Neoplastic Transformation of T Lymphocytes through Transgenic Expression of a Virus Host Modification Protein

Virus host evasion genes are ready-made tools for gene manipulation and therapy. In this work we have assessed the impact in vivo of the evasion gene A238L of the African Swine Fever Virus, a gene which inhibits transcription mediated by both NF-κB and NFAT. The A238L gene has been selectively expressed in mouse T lymphocytes using tissue specific promoter, enhancer and locus control region sequences for CD2. The resulting two independently derived transgenic mice expressed the transgene and developed a metastasic, angiogenic and transplantable CD4(+)CD8(+)CD69(-) lymphoma. The CD4(+)CD8(+)CD69(-) cells also grew vigorously in vitro. The absence of CD69 from the tumour cells suggests that they were derived from T cells at a stage prior to positive selection. In contrast, transgenic mice similarly expressing a mutant A238L, solely inhibiting transcription mediated by NF-κB, were indistinguishable from wild type mice. Expression of Rag1, Rag2, TCRβ-V8.2, CD25, FoxP3, Bcl3, Bcl2 l14, Myc, IL-2, NFAT1 and Itk, by purified CD4(+)CD8(+)CD69(-) thymocytes from A238L transgenic mice was consistent with the phenotype. Similarly evaluated expression profiles of CD4(+)CD8(+) CD69(-) thymocytes from the mutant A238L transgenic mice were comparable to those of wild type mice. These features, together with the demonstration of (mono-)oligoclonality, suggest a transgene-NFAT-dependent transformation yielding a lymphoma with a phenotype reminiscent of some acute lymphoblastic lymphomas.

Intracellular survival of apicomplexan parasites and host cell modification

The intracellular stages of apicomplexan parasites are known to extensively modify their host cells to ensure their own survival. Recently, considerable progress has been made in understanding the molecular details of these parasite-dependent effects for Plasmodium-, Toxoplasma- and Theileria-infected cells. We have begun to understand how Plasmodium liver stage parasites protect their host hepatocytes from apoptosis during parasite development and how they induce an ordered cell death at the end of the liver stage. Toxoplasma parasites are also known to regulate host cell survival pathways and it has been convincingly demonstrated that they block host cell major histocompatibility complex (MHC)-dependent antigen presentation of parasite epitopes to avoid cell-mediated immune responses. Theileria parasites are the masters of host cell modulation because their presence immortalises the infected cell. It is now accepted that multiple pathways are activated to induce Theileria-dependent host cell transformation. Although it is now known that similar host cell pathways are affected by the different parasites, the outcome for the infected cell varies considerably. Improved imaging techniques and new methods to control expression of parasite and host cell proteins will help us to analyse the molecular details of parasite-dependent host cell modifications.

Tri-level study: modification. Task 1: final report on potential benefits of various improvements in vehicle systems in preventing accidents or reducing their severity. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Tri-level study: modification. Task 3: validity assessment of police-reported accident data. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Tri-level study: modification. Task 4: final report on the relationships between driver characteristics and accident causation.

National Highway Traffic Safety Administration, Washington, D.C.

Tri-level study: modification. Task 5: an examination of driver characteristics and collision producing errors of accident and traffic violation repeaters. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Tri-level study: modification. Task 6: a final report on supplemental causation assessments through hypothesis testing.

National Highway Traffic Safety Administration, Washington, D.C.

Study of the effects of applying federal motor vehicle safety standard 201 to light trucks and vans. Modification No. 2. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Study of the effects of applying federal motor vehicle safety standards 203 & 204 to light trucks and vans. Modification No. 3. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Toxicity reduction through chemical and biological modification of spent pulp bleaching liquors /

Mode of access: Internet.

Description of Cook's modification of the Bonelli-Hipp letter printing telegraph.

Mode of access: Internet.

Impact resistance of non-ferrous passenger car wheels - modification number two (2). Final report.

National Highway Traffic Safety Administration, Office of Crash Avoidance, Washington, D.C.

Technical report of construction on modification of Grand Coulee Feeder Canal /

"Work Performed in 1977 through 1981 Under Specifications No. DC-7292"