Novel Mechanisms in Chronic Allograft Rejection: Matrix Metalloproteinases (MMS) as Proinflammatory Mediators and Therapeutic Targets to Sustain Long-term Graft Survival

Background
Chronic rejection remains one of the leading causes of late allograft loss. Thus, if MMP inhibition attenuates tissue damage, MMP represent novel targets for the prevention or even therapy of chronic allograft rejection in order to promote long-term graft survival. Associated with improved allograft half-lives are considerable social and economical benefits

Accumulation of extracellular matrix (ECM) proteins and increased proliferation/migration of certain cell types, particularly vascular smooth muscle cells leading to intimal hyperplasia and fibroblasts causing fibrosis and sclerosis, are characteristic histological findings in chronic rejection processes. Both features may be regulated by matrix metalloproteinases (MMP), which are generally increased in inflammatory processes. The precise role, however, of MMP as regulators of tissue remodeling in chronic allograft rejection remains to be defined.

Objective 
Our studies will describe the role of MMP as novel, pro-inflammatory mediators in chronic rejection processes. Importantly, the clinical relevance of these proteases will be assessed by the intervention aimed at inhibiting excess MMP activity.

Approach
In accordance with previously published studies and our own preliminary results, we hypothesize the following:
- MMP are up-regulated during the earlier decisive stages of chronic rejection, prior to the occurrence of end-stage tissue sclerosis. Thereby, MMP act as pro-inflammatory mediators and actively participate in tissue damage associated with chronic allograft rejection. Possible mechanisms are direct tissue injury, augmentation of excess cell proliferation/migration (e.g.vascular smooth muscle cells and fibroblasts), and facilitation of tissue invasion by extrinsic inflammatory cells (e.g. lymphocytes).
- MMP inhibition, for instance by the use of synthetic MMP inhibitors, ameliorates tissue damage during chronic allograft rejection
MMP expression and activity may vary between different organs. Thus, several types of allografts need to be analyzed to define the clinical significance of these proteases.

Part 1: We propose to investigate MMP activity and expression in three different types of rat allografts, such as kidney (F344-to-Lewis), heart (F344-to-Lewis), and trachea (Brown-Norway-to-Lewis) transplantation

Part 2: We propose to analyze the functional role of up-regulated MMP by systemic application of synthetic MMP inhibitors  

Investigators
Prof. Hans-Peter Marti

Sponsor
Swiss National Science Foundation, NRP 46 (Implants and Transplants), Project no. 101082