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THE USE OF A TEC KINASE INHIBITOR, IBRUTINIB, FOR THE DEVELOPMENT OF IMMUNOTHERAPIES AGAINST CANCER AND LEISHMANIASIS.

Natarajan, Gayathri
http://rave.ohiolink.edu/etdc/view?acc_num=osu1461200133

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Microbiology.
Proteins belonging to the TEC family of kinases are critical for the function of immune cells. One of the kinases in this family, BTK (Bruton’s tyrosine kinase), is required for the function of B cells. BTK also plays key roles during the pathogenesis of B cell malignancies. Hence, a therapeutic strategy against B cell malignancies involves the inhibition of BTK by small molecule inhibitors. In this respect, ibrutinib, an irreversible inhibitor of BTK, has shown promise in the treatment of B cell malignancies and has received FDA approval as a `Breakthrough Therapy Drug’ in 2013. In addition to treating B cell malignancies, ibrutinib can potentially target other immune cells expressing BTK, such as dendritic cell (DCs). DCs, known as `sentinels of the immune system’, survey the body for the presence of `danger signals’ from infections and cancer cells. Following detection of such danger signals, DCs undergo maturation and increase the expression of surface activation markers including MHC-II and CD80. These activation markers activate T cells, a process critical for eliminating cancer cells or infectious agents. Previous studies showed that BTK deficiency leads to higher expression of MHC-II and CD80, therefore leading BTK-deficient DCs to promote higher levels of T cell activation compared to control DCs. Since ibrutinib inhibits BTK, we hypothesized that treatment of DCs with this inhibitor would enhance the expression of DC surface activation markers and promote DC-mediated T cell activation. Hence, we decided to evaluate the effect of ibrutinib on the maturation of mouse DCs using an in vitro cell culture model. As expected, we observed that inhibition of BTK enhanced the expression of MHC-II and CD80 on DCs. Further, ibrutinib-treated DCs promoted higher rates of T cell proliferation and production of T cell-derived cytokines compared to ibrutinib-untreated DCs. Taken together our study indicates that inhibition of BTK by ibrutinib promotes the development and activation status of DCs, which consequently leads to more efficient activation of T cells. Since ibrutinib effectively inhibits the function of B cells, it could also be expanded for the treatment of infectious diseases involving B cells. B cells contribute to susceptibility to the parasitic, vector-borne disease cutaneous leishmaniasis (CL), which is characterized by localized lesions at the site of the vector sandfly bite. We hypothesized that inhibition of BTK using ibrutinib would promote resistance to CL. Mice footpads were infected with causative organism for CL, Leishmania major. From the first day of infection and throughout the course of the experiment, mice were administered vehicle (control) or ibrutinib via drinking water. We observed that mice treated with the inhibitor displayed slower progression of disease with smaller lesions and lower parasite burdens compared to vehicle-treated mice. These results indicate that inhibition of BTK curtails the progression of CL, thereby providing a rationale for the use of ibrutinib as a potential drug candidate for the treatment of cutaneous leishmniasis. In summary, both our studies demonstrate novel indications for BTK inhibitors, such as ibrutinib, for the development of DC-based therapies and for the treatment of leishmaniasis.
Abhay Satoskar, M.B.B.S., M.D., Ph.D. (Advisor)
Virginia Sanders, Ph.D (Committee Member)
Stephanie Seveau, Ph.D. (Committee Member)
Pravin Kaumaya, Ph.D. (Committee Member)
Immunology; Microbiology
ibrutinib; BTK; ITK; immunotherapy; dendritic cells; cancer; leishmaniasis

Recommended Citations

Citations

  • Natarajan, G. (2016). THE USE OF A TEC KINASE INHIBITOR, IBRUTINIB, FOR THE DEVELOPMENT OF IMMUNOTHERAPIES AGAINST CANCER AND LEISHMANIASIS. [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461200133

    APA Style (7th edition)

  • Natarajan, Gayathri. THE USE OF A TEC KINASE INHIBITOR, IBRUTINIB, FOR THE DEVELOPMENT OF IMMUNOTHERAPIES AGAINST CANCER AND LEISHMANIASIS. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1461200133.

    MLA Style (8th edition)

  • Natarajan, Gayathri. "THE USE OF A TEC KINASE INHIBITOR, IBRUTINIB, FOR THE DEVELOPMENT OF IMMUNOTHERAPIES AGAINST CANCER AND LEISHMANIASIS." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461200133

    Chicago Manual of Style (17th edition)

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