Untitled - Roche Trasplantes

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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 65
BIOPSIA DE PROTOCOLO EN EL TRASPLANTE RENAL decreases the concentration of pre-existing and post-transplantation antibodies. Recently, results from a single center study were published indicating that multiple plasmapheresis treatments leads to more reproducible desensitization and lower humoral rejection rates than a single high-dose of IVIG. In this study, comprising 61 patients, three different treatment regimens were compared: plasmapheresis + low-dose IVIG + anti-CD20- antibody versus high-dose IVIG versus plasmapheresis + low-dose IVIG + anti-CD20-antibody + pre-transplant thymoglobulin. However, none of these three therapeutical regimens was completely effective in preventing humoral rejection in renal allograft recipients with high levels of donor specific alloantibodies. Prospective treatment guidelines can not be drawn from these small studies yet, since rituximab is usually combined with other drugs and therapies in these uncontrolled trials. However, plasma cells, the physiological source of antibodies do express little or no CD20 and are therefore resistant to rituximab mediated depletion. Plasma cells express various cell surface molecules (CD138, CD38, alpha4-beta1-integrin, CXCR4) which are however all not entirely plasma-cell specific. In mouse models treatment with anti TACI immunoglobulin (=transmembrane activator and calcium-modulating cyclophilinligand interactor), which is expressed by B cells and plasma cells as a member of TNFreceptor family, depleted long-living plasma cells. TACI-immunoglobulin is already in Phase I clinical trials for treatment of systemic lupus erythemathodes and B-cell lymphomas with signs of plasma cellular maturation. This approach might lead to more specific and more effective plasma cell depletion than currently achieved by thymoglobulins alone. Future strategies might be directed towards a highly specific complement blockade by complement receptor antagonists like C5a receptor inhibitors. Antagonizing activation of complement component C5 leads to blockade of C5a and MAC formation and herewith should prevent complement mediated cell damage. First candidate compounds are in preliminary stages of evaluation for clinical use. CONCLUSIONS Humoral rejection is beside cellular rejection a relevant pathogenetic factor for acute and chronic immunologic allograft damage. Under modern, mainly T cell targeted immunosuppression and as a consequent of an increasing number of patients with repetitive transplantations alloantibodies will become a major obstacle to short- and long-term allograft survival. For the detailed understanding of the ambivalent potential of alloantibodies (rejection versus accommodation) more insights into the regulation of B cells and the development and differentiation pathways of memory B cells and plasma cells are desperately needed. This can be the basis for developing methods to promote accommodation and to pre- 66
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