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New Approaches to Graft Loss

Chronic rejection remains the biggest hurdle in transplantation and much research is heing carried out in centres around the world to try and understand its pathophysiology, in the hope ot developing strategies to overcome it. Reports trom the meeting suggest that progress is being made, hut the overall teeling is that there is still much hard work to he done hetore an impressive impact is made on the incidence of chronic rejection. Much ot the research into chronic rejection has recently tocused on vascular aspects ot transplantation, especially on the prevention of grab-vessel disease (GVD).

"There is still much hard word to be done before an impressive impact is made on the incidence of chronic rejection"

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Nigel Cook (Novartis, Switzerland) outlined the ditticulfies of study in this area. The mechanisms of GVD are poorly understood. It is a multi-factorial process involving both immunological and vascular components, and events at or after transplantation may influence long-term graft survival jeg graft ischanmia, infection, age of the graft, and cause of/concomitant events with brain death). All these factors may converge on endothelial cells and/or smooth muscle cells and lead to SVC (Figure 1). SVD can be visualised as a cascade of events, including ischaemia-repedusion injury, endothelial cell activation, expression of adhesion molecules/cytokines/chemokines, recruitment of leucocytes and release of growth factors.These events may culminate in smooth muscle cell migration and proliferation. This 'cascade hypothesis' is simplistic but attractive from a therapeutic perspective. It focuses attention on the potential benefit of early intervention, rather than waiting until symptomatic stages, where it may no longer be possible to contain the multi-factorial remodelling process, Possibly, if some of these early components can be kept in check for the first weeks to months post-transplant, the onset of later GVD might be postponed. This vascular approach to patient care seeks to examine a variety of novel targets for therapeutic intervention. Hence, supplementation of immuno-suppressive regimens with agents working through various vascular mechanisms may represent attractive ways to combat late graft loss.

The endothelial cell in particular is an attractive target because it forms the interface between the graft and the host; indeed, the cascade of SVD events centres on this cell. The integrity and function of the endothelial cells are clearly important to the outcome of a transplant. Vascular gene therapy is just one approach being explored to target events occurring in the first few months after transplantation that may contribute to GVD. An alternate strategy harnesses gene therapy to introduce vectors into the graft in the pedusate before transplantation, thereby avoiding many systemic problems normally associated with gene therapy (Figure 2). Some small benefits are discernible in animal models with a few of the current immunosuppressive agents. However, the relevance of animal experiments is uncertain because they use rodent rather than human materials, and because they freguently study the rataorta model of CVD, which may be different from the vessels of solid organs.

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