Abstract
To study the role of bronchus-associated lymphoid tissue (BALT) in respiratory immunity, investigators used mice lacking conventional lymphoid organs but reconstituted with bone marrow cells from normal mice. Chimeric and control mice were challenged intranasally with influenza virus, and the development of specific immunity to the virus and of induced BALT (iBALT) was evaluated. Even in the absence of normal lymphoid organs, chimeric mice generated robust CD8+ T-cell responses to the virus and isotype-switched, influenza-specific antibodies. Chimeric mice survived infection even better than wild-type mice. Generation of a protective immune response was associated with the development of iBALT, with distinct B-cell follicles and T-cell areas that supported B- and T-cell proliferation. Although constitutive BALT is located in the upper bronchi of some species, iBALT develops in perivascular and peribronchial areas in the lower lung. On the basis of these findings, it was concluded that iBALT is an inducible secondary lymphoid organ that supports the development of effective respiratory immune responses.
Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, Woodland DL, Lund FE, Randall TD: Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10:927–394, 2004
Japanese scientists have created mice with almost completely humanized livers. Urokinase-type plasminogen activator transgenic mice were crossed with SCID mice to yield immunodeficient mice, which undergo liver failure. Human hepatocytes were transplanted into the mice to repopulate the liver, and mice were treated with Futhan, a drug with anti-human complement activity. More than 90% of mice treated in this manner were successfully engrafted with human hepatocytes, and one-third of the animals had replacement indices of more than 70%. The transplanted human hepatocytes expressed human P-450 enzymes in a relatively normal manner, and these P-450s were induced appropriately when mice were treated with rifampicin and 3-methylcho-lanthrene. This may be a useful system for testing the response of human hepatocytes to pharmacologic agents in a humanized rodent model.
Tateno C, Yoshizane Y, Saito N, Kataoka M, Utoh R, Yamasaki C, Tachibana A, Soeno Y, Asahina K, Hino H, Asa-hara T, Yokoi T, Furukawa T, Yoshizato K: Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol 165:901–912, 2004
Veterinary scientists at the College of Veterinary Medicine at Texas A&M University have developed a microsatellite-based assay useful in forensic genetic investigations in dogs. Microsatellites are abundant, tandemly repeated 1–6 base pair genetic elements, which are evenly distributed throughout the genome. Microsatellites are highly polymorphic, that is, at each site, the number of repeats varies considerably among the individuals. Microsatellites are passed to offspring in a Mendelian manner. On the basis of these characteristics, microsatellite analysis can be used to identify individual members of a species and to determine parentage. For optimal ease of analysis, it is desirable to identify a small set of microsatellite markers that are highly polymorphic among individuals and that can be coamplified by the polymerase chain reaction from a minimal amount of starting material. The Texas investigators have developed a technique for the efficient coamplification of seven canine microsatellite markers that unequivocally identify individual canids, including dogs, wolves, and coyotes. This technique is so sensitive that it can identify sires of mixed litters of purebred dogs.
Clark LA, Famula TR, Murphy KE: Evaluation of a rapid single multiplex microsatellite-based assay for use in forensic genetic investigations in dogs. Am J Vet Res 65:1446–1450, 2004
Short interfering RNAs (siRNAs) are 21–25 nucleotide RNA molecules that mediate posttranscriptional gene silencing in mammalian cells by binding to target mRNA and stimulating its degradation. Recent studies reveal that si-RNAs can also mediate transcriptional gene silencing. Cloned siRNAs targeted to the CpG islands in the E-cadherin promoter were introduced into cultured human breast cell lines. These siRNAs induced DNA methylation of the E-cadherin promoter accompanied by histone methylation and decreased E-cadherin expression. This effect was specific for the targeted promoter and required the activity of DNA methyltransferases. Thus, siRNAs can specifically target mammalian genes to silence their expression both at the transcriptional and posttranscriptional levels and show considerable potential for gene therapy.
Kawasaki H, Taira K: Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 431:211–217, 2004
Dysregulated expression of the BCL6 gene, because of chromosomal rearrangement or mutation, is found in many human non-Hodgkin lymphomas. Transgenic mice that express BCL6 die in utero. Using a two-mouse model, investigators have now successfully constructed a transgenic mouse that constitutively expresses BCL6 in lymphocytes. The strategy was to cross a mouse engineered to express transgenes in B cells only in the absence of tetracycline (a “tet-off” mouse) with a mouse that had a BCL transgene under the control of a tetracycline-inhibitable promoter. In the presence of tetracycline, doubly transgenic mice did not express the transgene; in the absence of tetracycline, the BCL transgene was expressed only in lympocytes. These mice developed normally, and a few developed B- and T-cell lymphomas after a long latent period. However, the carcinogen N-ethyl-N-nitrosourea induced T-cell lymphomas in almost one-third of these animals. This is a promising system for studying the role of BCL6 in human lymphomas and highlights the fact that mutations in addition to changes in BCL6 may be required for the emergence of lymphoma.
Baron BW, Anatasia J, Montag A, Huo D, Baron RM, Karrison T, Thirman MJ, Subudhi SK, Chin RK, Felsher DW, Fu YX, McKeithan TW: The human BCL6 transgene promotes the development of lymphomas in the mouse. Proc Natl Acad Sci USA 101:14198–14203, 2004