Publication Date

2019-03-04

Availability

Embargoed

Embargo Period

2021-03-03

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2018-12-19

First Committee Member

Thomas R. Malek

Second Committee Member

Robert Levy

Third Committee Member

Alberto Pugliese

Fourth Committee Member

Peter Buchwald

Fifth Committee Member

John Koreth

Abstract

Produced primarily by CD4+ T cells, IL-2 is a cytokine, which promotes proliferation but more importantly is critical for regulatory T cell (Treg) development, homeostasis, and competitive fitness. For over 20 years, IL-2 therapy has been used in the treatment of malignant disorders, however, with toxic effects. A new and promising therapeutic application for IL-2 uses administration of low doses to selectively expand Tregs in attempt to boost immunity and promote tolerance in patients with autoimmunity. In clinical studies as well as preclinical studies, low-dose IL-2 has been promising in increasing Treg numbers and enhancing their suppressive function. Most importantly, administration has been well tolerated and not accompanied by serious side effects. Though promising, there are still limitations such as we do not understand in much detail the mechanism of action and the protective effect of low-dose IL-2 therapy as well as the extremely short in vivo half-life of IL-2. All of which are fundamental to develop low-dose IL-2 as a useful immunotherapy. To circumvent these limitations, we have developed a novel chimeric fusion protein of mouse IL-2 and CD25 alpha (IL-2/CD25) that has greater efficacy than recombinant IL-2 at Treg expansion and the control of islet autoimmunity in NOD mice. Functional studies have shown that IL-2 interacts with CD25 alpha at the binding site forming a stable dimer configuration that slowly dissociates into an active monomer. IL-2/CD25 has low activity in vitro however, in vivo, the activity is long lived and able to persistently and preferentially stimulate Tregs. In female NOD mice, administration of IL-2/CD25 increased Tregs in pancreas, reduced the incidence of diabetes, and decreased lymphocytic infiltration in pancreatic islets. Given these results, IL-2/CD25 represents a new IL-2-biologic with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.

Keywords

IL-2; Regulatory T cells; IL-2 therapy; fusion protein

Available for download on Wednesday, March 03, 2021

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