Immunomodulatory functions of low-molecular weight hyaluronate in an acute rat renal allograft rejection model.
Low molecular weight hyaluronate (LMW-HA) blocks interactions between T lymphocyte 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) rats were bilaterally nephrectomized and received an orthotopic, fully MHC-mismatched, Wistar-Furth (WF) kidney transplant. Animals received either no treatment, 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 treatment, CsA monotherapy, or HA monotherapy, animals rejected their allografts at a median of 15, 13, and 7.5 d, respectively (P = NS). In contrast, combined 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-treated grafts also demonstrated better preservation of renal function at day 30 (serum creatinine level, 1.38+/-0.8 mg/dl), compared with surviving animals treated with CsA alone (2.9+/-0.55 mg/dl, P<0.05). Histologic graft analysis of CsA/LMW-HA-treated animals at day 7 after transplantation showed minimal rejection and leukocyte infiltration, compared with all other groups. Intragraft gene expression analysis, using semiquantitative reverse transcription-PCR, at the same time point showed reductions of CD4, CD8, and interferon-gamma transcript levels in the combined-treatment group. This is the first study demonstrating the immunomodulatory functions of LMW-HA in vivo in the setting of organ transplantation. Defining the exact mechanisms that underlie this immunomodulation may provide the rationale to develop novel strategies for use in clinical transplantation.
Knoflach
A
A
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Azuma
H
H
Magee
C
C
Denton
M
M
Murphy
B
B
Iyengar
A
A
Buelow
R
R
Sayegh
M H
MH
D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015870:Gene Expression / Q000502:physiology; D006084:Graft Rejection / Q000503:physiopathology* / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000494:pharmacology*; D007107:Immune System / Q000187:drug effects* / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008970:Molecular Weight; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D013997:Time Factors
D000276:Adjuvants, Immunologic; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D006820:Hyaluronic Acid