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Molecular Analysis of Regulation of Macrophage Fcγ Receptor Function: Implications for Tumor Immunotherapy

Mehta, Payal
http://rave.ohiolink.edu/etdc/view?acc_num=osu1313606589

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Therapeutic monoclonal antibodies (MAB) are used as a part of induction as well as salvage regimen for treatments of various malignancies. Despite a large number of MAB available, the efficacy of tumor immunotherapy remains suboptimal. Fcγ Receptor (FcγR), play a critical role in mediating cytotoxic effects of MAB. FcγR activation results in elimination of immune complexes (IC) and antibody-coated tumor targets via phagocytosis and antibody-dependent cell-mediated cytotoxicity (ADCC) respectively, generation of reactive oxygen and nitrogen species (ROS), and release of pro-inflammatory cytokines. These effector functions are tightly regulated by simultaneous engagement of activating and inhibitory FcγR as well as recruitment of downstream signaling kinases and phosphatases. A thorough understanding of the regulatory pathways that impede sustained and robust immune response is critical for designing MAB therapy with enhanced efficacy. For this study we have specifically examined the role of such regulatory pathways on FcγR-mediated functional responses and its influence on tumor immunotherapy. In the first part of the study, demonstrate that not all FcγR contribute equally to monocyte response against antibody-coated tumor targets. Further we show that FcγRI predominantly mediates ADCC and cytokine production but not FcγRIIa that preferentially associates with inositol phosphatase SHIP. In the second part of the study, we have identified a novel SHIP-interacting protein that negatively regulates FcγR function and in the last part of the study, we examined the regulation of FcγR expression and function by bacterial unmethylated CG containing DNA motif, CpG that activates TLR9 and further tested its role as an adjuvant for Rituximab therapy in B-CLL patients. Taken together, our finding have established novel ways by which FcγR-mediated signaling response are regulated in human monocytes. We have also demonstrated the importance of modulating these regulatory pathways specifically within the context of tumor immunotherapy. In future findings of this study may contribute to the design of better immunotherapeutic strategies.
Susheela Tridandapani, PhD (Advisor)
Clay Marsh, MD (Other)
Mark Wewers, MD (Other)
Arthur Strauch, PhD (Other)
184 p.
Immunology
Fc&947; R, tumor immunotherapy, monoclonal antibody, SHIP

Recommended Citations

Citations

  • Mehta, P. (2011). Molecular Analysis of Regulation of Macrophage Fcγ Receptor Function: Implications for Tumor Immunotherapy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313606589

    APA Style (7th edition)

  • Mehta, Payal. Molecular Analysis of Regulation of Macrophage Fcγ Receptor Function: Implications for Tumor Immunotherapy. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1313606589.

    MLA Style (8th edition)

  • Mehta, Payal. "Molecular Analysis of Regulation of Macrophage Fcγ Receptor Function: Implications for Tumor Immunotherapy." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313606589

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.