Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


34261.pdf (4.52 MB)

ETD Abstract Container

Abstract Header

A natural killer cell-centric approach toward new therapeutics for autoimmune disease.

Reighard, Seth D
http://orcid.org/0000-0002-3969-9651
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563273969849993

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Immunology.
The debilitating autoimmune disease systemic lupus erythematosus (SLE) is the 5th leading cause of death for African American and Hispanic women between 15 and 24 years of age. Current therapeutics for SLE are blunt weapons that broadly suppress a patient’s immune system, and only one new treatment option has been approved in over 50 years. Standard treatments for SLE potentially lack efficacy because they do not specifically target the immune dysfunction underlying disease. SLE is characterized by the abnormal production of self-targeting autoantibodies that cause widespread organ damage. SLE autoantibodies are generated by rampant germinal center (GC) reactions: immune processes wherein memory B cells and antibody secreting cells (ASC) arise from naive B lymphocytes following clonal expansion, somatic hypermutation, affinity maturation, and antibody class switching while receiving critical help from follicular helper T (Tfh) cells. We hypothesize that inhibition of Tfh and GC responses in SLE may be accomplished by harnessing the therapeutic potential of the natural killer (NK) cell. Though classically implicated in anti-tumor and antiviral immunity, NK cells also suppress activated Tfh cells, resulting in reduced GC reactions and decreased antibodies. Of added relevance, NK cells are diminished and defective in SLE patients. Thus, we tested whether increasing endogenous NK cell numbers or artificially enhancing their function could achieve a beneficial result in an autoimmune context like SLE. We treated mice exhibiting an SLE-like disease with drugs that expand the endogenous NK cell (and CD8 T cell) pool and, contrary to our hypothesis, observed worsened autoimmunity. Disease aggravation was attributed to the expansion of CD8 T cells, with expanded NK cells exhibiting negligible effects. Our findings suggest that current cancer treatments that expand these cell populations in vivo should be used with caution in patients with cancer and concurrent SLE. Separately, we utilized chimeric antigen receptor (CAR) technology, a clinical tool currently being used to safely target tumors, to engineer an NK cell that selectively eliminates Tfh cells in hopes of subduing autoreactive GCs. In vitro studies demonstrated that our CAR NK cells not only killed Tfh cells but also limited subsequent B cell-mediated generation of ASCs and the downstream production of antibodies. Furthermore, we used RNA sequencing to identify differences in human SLE NK cell gene expression and uncovered several transcriptional alterations with known relevance to both SLE pathogenesis and NK cell function. Gene network analysis predicted the transcription factor PU.1 to underlie several SLE NK cell transcriptional changes, and the upregulation of PU.1 may explain an aberrant and proinflammatory phenotype often observed in disease. Future studies will aim to attenuate the expression of PU.1 in NK cells and determine whether the resulting phenotype is of benefit to disease, thereby identifying PU.1 as a potentially valuable therapeutic target in SLE. Altogether, our innovative NK cell-based therapeutic strategies have the potential to limit the autoantibody-mediated pathology of SLE in a more targeted manner, offering a new hope to thousands of people who suffer from this incurable disease.
Stephen Waggoner, Ph.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
William Ridgway, M.D. (Committee Member)
Wen-Hai Shao, Ph.D. (Committee Member)
181 p.
Immunology
natural killer cell; systemic lupus erythematosus; autoimmunity; chimeric antigen receptor; follicular helper T cell; immunotherapy

Recommended Citations

Citations

  • Reighard, S. D. (2019). A natural killer cell-centric approach toward new therapeutics for autoimmune disease. [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563273969849993

    APA Style (7th edition)

  • Reighard, Seth. A natural killer cell-centric approach toward new therapeutics for autoimmune disease. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563273969849993.

    MLA Style (8th edition)

  • Reighard, Seth. "A natural killer cell-centric approach toward new therapeutics for autoimmune disease." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563273969849993

    Chicago Manual of Style (17th edition)

ucin1563273969849993
122
© 2019, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.