Biomedical subjects

Dhaya Seshasayee

Publications and source records attributed to Dhaya Seshasayee.

6 recordsLinked to original sources

PubMed2006

A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys.

BAFF (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.

Animals↗

PubMed2004

A novel in vivo role for osteoprotegerin ligand in activation of monocyte effector function and inflammatory response.

Osteoprotegerin Ligand (OPGL) is a member of the tumor necrosis factor ligand superfamily and has been shown to be involved in interactions between T cells and dendritic cells. Its role in monocyte effector function, however, has not been defined. In the present study a role for OPGL in activating monocytes/macrophages has been characterized. OPGL was found to up-regulate receptor activator of NF-kappaB (RANK) receptor expression on monocytes, regulate their effector function by inducing cytokine and chemokine secretion, activate antigen presentation through up-regulation of co-stimulatory molecule expression, and promote survival. This activation is mediated through the MAPK pathway as evidenced by activation of p38 and p42/44 MAPK and up-regulation of BCL-XL protein levels. A physiological role for OPGL in monocyte activation and effector function was tested in a model of lipopolysaccharide-induced endotoxic shock. Administration of receptor activator of NF-kappaB (RANK)-Fc to block OPGL activity in vivo was able to protect mice from death induced by sepsis, indicating a hitherto undescribed role for OPGL in monocyte function and in mediating inflammatory response. This was further tested in an animal model of inflammation-mediated arthritis. Treatment with RANK-Fc significantly ameliorated disease development and attenuated bone destruction. Thus, our study strongly suggests that administration of receptor fusion proteins to specifically block OPGL activity in vivo may result in blocking development of monocyte/macrophage-mediated diseases.

Animals↗

PubMed2004

NTB-A, a new activating receptor in T cells that regulates autoimmune disease.

The CD28 co-stimulatory pathway is well established for T cell activation; however, results from CD28 -/- mice suggest the existence of additional co-stimulatory pathways. Here we report the further characterization of a new member of the CD2 superfamily, NTB-A, important in T cell co-stimulation. NTB-A is expressed on T cells, and its expression is up-regulated on activated cells. Triggering of NTB-A with monoclonal antibodies in the absence of CD28 signals leads to T cell proliferation and interferon-gamma secretion but not interleukin-4. Cross-linking of NTB-A also induces phosphorylation of NTB-A and the association of SAP (SLAM-associated protein), the protein absent in X-linked lymphoproliferative disease. T helper cells differentiated by cross-linking NTB-A and CD3 developed predominantly into Th1 cells not Th2 cells. In vivo blocking of NTB-A interactions with its ligands by using soluble NTB-A-Fc fusion protein inhibits B cell isotype switching to IgG2a and IgG3, commonly induced by Th1-type cytokines. Most important, treatment of mice with NTB-A-Fc delays the onset of antigen-induced experimental allergic encephalomyelitis in myelin basic protein-T cell receptor transgenic mice, suggesting a role in T cell-mediated autoimmune disease. Regulation of interferon-gamma secretion, and not interleukin-4 in vitro, as well as inhibition of Th1 cell-induced isotype switching and attenuation of experimental allergic encephalomyelitis indicate that NTB-A is important for Th1 responses. The observation that cross-linking of NTB-A induces T cell activation, expansion, and Th1-type cytokine production suggests NTB-A is a novel co-stimulatory receptor. The identification of NTB-A as a regulator of T cell response paves the way to provide novel therapeutic approaches for modulation of the immune response.

Animals↗

PubMed2004

APRIL-deficient mice have normal immune system development.

APRIL (a proliferation-inducing ligand) is a member of the tumor necrosis factor (TNF) superfamily. APRIL mRNA shows high levels of expression in tumors of different origin and a low level of expression in normal cells. APRIL shares two TNF receptor family members, TACI and BCMA, with another TNF homolog, BLyS/BAFF. BLyS is involved in regulation of B-cell activation and survival and also binds to a third receptor, BR3/BAFF-R, which is not shared with APRIL. Recombinant APRIL and BLyS induce accumulation of B cells in mice, while BLyS deficiency results in severe B-cell dysfunction. To investigate the physiological role of APRIL, we generated mice that are deficient in its encoding gene. APRIL(-/-) mice were viable and fertile and lacked any gross abnormality. Detailed histological analysis did not reveal any defects in major tissues and organs, including the primary and secondary immune organs. T- and B-cell development and in vitro function were normal as well, as were T-cell-dependent and -independent in vivo humoral responses to antigenic challenge. These data indicate that APRIL is dispensable in the mouse for proper development. Thus, BLyS may be capable of fulfilling APRIL's main functions.

Animals↗

PubMed2003

Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor.

BLys , a key cytokine that sustains B cell maturation and tolerance, binds three receptors: BR3, BCMA, and TACI. Results from knockout mice implicate a major functional role for BR3 and a redundant one for BCMA in B cell function. TACI's role is controversial based on defects in TI antibody responses accompanied by B cell hyperplasia in knockout mice. We have presently characterized a precise role for TACI in vivo. TACI(-/-) mice develop fatal autoimmune glomerulonephritis, proteinurea, and elevated levels of circulating autoantibodies. Treatment of B cells with TACI agonistic antibodies inhibits proliferation in vitro and activation of a chimeric receptor containing the TACI intracellular domain induces apoptosis. These results demonstrate the critical requirement for TACI in regulating B cell homeostasis.

Animals↗

PubMed2002

BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2.

The TNF-like ligand BAFF/BLyS is a potent survival factor for B cells. It binds three receptors: TACI, BCMA, and BR3. We show that BR3 signaling promotes processing of the transcription factor NF-kappaB2/p100 to p52. NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells. Furthermore, wild-type mice injected with BAFF-neutralizing BR3-Fc protein showed reduced basal NF-kappaB2 activation. BR3-Fc treatment of NZB/WF1 mice, which develop a fatal lupus-like syndrome, inhibited NF-kappaB2 processing and attenuated the disease process. Since inhibiting the BR3-BAFF interaction has therapeutic ramifications, the ligand binding interface of BR3 was investigated and found to reside within a 26 residue core domain. When stabilized within a structured beta-hairpin peptide, six of these residues were sufficient to confer binding to BAFF.

Amino Acid Sequence↗