SYNERGISTIC EFFECT OF LOW MOLECULAR WEIGHT HYALURONIC ACID (LMWHA) AND CYCLOSPORINE A (CsA) IN PROLONGATION OF RAT KIDNEY ALLOGRAFT SURVIVAL:

220 Lymphocyte activation and infiltration into a transplanted organ is an integral component of the rejection process. Graft infiltration of lymphocytes requires adhesion of leukocytes to the endothelium, diapedesis and transmigration. One of several proteins involved in this process is CD44 which is known to interact with endothelial hyaluran (HA). HA is a large polysaccharide found in body fluids and extracellular matrix. Besides CD44, other proteins have been shown to interact with HA, in particular RHAMM (receptor for HA modified motility) and IHABP (intracellular hyaluronic acid binding protein). Blockade of cell-matrix and cell-cell interactions have been used extensively for modulation of immune responses and graft rejection. Based on these observations, we evaluated the effects of blocking protein-HA interactions in a transplantation model. We used a low molecular weight hyaluronic acid formulation (LMWHA) for the treatment of Wistar Furth (WFu, RT1u) rat recipients (n=8/group) of Buffalo (BUF, RT1b) renal allografts. Recipients were treated intraperitoneally with LMWHA at the indicated doses for 5 days and/or orally with CsA at 1 mg/kg/day for 14 days postoperatively. (Table)TableLMWHA monotherapy prolonged renal allograft survival significantly, but only for a few days. In combination with low dose cyclosporine a prolongation of graft survival of up to 40 days was observed. Thirty three percent (33%) of animals receiving LMWHA (>0.25 mg/kg) and CsA (1 mg/kg) survived for more than 90 days. Our results demonstrate the immunomodulatory effects of hyaluronic acid in a renal allograft model. Further definition of the underlying mechanism may provide rational for the development of novel, non-toxic, non-immunogenic immunotherapies.