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