Abstract
Naïve T cells migrate only to lymphoid organs, while antigen-activated lymphocytes are able to home to nonlymphoid sites. Tissue tropism of activated T cells is largely determined by the location of the secondary lymphoid organs where they first encounter the activating antigen. To determine if the antigen-presenting cells in secondary lymphoid organs influence the ability of activated T cells to home to different sites, scientists investigated the effect of dendritic cells from various sites on the homing behavior of activated T cells. Dendritic cell populations from Peyer's patches, spleen, and peripheral lymph nodes were expanded in vivo with Flt-3 ligand and used to present antigen to naïve T cells in vitro, then the ability of these activated T cells to home to different non-lymphoid sites was tested. Dendritic cells from all sites were able to activate T cells effectively, but only cells from Peyer's patches were able to cause T cells to localize in the small intestine. Localization to the small intestine was associated with increased T cell expression of gut-specific traffic molecules, including the integrin α4β7 and a receptor for a gut-associated chemokine. It is thus clear that dendritic cells can confer homing specificity on T cells; however, the mechanism by which this specificity is conferred is not known.
Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH: Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424:88–93, 2003
Pre-trans splicing molecules (PTMs) are RNA species that base-pair with target mRNAs, thus promoting spliceosome-mediated RNA repair. This mechanism of RNA repair has been shown to be effective in correcting the effects of some mutations in cultured cells. Investigators recently applied this approach to treatment of hemophilia A in mice resulting from a specific genetic change in exon 16 of the factor VII. The PTM was delivered to mice as plasmid DNA injected into the portal vein or as recombinant adenovirus administered intravenously. In both cases, sufficient functional factor VIII was produced to correct the hemophilia. Because only small regions of genes are targeted and only small segments of the gene must be delivered to cells in this technique of gene therapy, it is likely to prove especially useful for producing functional copies of proteins encoded by very large genes. Furthermore, the level and localization of gene expression continue to be determined by the endogenous promoter of the gene.
Chao H, Mansfield SG, Bartel RC, Hiriyanna S, Mitchell LG, Garcia-Blanco MA, Walsh CE: Phenotype correction of hemophilia A mice by spliceosome-mediated RNA transsplicing. Nat Med 9:1015–1019
Anthrax is now of considerable interest as a bioterrorism agent. Anthrax acquired by inhalation is particularly deadly, resulting in almost 100% mortality if untreated. Investigators in search of a readily available animal model for inhalation anthrax investigated the pathology of the disease in cynomolgus monkeys. Following inhalation of at least 4.56 × 104 aerosolized spores of Bacillus anthracis, all monkeys died within 10 days. The most consistently observed findings at necropsy were mild splenomegaly, mild enlargement of thoracic lymph nodes, and hemorrhage and edema in a variety of tissues. Microscopic lesions included the presence of rod-shaped bacteria in many tissues and evidence of lymphocytolysis (tingible body macrophages and karyorrhectic debris) in lymphoid tissues. Based on these findings, it appears that cynomolgus monkeys are a satisfactory nonhuman primate model for inhalation anthrax. Cynomolgus monkeys are more readily available than the rhesus monkeys commonly used in anthrax studies.
Vasconcelos D, Barnewall R, Babin M, Hunt R, Estep J, Nielsen C, Carnes R, Carney J: Pathology of inhalation anthrax in cynomolgus monkeys (Macaca fascicularis). Lab Invest 83:1201–1209, 2003
The deposition of extracellular matrix material in the interstitium of fibrotic kidneys is due to the activation of myofibroblasts. Recent investigations of the factors that regulate myofibroblast activation demonstrated that transforming growth factor-β (TGF-β) stimulated the synthesis of smooth muscle actin, a hallmark of activated myofibroblasts, in vitro and that hepatocyte growth factor (HGF) abrogated this effect. HGF appeared to exert its effect by preventing TGF-β-stimulated translocation of the Smad-2/3 signaling molecule to the nucleus. In an in vivo model of kidney fibrosis in rats, HGF also prevented nuclear translocation of Smad-2/3. Thus, HGF may have potential as a therapeutic agent for blocking the development of interstitial fibrosis in the kidney.
Yang J, Dai C, Liu Y: Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction. Am J Pathol 163:621–632, 2003
It has been postulated that oxidative damage to the brain contributes to impairment of learning and memory during aging and that dietary or pharmaceutical anti-oxidants might provide protection from these alterations. Recent studies by investigators in the United States provided strong support for the role of oxidative stress in age-related cognitive impairment. They showed that, in C57BL/6 mice, there was a dramatic loss in learning ability and memory between 8 and 11 months of age. This decrement in cognitive function was associated with marked increases in markers of oxidative stress in the brain, including lipid peroxidation and protein and nucleic acid oxidation. Further, these investigators were able to reverse the cognitive changes and the oxidative changes in the brain almost completely by chronically administering recently developed superoxide dismutase/catalase mimetics. Thus, there was a strong relationship between oxidative damage to the brain and cognitive impairment, and it was possible to prevent cognitive changes by preventing oxidative stress.
Liu R, Liu IY, Bi X, Thompson RF, Doctrow SR, Malfroy B, Baudry M: Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics. Proc Natl Acad Sci U S A. 100:8526–8531, 2003