Untitled - Roche Trasplantes

PROTOCOL BIOPSIES AND THE DIAGNOSIS OF HUMORAL REJECTION
activity PI3K and AKT, two further cytoprotective cell signaling molecules. Complement
regulation might theoretically be involved in accommodation, too. Under physiological
conditions the endothelial surface in the renal microcirculation (in peritubular capillaries
and glomeruli) is unopposed concerning complement activation via the classical pathway.
In general, four cell-surface inhibitors of complement activation has been identified:
complement receptor 1 (CR1), decay-accelerating factor (DAF, CD55), membrane cofactor
protein (MCP, CD46), and CD59 which are usually expressed in the endothelium at
low or undetectable levels. However, DAF expression can be increased in cultured endothelial
cells in the presence of various mediators like thrombin, bFGF, TNF, IFN-gamma,
or VEGF. In vitro upregulation of DAF inhibits complement-mediated cytotoxicity of
endothelial cells and reduces complement deposition. In animal models it has been shown
that DAF is required to prevent acute antibody-mediated rejection. Alternatively, exposure
to C-reactive protein increases the expression of DAF, CSD59, and MCP by cultured
endothelial cells. Anecdotally it has been reported that increased CD59 expression by
endothelial cells is a common event in acute and chronic humoral rejection and that increased
endothelial-cell expression of DAF can be seen in chronic humoral rejection.
Although this response might function to attenuate acute antibody-mediated allograft
damage, but accommodation is obviously inadequate to prevent the onset of chronic humoral
rejection. Nevertheless, a short term studies of pig-to-baboon solid organ (heart,
lung, and kidney) xenografts showing accommodation supported the concept that accommodation
is a consequence of full inhibition of complement activation. However, further
studies are needed to understand how complement activation can therapeutically
be controlled to achieve accommodation renal transplantation.
THERAPEUTIC IMPLICATIONS
At present, no definite guidelines for treatment of acute and chronic humoral rejection
are available. Various therapy regimes are still evolving but few prospective controlled
studies are currently underway. The most common treatment strategies are based on
the quick as possible removal of the circulating antibodies using plasmapheresis in combination
with immunosuppression targeting B cells as well as T cells. The intravenous application
of immunoglobulin (IVIG) or thymoglobulin represents a frequent therapeutic
approach that effect especially B cells and antibodies or to a lesser extent also plasma
cells (thymoglobulin) as the source of antibodies. IVIG induces apoptosis in B cells and
monocytes as well as inhibiting binding of donor-reactive antibodies to target cells in 80%
of patients, although the molecular mechanism is not known in detail. IVIG and thymoglobulin
might also function, in part, by inhibition of complement activation.
New therapeutic strategies are available in form of highly specific monocloncal antibodies
selectively inhibiting B cells (rituximab). This antibody binds to CD20, a surface molecule
expressed by precursor and mature B cells, and leads to transient B-cell depletion,
with typical B-cell recovery after 6-9 months. Preliminary studies indicate that rituximab
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