A Soluble BAFF Antagonist, BR3-Fc, Decreases Peripheral Blood B Cells and Lymphoid Tissue Marginal Zone and Follicular B Cells in Cynomolgus Monkeys
2006; Elsevier BV; Volume: 168; Issue: 2 Linguagem: Inglês
10.2353/ajpath.2006.050600
ISSN1525-2191
AutoresYulia Vugmeyster, Dhaya Seshasayee, Wesley Chang, Anahid Storn, Kathy Howell, Susan Sa, Tenea Nelson, Flavius Martin, Iqbal S. Grewal, Ellen Gilkerson, Ben Wu, Jeff Thompson, Barbara Ehrenfels, Ren Song, An Song, Thomas Gelzleichter, Dimitry M. Danilenko,
Tópico(s)Immunotherapy and Immune Responses
ResumoBAFF (also known as BLyS), a member of the tumor necrosis factor superfamily, plays a critical role in the maturation and development of B cells. BAFF has three receptors on B cells, the most crucial of which is BR3. In this study, we demonstrate the biological outcome of BAFF blockade in cynomolgus monkeys using a soluble fusion protein consisting of human BR3 and human IgG1 Fc. In vitro, BR3-Fc blocked BAFF-mediated survival and proliferation of cynomolgus monkey B cells. Weekly treatment of cynomolgus monkeys with BR3-Fc for 13 to 18 weeks resulted in significant B-cell reduction in the peripheral blood and in lymphoid organs. CD21(high) B cells in lymphoid tissues, a subset analogous to human marginal zone B cells, expressed nearly twofold higher BR3 levels than did CD21(med) B cells. Lymphoid tissue flow cytometric analysis showed that BR3-Fc reduced this CD21(high) B-cell subset to a greater extent than it reduced CD21(med) B cells. Dual-label immunohistochemistry and morphometric image analysis supported these results by demonstrating that BR3-Fc reduced a significant proportion of the B cells within the splenic inner and outer marginal zones. These findings should prove very useful in guiding the desired therapeutic use of BR3-Fc for autoimmune diseases in the clinic.
Referência(s)