BACKGROUND: In the past decade, regenerative medicine and cell‐based therapies have emerged as new science and technology, with the main goal of repairing, replacing, or regenerating new tissues. A critical issue in this field is the high polymorphism of HLA, which compromises immune acceptance. The lentivirus‐mediated delivery of short‐hairpin RNAs (shRNAs) has proved to be an efficient method to inhibit the translation of a specific gene.

STUDY DESIGN AND METHODS: A lentiviral‐based vector system was used for drug‐inducible expression of shRNA sequences that target either β2‐microglobulin (β2m) or HLA heavy‐chain transcripts.

RESULTS: The transduction of inducible RNA interference cassettes containing the sequences for shRNAs targeting β2m or HLA heavy chain suppressed HLA class I expression by up to 90 percent in HeLa and B‐lymphocyte cell lines as well as in peripheral blood monocytes. The expression of HLA class I antigens was fully restored in these cells after the drug had been discontinued. It was demonstrated that HLA class I knockdown was effective in preventing antibody‐mediated cell lysis and CD8+ T‐cell response. The residual HLA expression in HLA‐silenced cells may provide sufficient protection against natural killer cell–mediated lysis.

CONCLUSIONS: These data demonstrate the feasibility of controlling HLA expression by genetically modifying cell‐based therapeutics to overcome the limitations of immune rejection, bringing cellular therapies closer to reality.