U.S. Department of Defense
Date of this Version
2011
Abstract
Activation of the innate immune system by toll-like receptors (TLR) provides an early response to pathogens and shapes the subsequent antigen-specific adaptive immune response. Unmethylated cytosine-guanine dinucleotide (CpG)motifs present in bacterial DNA, but not vertebrate DNA, can be detected by Toll like receptor 9 (TLR9)—bearing DC and B cells resulting in a pro-inflammatory Th1 response. Synthetic oligodeoxynucleotides (ODN) expressing these CpG motifs exhibit similar in vivo biologic activity and have been shown to reduce disease severity for selected pathogens, to promote vaccine responses and to enhance anti-tumor responses (reviewed in Ref.). Conversely, suppressive DNA sequences have also been identified. TTAGGG elements in mammalian telomeric DNA and synthetic ODNs containing these motifs can inhibit pro-inflammatory and Th1 cytokine production and have been reported as beneficial in autoimmune conditions such as collagen-induced arthritis and lupus nephritis.
Microsatellite (MS) DNA is composed of short tandemly repeated DNA sequences widely distributed in the human genome. MS DNA has been used as a molecular marker for DNA fingerprinting analyses and alterations in MS DNA triplet repeats have been associated with several hereditary diseases, primarily neurological (reviewed in Ref.). Recently, ODNs with sequences based on MS DNA have been shown to exhibit inhibitory effects on the immune response. One of these MS DNA-mimicking ODNs with CCT repeats (compound SATO5f) was reported to down regulate TLR7/9- dependent interferon alpha (IFN-a) production raising the possibility that SATO5f and similar compounds may be beneficial in conditions where increased IFN-a has a pathogenic role e.g., lupus. Data supporting this idea are presented in the current issue where in the article by He et al., in vivo administration of SATO5f is effective in preventing lupus-like renal disease occurring in an induced model of murine lupus, the parent-into-F1 (p→F1) model of chronic graft-vs.-host disease (GVHD). Administration of SATO5f was administered twice weekly i.p. beginning at the time of first donor cell transfer and continued for 8– 10 weeks resulted in significant reduction of autoantibodies and ICGN severity compared to untreated chronic GVHD mice. An intermittent dosing scheme was also effective. This work not only supports the potential clinical application of a new class of immunomodulatory compounds in lupus but it also underscores the usefulness of animal models in screening for biologic agents with therapeutic potential.
Comments
Published in Clinical Immunology (2011) 140, 212–215; doi:10.1016/j.clim.2011.06.001