Intravenous Administration of RNA Suppresses the Induction of Delayed-type Hypersensitivity (DTH) to Tumor-associated Antigens.

Abstract

Intravenous (iv) administration of protein antigens can induce relative tolerance to subsequent immunization with that antigen. We hypothesized that iv injection of RNA may also reduce cell-mediated immunity to antigens encoded by the RNA utilized. To test this hypothesis, we utilized the S1509a murine tumor system. CAF1 mice (H-2,a/d) were injected with I 00 g of total cellular RNA from the S1509a spindle cell tumor line (H-2a). Control animals were injected iv with saline. All mice were then immunized by subcutaneous injection of disrupted S1509a cells 3 times at 6-7 d intervals. One week after the last injection, syngeneic epidermal cells enriched for Langerhans cell content (eEC) by antibody and complement-mediated deletion of Thy-1-bearing cells were pulsed with a soluble extract of the S1509a cells as a source of tumor-associated antigens (TAA). eEC were then thoroughly washed and 7.5 x 105 injected into a hind footpad of each mouse. For negative controls, mice primed iv with RNA or saline alone prior to immunization were challenged with eEC not pulsed with TAA. Twenty-four hr footpad swelling was assessed as a measure of DTH. Mice given SI509a-derived RNA demonstrated a significantly smaller DTH response (p<0.001) compared to mice primed iv with saline. In a preliminary experiment, mice primed iv with unrelated RNA (derived from the NS cell line), S1509a RNA pretreated with RNase or saline pretreated with RNase prior to immunization failed to show a significantly inhibited DTH response compared to positive control mice primed iv with saline alone prior to immunization. These results demonstrate that iv administration of total cellular RNA from the S1509a tumor suppresses the induction of DTH to S1509a-derived TAA.