Antibodies can be mediators of important biological changes when bound to living cells. We seek to modulate immunity by engaging receptors on cells that regulate the immune system. These studies address the mechanisms underlying the potentiation of the immune response by a novel antibody, sHIgM12, which binds to B7-DC, a B7 family member expressed on dendritic cells (DC). Administration of the antibody in vivo or in vitro potentiates antigen specific responses by T cells. A strong anti-tumor response to B16 melanoma is seen in animals receiving antibody. The antibody does not bind tumor cells or lymphocytes, suggesting that potentiation of the immune response is mediated by physiological changes induced in the bound DC. We have accumulated lines of evidence demonstrating that cross-linking B7-DC on DC transduces a signal activating NF-kappaB and up-regulating expression of immune modulating cytokine IL-12. B7-DC is known as a ligand for receptors on T cells and not as a receptor mediating intracellular signals. Our finding simply that this molecule provides for two-way communication between DC and their environment. Mechanistic issues to be addressed include identification of the molecules expressed by DC that mediate the transduction of signals into the cells, the nature of intracellular signals in DC induced by the antibody, and the influence of the antibody on gene expression, with particular emphasis on chemokine receptors and cytokines. The intercellular interaction of DC with T cells that become activated in vivo and in culture will also be explored with attention to the role of B7-DC in upregulating the ability of antibody treated DC to activate na?ve T cells. Among these functions are those associated with cross-presentation of exogenous antigen by the class I pathway. The requirements for intercellular contact and cytokine release will also be investigated. Our intention is to discern how this antibody functions as an immune potentiator and to glean from these studies approaches to enhance immunity in vivo, while obtaining insight into natural B7-DC functions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096859-03
Application #
6922007
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
2003-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$255,500
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Xu, Xiaohua; Warrington, Arthur E; Bieber, Allan J et al. (2011) Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network. CNS Drugs 25:555-73
Warrington, Arthur E; Rodriguez, Moses (2010) Method of identifying natural antibodies for remyelination. J Clin Immunol 30 Suppl 1:S50-5
Arneson, Laura N; Upshaw, Jadee L; Howe, Charles L et al. (2010) Retraction: TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. J Immunol 184:6557
Rodriguez, Moses; Warrington, Arthur E; Pease, Larry R (2009) Invited Article: Human natural autoantibodies in the treatment of neurologic disease. Neurology 72:1269-76
Wright, Brent R; Warrington, Arthur E; Edberg, Dale D et al. (2009) Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies. Arch Neurol 66:1456-9
Radhakrishnan, Suresh; Arneson, Laura N; Upshaw, Jadee L et al. (2008) TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. J Immunol 181:7863-72
Radhakrishnan, Suresh; Wiehagen, Karla R; Pulko, Vesna et al. (2007) Induction of a Th1 response from Th2-polarized T cells by activated dendritic cells: dependence on TCR:peptide-MHC interaction, ICAM-1, IL-12, and IFN-gamma. J Immunol 178:3583-92
Blocki, Frank A; Radhakrishnan, Suresh; Van Keulen, Virginia P et al. (2006) Induction of a gene expression program in dendritic cells with a cross-linking IgM antibody to the co-stimulatory molecule B7-DC. FASEB J 20:2408-10
Van Keulen, V P; Ciric, B; Radhakrishnan, S et al. (2006) Immunomodulation using the recombinant monoclonal human B7-DC cross-linking antibody rHIgM12. Clin Exp Immunol 143:314-21
Radhakrishnan, Suresh; Celis, Esteban; Pease, Larry R (2005) B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells. Proc Natl Acad Sci U S A 102:11438-43