Abstract
Autologous T cells with anti-tumor specificity are a promising form of tumor therapy. However, generation of large numbers of highly specific and long-lived effector T cells is challenging. A group of collaborating scientists has demonstrated that they can transduce peripheral human T lymphocytes with a CD19-specific chimeric antigen receptor and expand these cells using CD19+ artificial antigen-presenting cells and interleukin 15, thus generating large numbers of CD19-specific cytotoxic T cells. When these cells were transplanted into SCID-Beige mice bearing a widely meta-static CD19+ human lymphoma, tumors in many of the mice regressed completely and the mice remained tumor-free for more than 300 days. This approach shows great promise for immunotherapy of a variety of tumors.
Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane C, King PD, Larson S, Weiss M, Riviere I, Sadelain M: Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nature Med 9:279–286, 2003
Because they direct long-term expression of exogenous genes in non-dividing tissues, recombinant adeno-associated virus (rAAV) vectors show promise in human gene therapy. Although these vectors integrate into the genome of cultured human cells in a site-specific manner, the form in which they persist in vivo is not known. Investigators used several approaches to look for rAAV integration in the genome of mouse muscle cells transduced in vivo with rAAV: generation and screening of a lambda phage library, a novel PCR assay, and digestion with an exonuclease that digests genomic but not episomal DNA. Junctions between rAAV vector DNA and genomic DNA were not identified and rAAV DNA was endonuclease-resistant. Based on the findings from these studies, it was concluded that rAAV is maintained primarily in an episomal state in vivo.
Schnepp BC, Clark KR, Klemanski DL, Pacak CA, Johnson PR: Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J Virol 77:3495–3504, 2003
Primary congenital glaucoma (PCG) is a severe but uncommon form of glaucoma in man often due to mutations in the gene encoding P450–1B1 (CYB1B1). Knockout mice deficient in CYB1B1 develop histologically evident abnormalities of the iridocorneal drainage angle structures. Scientists searched for strain-specific modifiers that might influence disease development in these mice and discovered that tyrosinase-deficient albino mice developed more severe angle abnormalities than pigmented mice. Dietary supplementation of mothers and their offspring with the tyrosinase product L-dopa markedly reduced the angle dysgenesis in albino P450–1B1 knockout mice. These findings suggest that L-dopa plays a role in angle development and that it may also be effective in therapy for PCG.
Libby RT, Smith RS, Savinova OV, Zabaleta A, Martin JE, Gonzalez FJ, John SWM: Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 299:1578–1581, 2003
A group of international investigators sought to determine if inbreeding affected disease susceptibility in California sea lions. For 371 stranded sea lions undergoing rehabilitation, age, disease condition (trauma, carcinoma, bacterial infection, helminth infection, unspecified disease state) and internal relatedness (based on DNA microsatellite analysis) were determined. Their findings showed that susceptibility to all disease states except trauma were related to inbreeding, with carcinoma susceptibility being the most highly related. Furthermore, more inbred animals had a wider range of helminth infections than less inbred animals and took longer to recover from nonspecific disease. Thus, inbreeding appears to have an adverse effect on individual fitness in sea lions.
Acevedo-Whitehouse K, Gulland F, Grieg D, Amos W: Disease susceptibility in California sea lions. Nature 422:35, 2003
RAGE is a member of the immunoglobulin superfamily of receptors expressed on the surface of a variety of cell types, including phagocytes, lymphocytes, and vascular endothelial cells. Endogenous ligands include S100-calgranulin family members and amphoterin. RAGE is highly expressed in lesions of multiple sclerosis and murine experimental autoimmune encephalomyelitis (EAE). A RAGE inhibitor given intraperitoneally protected mice from EAE induced by immunization with myelin basic protein, and treating mice with RAGE-specific blocking antibodies prevented EAE following injection of encephalitogenic T cells. Furthermore, T-cell receptor transgenic mice that develop EAE spontaneously were protected from disease by RAGE blockade, and transgenic mice that overexpressed dominant-negative RAGE in CD4+ T cells were resistant to induction of EAE by immunization with myelin basic protein. It thus appears that RAGE may play an important role in the pathogenesis of multiple sclerosis.
Yan SS, Wu ZY, Zhang HP, Furtado G, Chen X, Yan SF, Schmidt AM, Brown C, Stern A, LaFaillle J, Chess L, Stern DM, Jiang H: Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nature Med 9:287–293, 2003