Immunomodulatory functions of hyaluronate in the LEW-to-F344 model of chronic cardiac allograft rejection

Background. CD44 is an important leukocyte cell surface glycoprotein with d iverse functions including cell adhesion, homing, migration, and activation . Methods. Because administration of the principal ligand of CD44, hyaluronat e (HA), in soluble form, can inhibit CD44-HA interaction, we tested the eff ects of HA in vivo in an established model of chronic allograft rejection. Control F344 recipients of LEW hearts received either no treatment or low-d ose cyclosporine (CsA) for 30 days from the day of transplantation. Experim ental animals received 30 days of CsA in combination with 30 or 90 days of low molecular weight HA (LMW-HA). Results. CsA therapy alone resulted in approximately 40% long-term (>100 da ys) graft survival, whereas CsA + LMW-HA (30-day and 90-day protocols) sign ificantly increased long-term graft survival to 60% and 92%, respectively, Light microscopy and immunohistology of CsA-treated and CsA + LMW-HA-treate d grafts harvested at day 30 after transplantation demonstrated that LMW-HA + CsA therapy decreased mononuclear cell infiltration and afforded better preservation of myocardial architecture. In addition, LMW-HA + CsA-treated grafts exhibited decreased expression of interferon-gamma and the growth fa ctors transforming growth factor-p, platelet-derived growth factor, and fib rogenic growth factor-p, Long-term surviving grafts were assessed for arter iosclerosis, the sine qua non of chronic rejection in this model, Using a s tandardized scoring system, significantly less arteriosclerosis was seen in grafts from LMW-HA + CsA treated animals at 120 days after transplantation compared with CsA alone-treated grafts. This difference was not significan t, however, in grafts harvested at >150 days. Conclusion, This is the first report indicating that CD44-HA interactions p lay an important role in chronic allograft rejection.