Transplantation Immunology.pdf - E-Lib FK UWKS

14 Callaghan and Bradley
adhesion molecules in the urine by enzyme-linked immunosorbent assay (77).
Noninvasive tests for CAN are also being investigated (78,79), but none have
undergone large-scale trials or entered routine clinical use.
6.1. Management of Acute Rejection
First-line treatment of acute rejection is with high-dose intravenous steroid
(e.g., methylprednisolone 0.5–1 g daily for 3 d). In up to 50% of cases, acute
rejection is steroid resistant and treatment with polyclonal antithymocyte globulin
(ATG) is required (80). This is given under close supervision as a result of
the risk of pulmonary edema from cytokine release syndrome. Anti-CD3 monoclonal
antibody (muromonab-CD3, Orthoclone OKT ® 3, Ortho Biotech) has also
been used with similar efficacy and side effects (81). Early reports have suggested
that high-dose pooled human immunoglobulin may be superior because
of its relatively benign side-effect profile (82).
As already noted, both daclizumab and basiliximab, monoclonal antibodies
directed against the interlukin-2 receptor α chain (CD25), reduce the incidence
of acute rejection by approx 30% when given prophylactically around the time of
transplantation (83,84). These agents, which are widely used, appear to be free
from significant side effects, and their ability to reduce acute rejection makes
them cost-effective (85).
6.2. C4d Staining and Antibody-Mediated Rejection
Since the mid-1990s, it has become increasingly apparent that antibody may
mediate allograft rejection in settings other than hyperacute rejection. This has
occurred through the recognition that C4d deposition in graft peritubular capillaries
is a reliable marker of antibody-mediated acute rejection (86). C4d is a
stable inactive degradation product of complement factor C4, formed when the
classical complement cascade is activated by the binding of antidonor antibodies
to the endothelium of the allograft.
Capillary C4d staining has been found in 30% of biopsies performed for
renal graft deterioration (87) and has been found to be 95% sensitive and specific
for the presence of antidonor antibodies (88). The definitive diagnosis of
acute antibody-mediated rejection requires morphological evidence of acute
tissue injury with immunopathological evidence for antibody action (C4d staining
or immunoglobulin and complement in arterial fibrinoid necrosis) and
serological evidence of antidonor antibodies (69).
C4d staining may also occur in CAN, mildly altered graft function, or with
normal histology. In these settings, the clinical significance of C4d staining
remains unclear. However, when features of acute cellular or humoral rejection
are present, C4d staining appears to be a marker of severity (89). Therefore,
anti-B-cell therapy (antithymocyte globulin, intravenous immunoglobulin,