RATIONALE:We and others have previously demonstrated that SLIT can effectively desensitize peanut allergic children, albeit its molecular mechanism(s) is not elucidated. We hypothesized that SLIT acts, in part, by regulating transcription factors and interleukins that are critical to lymphocyte functions and allergic responses. METHODS: Peanut-allergic subjects (1.5-10 years old) were SLITtreated, with a brief escalating dose phase, and then maintained with a dose of 2 mg daily for 3 or 5 years. Subjects then were challenged with peanut, and clinically defined as non-sustained unresponsiveness (non-SU) or sustained unresponsiveness (SU). PBMC from the SLIT-treated subjects were contemporaneously obtained, cultured with the individual's own plasma; and their cryopreserved mRNA was RT-PCR analyzed. RESULTS: The abundance of mRNA for Foxp3, Blimp1, and T-bet in PBMC cultures derived from SU subjects (N55), who underwent 3 years of SLIT-treatment, was increased by ;500% (p<0.05), ;320% (p<0.05), and ;80% (p<0.05), respectively, as compared to their non-SU counterparts (N54). In PBMC from SU subjects (N54) treated for 5 years, ZNF90 mRNA abundance became moderately increased, being ;150% (p<0.05) of that in non-SU cultures (N59). However, the expression of GATA3 and Bcl-6 did not change. In contrast, IL-5 and IL-13 mRNA abundance was reduced in PBMC of SU subjects treated for 3 years, and further reduced and became statistically significant 5 years after SLIT-treatment. CONCLUSIONS: Peanut SLIT treatment up-regulates the expression of the transcription factors Foxp3, Blimp1, T-bet, and ZNF90, while downregulating IL-5 and IL-13, suggesting that these genes play an important role in SLIT-induced peanut sustained unresponsiveness.