Chronic rejection: risk factors, regulation, and possible sites of therapeutic intervention.
Clinical chronic rejection corresponds histologically to proliferative allograft vasculopathy. This disorder reflects the cumulative trauma to the allograft regardless of its origin. As a consequence of trauma, inflammation is generated, leading to endothelial and smooth muscle cell activation, smooth muscle replication and migration, and graft arterial intimal thickening. According to the current paradigm, chronic rejection can be avoided by more intensive and selective immunosuppression and by avoiding the known predisposing factors. Retransplantation experiments in experimental animals to donor or F1-strain suggest, however, that elimination of histoincompatibility does not prevent the progression of the disorder once it has been initiated. To design additional sites of intervention after the "point-of-no-return," attention has been focused on the regulation of the synthesis of growth factors, binding of the growth factors to the receptors, and to signalling downstream of the receptor. Also, inhibition of proteolytic enzymes, necessary for the locomotion of the smooth muscle cells, is a possible target. On most occasions, however, the inhibitory effect is at the most 30 to 50% of the maximal, and only the future will show whether several of these approaches must be applied concomitantly or whether genes regulating several of these processes simultaneously can be identified and exploited.
Häyry
P
P
Transplantation Laboratory, University of Helsinki, Finland.
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000276:immunology; D002908:Chronic Disease; D015316:Genetic Therapy; D006084:Graft Rejection / Q000453:epidemiology* / Q000517:prevention & control / Q000628:therapy; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use; D011183:Postoperative Complications; D012307:Risk Factors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D010455:Peptides