Sustained immunotolerance in multiple sclerosis after stem cell transplant

Malini Visweswaran; Kevin Hendrawan; Jennifer C Massey; Melissa L Khoo; Carole D Ford; John J Zaunders; Barbara Withers; Ian J Sutton; David D F Ma; John J Moore

doi:10.1002/acn3.51510

Sustained immunotolerance in multiple sclerosis after stem cell transplant

Ann Clin Transl Neurol. 2022 Feb;9(2):206-220. doi: 10.1002/acn3.51510. Epub 2022 Feb 1.

Authors

Malini Visweswaran^{1

2}, Kevin Hendrawan^{1

2}, Jennifer C Massey^{1

2

3

4}, Melissa L Khoo^{1

2}, Carole D Ford^{1

2}, John J Zaunders⁵, Barbara Withers^{1

2

4}, Ian J Sutton³, David D F Ma^{1

2

4}, John J Moore^{1

2

4}

Affiliations

¹ Blood, Stem Cells and Cancer Research Laboratory, St Vincent's Centre for Applied Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
² St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
³ Department of Neurology, St Vincent's Hospital Sydney, Darlinghurst, Sydney, New South Wales, Australia.
⁴ Department of Haematology, St Vincent's Hospital Sydney, Darlinghurst, Sydney, New South Wales, Australia.
⁵ NSW State Reference Laboratory for HIV, St Vincent's Centre for Applied Medical Research, Darlinghurst, Sydney, New South Wales, Australia.

Abstract

Objective: Autologous haematopoietic stem cell transplantation (AHSCT) has the potential to induce sustained periods of disease remission in multiple sclerosis (MS), which is an inflammatory disease of the central nervous system (CNS) characterised by demyelination and axonal degeneration. However, the mechanisms associated with durable treatment responses in MS require further elucidation.

Methods: To characterise the longer term immune reconstitution effects of AHSCT at 24 and 36 months (M) post-transplant, high-dimensional immunophenotyping of peripheral blood mononuclear cells from 22 MS patients was performed using two custom-designed 18-colour flow cytometry panels.

Results: The higher baseline frequencies of specific pro-inflammatory immune cells (T-helper-17 (Th17) cells, mucosal-associated invariant T-cells and CNS-homing T-conventional (T-conv) cells observed in MS patients were decreased post-AHSCT by 36M. This was accompanied by a post-AHSCT increase in frequencies and absolute counts of immunoregulatory CD56^hi natural killer cells at 24M and terminally differentiated CD8⁺ CD28^- CD57⁺ cells until 36M. A sustained increase in the proportion of naïve B-cells, with persistent depletion of memory B-cells and plasmablasts was observed until 36M. Reconstitution of the B-cell repertoire was accompanied by a reduction in the frequency of circulating T-follicular helper cells (cTfh) expressing programmed cell death-1 (PD1⁺ ) at 36M. Associations between frequency dynamics and clinical outcomes indicated only responder patients to exhibit a decrease in Th17, CNS-homing T-conv and PD1⁺ cTfh pro-inflammatory subsets at 36M, and an increase in CD39⁺ T-regulatory cells at 24M.

Interpretation: AHSCT induces substantial recalibration of pro-inflammatory and immunoregulatory components of the immune system of MS patients for up to 36M post-transplant.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Female
Follow-Up Studies
Hematopoietic Stem Cell Transplantation*
Humans
Leukocytes, Mononuclear*
Male
Middle Aged
Multiple Sclerosis / blood*
Multiple Sclerosis / immunology*
Multiple Sclerosis / therapy*
Outcome Assessment, Health Care
Young Adult

Grants and funding

This work was funded by John Kirkpatrick Medical Foundation; Maple‐Brown Family Charitable Foundation; Medich Family Foundation; Multiple Sclerosis Research Australia ; National Health and Medical Research Council ; Reset Australia; St Vincent’s Clinic Research Foundation.