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Departments of
*
Immunology,
Renal Medicine, and
Histopathology, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom
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-
. 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.
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