The role of regulatory T cells in the pathophysiology of aplastic anaemia and their potential use as a treatment

Abstract

Aplastic anaemia is an immune mediated bone marrow failure syndrome characterized by reduced and dysfunctional regulatory T cells. Immunosuppressive treatment with anti-thymocyte globulins and ciclosporin A or allogeneic stem cell transplantation are the treatment of choice above and below forty years of age respectively. Not many options are available for elderly patients not fit for immunosuppressive treatment or relapsing after that.
The aim of this Ph.D. project was to investigate in more depth the role of regulatory T cells in the pathogenesis of aplastic anaemia and to explore if ex vivo expansion of Tregs could be an alternative treatment for refractory/relapsed aplastic anaemia in patients without a suitable human leukocyte antigen-matched donor.
During the first part of the project, we were able to identify, through mass cytometry, a specific immune signature - based on Treg subsets named A and B - able to predict response to treatment. Non-responders to immunosuppressive treatment seemed more likely to have higher Treg A number compared with non-responders, whereas responders had higher Treg B.
The following part of the Ph.D. has been aimed to assess whether Treg A and B are also functionally different, and we were able to show that Treg A and B are not only immunophenotypically different, but they also show a distinct functional profile, ontogeny, gene signature, and apoptosis propensity. The next aspect we wanted to explore, is weather Tregs are expandable to be used, in vitro first and in vivo afterwards, as a cellular therapy for aplastic anaemia. All our data show that aplastic anaemia Tregs are expandable, have a Treg-like immunophenotype, are functional, stable, cannot be induced to secrete interleukin-17A, and increase phosphorylated B cell lymphoma-2 expression.
Having assessed their “safety” in vitro, we investigated their use in vivo and preliminary data show that, in a graft versus host disease mouse model, they are able to mitigate autoimmunity and prolong overall survival.

Date of Award	1 Oct 2021
Original language	English
Awarding Institution	King's College London
Supervisor	Ghulam Mufti (Supervisor) & Farzin Farzaneh (Supervisor)