Publications by authors named "Zoran Kurepa"

2 Publications

  • Page 1 of 1

Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus.

J Clin Invest 2007 Aug;117(8):2186-96

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8884, USA.

Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-kappaB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene-dose-dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit.
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http://dx.doi.org/10.1172/JCI30398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1913486PMC
August 2007

Memory phenotype of CD8+ T cells in MHC class Ia-deficient mice.

J Immunol 2003 Jun;170(11):5414-20

Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

B6.K(b-)D(b-) mice are devoid of class Ia but express normal levels of class Ib molecules. They have low levels of CD8 T cells in both the thymus as well as peripheral T cell compartments. Although the percentage of splenic CD8 alpha alpha T cells is increased in these animals, approximately 90% of CD8 T cells are CD8 alpha beta. In contrast to B6 animals, most of the CD8 T cells from these mice have a memory phenotype (CD44(high)CD122(high) CD62L(low)) including both CD8 alpha beta and CD8 alpha alpha subsets. In the thymus of B6.K(b-)D(b-) animals, there is a decrease in the percentage of SP CD8 T cells, although most are CD44(low), similar to that seen in B6 mice. The spleens from day 1-old B6 and B6.K(b-)D(b-) mice have a relatively high proportion of CD44(high)CD62L(low) CD8 T cells. However, by day 28 most CD8 T cells in B6 mice have a naive phenotype while in B6.K(b-)D(b-) mice the memory phenotype remains. Unlike CD44(high) cells that are found in B6 animals, most CD44(high) cells from B6.K(b-)D(b-) mice do not secrete IFN-gamma rapidly upon activation. The paucity of CD8 T cells in B6.K(b-)D(b-) mice might be due in part to their inability to undergo homeostatic expansion. Consistent with this, we found that CD8 T cells from these animals expand poorly in X-irradiated syngeneic hosts compared with B6 CD8 T cells that respond to class Ia Ags. We examined homeostatic expansion of B6 CD8 T cells in single as well as double class Ia knockout mice and were able to estimate the fraction of cells reactive against class Ia vs class Ib molecules.
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http://dx.doi.org/10.4049/jimmunol.170.11.5414DOI Listing
June 2003