Immunomodulatory functions of low-molecular weight hyaluronate in an acuterat renal allograft rejection model

Low molecular weight hyaluronate (LMW-HA) blocks interactions between T lym phocyte CD44 and hyaluronate (HA), a heteropolysaccharide that is expressed on the surface of endothelial cells and ubiquitously in the extracellular matrix. This study was undertaken to assess the ability of LMW-HA to modify the course of experimental acute renal allograft rejection. Lewis (LEW) ra ts were bilaterally nephrectomized and received an orthotopic, fully MHC-mi smatched, Wistar-Furth (WF) kidney transplant. Animals received either no t reatment, low doses of cyclosporin A (CsA) on days 0 to 5, LMW-HA on days 0 to 5, or CsA plus LMW-HA on days 0 to 5 after transplantation. With no tre atment, CsA monotherapy, or HA monotherapy, animals rejected their allograf ts at a median of 15, 13, and 7.5 d, respectively (P = NS). In contrast, co mbined CsA plus LMW-HA therapy prevented acute rejection and significantly prolonged graft survival (P = 0.008) to a median of 49.0 d. CsA/LMW-HA-trea ted grafts also demonstrated better preservation of renal function at day 3 0 (serum creatinine level, 1.38 +/- 0.8 mg/dl), compared with surviving ani mals treated with CsA alone (2.9 +/- 0.55 mg/dl, P < 0.05). Histologic graf t analysis of CsA/LMW-HA-treated animals at day 7 after transplantation sho wed minimal rejection and leukocyte infiltration, compared with all other g roups. Intragraft gene expression analysis, using semiquantitative reverse transcription-PCR, at the same time point showed reductions of CD4, CD8, an d interferon-gamma transcript levels in the combined treatment group. This is the first study demonstrating the immunomodulatory functions of LMW-HA i n vivo in the setting of organ transplantation. Defining the exact mechanis ms that underlie this immunomodulation may provide the rationale to develop novel strategies for use in clinical transplantation.