Low-dose IL-2 for T-regulatory cell expansion after alemtuzumab therapy in relapsing-remitting multiple sclerosis

T-regulatory cells (Tregs) are vital for the prevention of autoimmunity, and they require interleukin-2 to function optimally. Their expression of the high-affinity IL-2 receptor, containing the CD25 subunit, renders them 10-fold more sensitive to IL-2 than effector cells (Teffs). Low-dose IL-2 preferentially expands Tregs in patients with a variety of autoimmune disease, correlating with clinical improvement. Autoimmunity is a frequent complication of treatment with the lymphocyte-depleting therapy alemtuzumab in patients with multiple sclerosis (RRMS)- and Treg insufficiency may be involved. In this work I: 1) tested whether low-dose IL-2 could selectively expand Tregs in this novel context; and 2) comprehensively characterised the reconstituting Treg compartment following alemtuzumab therapy. Using quantitative flow cytometry and PhosFlow techniques, I showed that following alemtuzumab therapy, naïve CD4 Teff cells gained higher CD25 expression and became more sensitive to IL-2 *in vitro*, potentially narrowing the therapeutic gap. In mice treated with alemtuzumab the timing of IL-2 treatment proved critical. Treg expansion predominated in animals whose immune system had partially reconstituted after alemtuzumab. However, early post-alemtuzumab, IL-2 clearly caused Teff proliferation, while not expanding Tregs. Gene expression analysis and spectral flow cytometry confirmed that human reconstituting Tregs early after alemtuzumab are highly activated, and remain responsive to endogenous IL-2, though they later acquired exhaustion markers. Given the limitations of my animal model to reflect human pharmacokinetics and pharmacodynamics, I performed a mechanistic study of low-dose IL-2 treatment in 6 RRMS patients following alemtuzumab therapy. There was unprecedented lack of Treg expansion with doses of IL-2 that ordinarily expand this population. I discuss the postulated mechanisms and clinical implications behind this unexpected outcome.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Georgieva, Zoya

Advisor dc:contributor.advisor

• Jones, Joanne

• autoimmune disease
• experimental medicine
• interleukin-2
• multiple sclerosis
• T-regulatory cells

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d75f2bda-29c9-4aa2-b433-429e4e72afbb/download
• https://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language

eng

Author Identifier

0000-0002-9531-8884

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/370164