAN). CD4+ T cells from all patients reveal donor-specific hyporesponsiveness by the direct pathway according to proliferation or the secretion of the cytokines IL-2, IL-5, and IFN-\u03b3. Donor-specific cytotoxic T cell responses were also attenuated. In contrast, the frequencies of indirectly alloreactive cells were maintained, patients with CAN having significantly higher frequencies of CD4+ T cells indirectly activated by allogeneic peptides when compared with controls with good allograft function. An extensive search for alloantibodies has revealed significant titers in only a minority of patients, both with and without CAN. In summary, this study demonstrates widespread donor-specific hyporesponsiveness in directly activated CD4+ T cells derived from longstanding recipients of renal allografts, whether they have CAN or not. However, patients with CAN have significantly higher frequencies of CD4+ T cells activated by donor Ags in an indirect manner, a phenomenon resembling split tolerance. These findings provide an insight into the pathogenesis of CAN and also have implications for the development of a clinical tolerance assay.<\/jats:p>","DOI":"10.4049\/jimmunol.167.12.7199","type":"journal-article","created":{"date-parts":[[2014,4,20]],"date-time":"2014-04-20T21:31:04Z","timestamp":1398029464000},"page":"7199-7206","source":"Crossref","is-referenced-by-count":176,"title":["Loss of Direct and Maintenance of Indirect Alloresponses in Renal Allograft Recipients: Implications for the Pathogenesis of Chronic Allograft Nephropathy"],"prefix":"10.1093","volume":"167","author":[{"given":"Richard J","family":"Baker","sequence":"first","affiliation":[{"name":"Immunology, Faculty of Medicine, Imperial College, Hammersmith Hospital , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria P","family":"Hernandez-Fuentes","sequence":"additional","affiliation":[{"name":"Immunology, Faculty of Medicine, Imperial College, Hammersmith Hospital , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A","family":"Brookes","sequence":"additional","affiliation":[{"name":"Immunology, Faculty of Medicine, Imperial College, Hammersmith Hospital , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afzal N","family":"Chaudhry","sequence":"additional","affiliation":[{"name":"Renal Medicine, Faculty of Medicine, Imperial College, Hammersmith Hospital , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H Terry","family":"Cook","sequence":"additional","affiliation":[{"name":"Histopathology, Faculty of Medicine, Imperial College, Hammersmith Hospital , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert I","family":"Lechler","sequence":"additional","affiliation":[{"name":"Immunology, Faculty of Medicine, Imperial College, Hammersmith Hospital , London ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2001,12,15]]},"reference":[{"key":"2026020208114724000_R1","first-page":"6","volume-title":"Hum. 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