A moonshot in autoimmune disease. Elevating cell therapy.

Engineered regulatory T (Treg) cells have emerged as precision therapeutics aimed at inducing immune tolerance while reducing the risks associated with generalized immunosuppression. This Viewpoint highlights the opportunities and challenges for engineered Treg cell therapies in treating autoimmune and other inflammatory diseases.

Descriptive categorical classifiers of multiple sclerosis (MS) – relapsing–remitting, chronic-progressive – do not correspond to mechanisms that explain symptomatic worsening. Persons with MS simultaneously exhibit relapse activity with clinical attacks accompanied by new magnetic resonance imaging (MRI) lesions and progression independent of relapse activity (PIRA), each to varying degrees throughout the disease course. Relapse activity has been successfully treated while PIRA has not. PIRA is mechanistically associated with chronic-active lesions (CALs) and cortical demyelination, both causally associated with meningeal lymphoid aggregates, as well as neurite degeneration. Conventional MRI does not detect pathology associated with PIRA except as tissue atrophy but recent advances using MRI to detect CALs may enable a personalized medicine approach to understanding and treating PIRA.

In this study the authors addressed the relationship between meningeal inflammation and demyelinating activity within white matter (WM) lesions, using autopsy-derived brain sections from the indispensable Netherlands Brain Bank. The novelty of this work lay in its focus on the activity of the WM lesions. Previously it was shown that total WM lesion number and volume were unrelated to the extent of meningeal inflammation. Here, Ramaglia et al. showed that WM lesion activity was strongly related to the level of meningeal inflammation – higher meningeal inflammation was associated with actively demyelinating WM lesions, while lower meningeal inflammation was seen in tissues that featured inactive or remyelinating WM lesions.

This study demonstrated that chronic-active lesions in the white matter of multiple sclerosis patients, the neuropathological correlate of paramagnetic rim lesions (PRLs) detected on MRI scans, are driven by the adaptive immune response, and not innate immunity, which has significant implications for drug development strategy.

Abata Therapeutics Launches to Usher in New Era of Cell Therapy Using Targeted Regulatory T Cells to Treat Serious Autoimmune and Inflammatory Diseases

Mouse polyclonal Tregs were isolated, engineered ex vivo with TCRs reacting to one or two myelin-associated antigens, and infused back into mice with autoimmune encephalomyelitis (a model representing the autoimmune features of multiple sclerosis). Whether targeting one or two antigens, in both cases Tregs expressing the high-quality TCRs were most effective in suppressing inflammation and disease score.

In MS, chronic-active demyelinating lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based MRI in vivo as T1-dark foci with paramagnetic rims. Presence and number of these lesions correlate with more severe clinical disease.

In this article, a pre-eminent neuropathologist who has been investigating MS for more than 40 years reviews data concluding that there are no meaningful biological differences between the autoimmune processes underlying primary progressive multiple sclerosis (PPMS) and secondary progressive MS (SPMS). Furthermore, the reviewer discusses the concept that ‘compartmentalized inflammation’, mainly localized in meningeal lymphoid aggregates (which include T cells), drives ongoing inflammatory demyelination during progressive MS behind an intact blood-brain barrier.

In this study, Abata co-founder Roland Martin and colleagues show that memory B cells drive proliferation of self-reactive brain-homing CD4+ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis.

This study demonstrates that T cells do not need to see the disease-driving antigen to confer efficacy in mouse EAE models. The authors utilize an MBP-specific TCR and observed that it can suppress MOG-induced/driven EAE in the mouse, thus demonstrating heterologous/infectious tolerance. The work teaches that T cells do not need to ‘see’ the disease-driving antigen: hence, a TCR can direct the Treg to the inflamed brain lesion and become locally reactivated to suppress immunity even if aimed at other antigens in the same microenvironment.

A clinical study in Type 1 diabetes patients shows autologous Tregs can be vastly expanded ex vivo and safely transfused, retaining high numbers and a stable Treg phenotype for at least one year.

Richard Ransohoff, co-founder of Abata, and Britta Engelhardt reviewed data leading to the concept that memory T cells traffic through the meningeal compartment to execute immune surveillance of the central nervous system (CNS). These T cells, previously stimulated by cognate antigen in the periphery, are restimulated within the CNS, primarily by antigen-MHC complexes on the surfaces of meningeal macrophages, which sample solutes in the cerebrospinal fluid (CSF). This paradigm provides understanding of how peripherally administered TCR-expressing Tregs can traffic through the compartment and be activated by antigen and ultimately retained locally.

Treg cells with a stable, terminally differentiated immunosuppressive phenotype (‘stable Tregs’) originate in the thymus before entering the blood stream and populating other organs in the body. Although Tregs express the key transcription factor FoxP3, it is also shown that under specific conditions FoxP3 is temporarily induced in effector T cells, without taking on a regulatory phenotype.

Studying the cellular origin and fate of Treg cells in mice, Abata co-founder Diane Mathis and collaborating scientists definitively demonstrate that a FoxP3-expressing Treg lineage can be identified. Born as a regulatory cell, it retains a stable regulatory cell phenotype and will not convert to an effector T cell phenotype even when exposed to highly pro-inflammatory conditions.

Decades of research using animal models including EAE had suggested strongly that T cell-mediated autoimmunity was the underlying pathogenic process in MS (see the 1981 reference below for an important early study).¹ These human genetic studies confirmed that hypothesis by showing the inherited susceptibility to MS was conferred by genes that govern the function of immune cells, most prominently T cells. Additional research showed both peripheral immune cells and brain immune cells termed microglia were also involved.

Tregs are shown to potently suppress autoimmune diabetes in mice following adoptive transfer, revealing a potential novel avenue for immunotherapy of human autoimmune disease. Successful in vitro expansion of antigen-specific Tregs yielded significant efficacy, reversing diabetes even after onset.

These two papers show the transcription factor Foxp3 is specifically expressed in Tregs, acting as a critical regulator of their development and function. Mice and human subjects carrying genetic defects in Foxp3 are demonstrated to develop autoimmune and inflammatory syndromes.

First convincing demonstration of immune suppressive capacity encased in a CD4+ T cell population identified by constitutive expression of CD25. Removing this subset of suppressive T cells led to a wide variety of autoimmune diseases in mouse experiments. This subset of CD4+ T cells was later named “regulatory T cells” or “Tregs”.