Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiencies in B7:CD28 costimulation are considered to be one of the major causes of the failure to generate a tumor-specific immune response. Up-regulating the expression of the B7 molecules on malignant B cells has been shown to stimulate cytotoxic T cells. Plasma cells from patients with myeloma express a tumor-specific idiotype but lack CD80 (B7-1) and have a variable expression of CD86 (B7-2). This study has identified the incidence and clinical significance of high CD86 expression on plasma cells at diagnosis and studied the ability of trimeric human CD40 ligand (huCD40LT) to up-regulate the expression of the B7 family on malignant plasma cells. CD86 expression on plasma cells was increased in 54% of the patients studied at diagnosis (n = 35) and was associated with a significantly shorter survival (median, 28 versus 57 months; chi(2) = 4.6; P =.03) and a higher tumor load (patients with more than 50% bone marrow plasma cells, 47% versus 6%; chi(2) = 7.2; P =.005). CD86 expression was highest on immature and primitive plasma cells (CD38(++), CD45(+)) of both patients and controls and was associated with a CD40(+), CD20(+), CD19(-), CD138(+) phenotype. The shortened survival was associated with high CD86 only on mature (CD38(++), CD45(-)) plasma cells (chi(2) = 7.6; P =.006). There was no significant correlation between high CD86 and other known prognostic markers, including serum beta(2)-microglobulin, serum thymidine kinase, and labeling index. The addition of huCD40LT to short-term cultures up-regulated both CD80 and CD86 expression on B cells (CD19(+)) and CD80 on plasma cells (CD38(++)), but did not up-regulate CD86 expression on plasma cells. Thus, B7-2-positive myeloma consists of a subgroup of patients with a relatively poor prognosis, and CD40LT may be useful in immunotherapy protocols because it up-regulates CD80 expression on malignant plasma cells without inducing B7-2-positive myeloma. (Blood. 2000;96:1274-1279)
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PMID:B7-2-positive myeloma: incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy. 1094 68

The herpes simplex virus thymidine kinase (HSV-tk) gene conferring ganciclovir (GCV)-specific sensitivity to transduced cells might control Graft-versus-Leukemia (GvL)/Graft-versus-Host Disease (GvHD). Human T lymphocytes were engineered with an LSN-tk retroviral vector encoding tk and neomycin resistance (NeoR) genes. A total of 80 x 10(6) tk(+) lymphocytes were injected intraperitoneally in NOD-SCID mice. Engraftment was evaluated by human CD45(+)/CD3(+) cytofluorimetric analysis and NeoR-based polymerase chain reaction (PCR) on peripheral blood, bone marrow, liver, thymus, and spleen on day +5. After 14 days, GCV (10 mg/kg daily) cytofluorimetric analysis and PCR were repeated (day +19). Immunohistological studies with anti-CD3 monoclonal antibody followed by alkaline phosphatase and monoclonal anti-alkaline phosphatase staining were performed on spleen and liver at the same time points. Human CD45(+)/CD3(+) cells were engrafted in all tissues on day +5 according to cytofluorimetry, immunohistology, and PCR. Lymphocytes "homed" to the white pulp T-cell area and to the red pulp; liver localization is prevalently at the periportal area. After GCV (day +19), cytofluorimetry and immunohistology showed very few CD3(+) cells. PCR identified the transgene in 22% tissue samples (positive only in thymus and spleen). GvHD did not occur in any animal. These data demonstrate elevated doses of human-transduced CD3(+) cells engraft in NOD/SCID mice; after GCV, very few CD3(+) cells can be detected and those that escape treatment can be found in the thymus and in the spleen on day +19. Lack of full response to GCV may account for cases of GvHD in patients receiving tk-transduced T lymphocytes.
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PMID:Homing and survival of thymidine kinase-transduced human T cells in NOD/SCID mice. 1218 25

The type I collagen promoter has been used to develop transgenic constructs that are able to mark different stages of osteoblastic differentiation. The pOBCol3.6 promoter is active in early mesenchymal progenitors, including preosteoblasts and osteoblasts, while the pOBCol2.3 promoter is more restricted, showing expression in mature osteoblasts and osteocytes. Transgenic mouse lines have been created that express various GFP reporters under the control of both promoters. These transgenic mice permit the tracking of osteoblastic lineage progression in vitro. They also represent a system to test lineage progression in vivo after the transplantation of progenitors. A parabiosis system was used in which pOBCol3.6GFP transgenic mice were surgically joined with mice bearing a Col2.3DeltaTK transgene. The Col2.3DeltaTK transgenic mouse bears a herpes thymidine kinase gene driven by the pOBCol2.3 promoter, and upon treatment with gancyclovir (GCV) displays extensive destruction of the bone lining cells. After a common circulation was established, parabiotic pairs were treated with GCV for 15 days. Histological analysis of their bones showed the clear presence of GFP positive cells in the Col2.3DeltaTK parabionts, around trabecular bone and on the endosteal and periosteal surfaces. Stromal cell cultures from these Col2.3DeltaTK parabionts did not display mineralized colonies coexpressing GFP. In contrast, scattered GFP positive clusters that contained large cells with morphology similar to osteoclast like cells (OCLs) were observed. These cells were also TRAP positive. They were readily detected in Col2.3DeltaTK mice treated with GCV and transplanted with purified hematopoietic stem cells (HSCs) isolated from pOBCol3.6GFP mice. OCLs were also generated in vitro from osteoclast progenitor cells obtained from pOBCol3.6GFP mice that were defined by the B220- CD3- CD11b- c-fms+ phenotype. Molecular analysis showed that OCLs did not express type I collagen indicating that the Col3.6 promoter contains elements that are active during osteoclastogenesis and are not strictly related to collagen transcription. In summary, we demonstrate that pOBCol3.6 unexpectedly directs the expression of transgenes in the osteoclast lineage and this effect must be considered when utilizing this promoter to study of mesenchymal progenitor cells.
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PMID:The 3.6 kb DNA fragment from the rat Col1a1 gene promoter drives the expression of genes in both osteoblast and osteoclast lineage cells. 1737 54