Blocking the CC chemokine receptor 5 pathway by antisense peptide nucleic acid prolongs islet allograft survival

Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. The CC chemokine receptor 5 (CCR5) is the receptor for the proinflammatory chemokines and plays an important role in islet allograft rejection. Peptide nucleic acid (PNA) is a nucleic acid analog in which the sugar phosphate backbone of natural nucleic acid has been replaced by a synthetic peptide backbone. Studies indicate that PNA inhibits both transcription and translation of targeted genes. Fully major histocompatibility complex (MHC)-mismatched murine islet transplant models were used to test the in vivo effect of PNA CCR5 by targeting CCR5 in acute allograft rejection. PNA CCR5-treated recipients demonstrated significant prolongation (12.0 +/- 1.75 days) of functional allograft survival compared with saline (6.5 +/- 0.58 days)- or PNA mismatch-treated recipients (6.5 +/- 0.50 days). The PNA CCR5 blocked the expression of CCR5 in spleen CD3+ T cells. Lymphocytes from PNA CCR5-treated mice exhibited a reduced degree of proliferation comparable to that of saline- and PNA mismatch-treated mice. The present study indicated that PNA CCR5 has a substantial therapeutic effect to inhibit acute allograft rejection.