Chronic rejection (CR) of solid organ transplants, a process involving the insidious development of vascular stenosis and organ fibrosis, is one of the major impediments to successful long-term graft survival. Thus, given that the half life of a cadeveric kidney transplant is eight years, children receiving transplants will likely require multiple organ replacements, a predicament that carries a large morbidity, mortality and hospital costs. Development of interventions to lengthen graft survival requires study of the mechanisms contributing to the development of CR. There are striking similarities between the vascular lesions of CR and the neointimal formation observed in atherosclerosis and restenosis after balloon angioplasty. In particular, inflammatory cell infiltration, disruption of the internal elastic lamina, proliferation and migration of smooth muscle cells into the intimal space followed by elaboration of extracellular matrix result in a narrowing of the lumen of the affected artery. Hyaluronan, a non-sulfated glycosaminoglycan acting through cell-associated receptors, such as the receptor for HA-mediated motility (RHAMM), has been implicated in inflammatory responses to injury, as well as in smooth muscle cell proliferation and migration. In the current project, using immunostaining, immunoblots, in situ hybridization and northern blots, we intend to study the expression of RHAMM and HA during the development of intimal hyperplasia after aortic allograft transplantation in rats, an established model of CR. The quantitation of this receptor and its ligand may be useful as early markers for the arteriopathy observed after transplantation. Sequestration of HA by exogenously administered agents would competitively inhibit this glycosaminoglycan's interaction with its receptors. We therefore propose to generate a fusion protein of RHAMM (as an HA-binding protein) with the hinge, CH2 and CH3 domain of a murine Fcy2a chain that has been mutated to prevent Fc receptor and complement binding (RHAMM-Ig). Constructs containing such Ig moieties resist degradation and removal from the bloodstream, resulting in prolonged serum concentrations in vivo. We will examine the in vitro effects of such a construct on macrophage locomotion and smooth muscle cell migration and proliferation, and determine its pharmacokinetics after intravenous administration to rats. Knowledge of the temporal and spatial expression of RHAMM and HA, and the pharmacokinetics of RHAMMIg will guide the treatment regimen in order to limit the CR observed in the model described. Success of this novel therapy would encourage us to examine its possible use in human disease.
| Grimm, Paul C; Nickerson, Peter; Gough, Jim et al. (2003) Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function. J Am Soc Nephrol 14:1662-8 |
| Grimm, P C; Nickerson, P; Jeffery, J et al. (2001) Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N Engl J Med 345:93-7 |
| Grimm, P C; McKenna, R; Nickerson, P et al. (1999) Clinical rejection is distinguished from subclinical rejection by increased infiltration by a population of activated macrophages. J Am Soc Nephrol 10:1582-9 |
