Regulatory T cell (Treg)

Regulatory T cell (Treg)

Tregs or regulatory T cells control self-tolerance, tissue inflammation and long-term homeostasis. Treg-based cell therapies are being developed to treat autoimmune diseases and inflammatory conditions.

About 1-2% of peripheral blood lymphocytes are Tregs. IPEX (immunodysregulation, polyhendocrinopathy, enteropathy, X-linked) syndrome is a severe Treg deficiency caused by mutations in a transcription factor controlling the Treg cell lineage. Reduced numbers or function of Tregs have been implicated in pathology for autoimmune diseases. Boosting Treg activity is a common goal being approached in the repurposing of drugs which enhance Treg function and also in Treg-based cell therapies.

Cell therapies using Tregs are being developed to treat autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease (GvHD), which can occur after bone marrow transplant and organ transplant rejection. Adoptive cell therapy (ACT) treatments for non-immune diseases such as Alzheimer’s disease, Parkinson’s disease, heart disease and type 2 diabetes are also being investigated. Evidence is accumulating that non-immune diseases can be exacerbated by inflammation, and preclinical studies suggest Tregs may calm inflammation and reduce morbidity through tissue homeostasis and repair by producing epidermal growth factor receptor (EGFR) ligand amphiregulin. Results from a clinical trial using Treg to treat amyotrophic lateral sclerosis indicate it may reduce disease progression. Tregs have been shown to increase bone marrow engraftment, decrease immune responses to gene therapy and facilitate would healing.

Tregs previously were referred to as suppressor cells and they were initially isolated based on multiple cell surface markers such as CD4, CD25 and CD62L. Purified Tregs with these markers and FOXP3+ Tregs have been used in clinical trials to treat organ transplant rejection, GvHD, type 1 diabetes and autoimmune syndromes.

To prepare polyclonal Treg ACTs, cells are purified from the peripheral blood of a patient and grown ex vivo with antibodies to CD3 and CD28 and high-dose IL-2. The expanded and enriched Treg population is characterized and transferred into patients. Polyclonal Treg ACTs have been shown to be safe in phase I studies and clinical activity is suggested in some of them. Results from a phase 2 study (NCT02691247) for type 1 diabetes are expected in 2019. Ongoing clinical trials testing efficacy in GvHD include NCT01795573 and NCT01937468).

It has been suggested that since Tregs have a self-antigen skewed TCR repertoire large tissues like skin or gut may activate sufficient Tregs in a polyclonal population. On the other hand, it is predicted that smaller tissues like pancreatic islets will require antigen-specific Tregs. To suppress organ rejection once strategy is to isolate Tregs from an organ transplant recipient and stimulate them with donor organ-derived antigen-presenting cells to expand donor-specific Tregs. These alloantigen-reactive Tregs are in clinical trials aimed at reducing the need for immunosuppressive drugs.

Tregs engineered with antigen-specific receptors (CARs and TCRs)

Polyclonal or in vitro expanded Tregs for therapy requires large amounts of cells and carries a risk for non-specific immunosuppression. Generation of antigen-specific Tregs is a strategy that requires less cells to exert a more localized and targeted suppression and which shows superior functionality in animal models. Antigen-specific Tregs can be generated by expanding them with antigen-presenting cells and specific antigens or by engineering Tregs with T-cell receptors (TCRs), called TCR-Tregs. TCR-Tregs are MHC (major histocompatibility complex)-restricted which limits their modular application.

Tregs engineered to express transgenic TCRs specific for autoantigens like Factor IX in hemophilia, myelin oligodentrocyte glycoprotein in Multiple Sclerosis (MS) and pancreatis islet-specific antigens in type 1 diabetes are being researched at the preclinical stage. Some approaches combine antigen receptor engineering with control of cell differentiation. Tregs are not a terminally differentiated cell population are able to acquire the phenotype of effector T cells similar to T helper cells and are categorized into different subsets of T helper-like Tregs.

CAR-Tregs are MHC-independent and are engineered with genes encoding chimeric antigen receptors. Chimeric antigen receptors (CARs) generally consist of a single-chain variable fragment which is a site for binding a monoclonal antibody, an extracellular hinge, a transmembrane region and intracellular signaling domains.

CAR-Treg generation is based on technology used for CAR modified T cells (CAR-T) which are mainly used for cancer immunotherapies. The first two CAR-T cell therapies were approved by the US Food and Drug Administration in 2017 for the treatment of CD19+ B cell lymphomas. Clinical trials are testing the therapy for solid tumors. While the main function of killer T cells used in CAR-T cell therapy is to attack their target, such as cancer cells, Tregs function to protect their target from being attacked by immune system.

CAR-Tregs and transplantation tolerance

CAR-Treg therapy, where the CAR is targeted to HLA-A2, found on leukocytes emigrating from a transplant graft, could increase transplantation tolerance. This strategy shows promise in graft-versus-host disease mouse models. A2-CAR-Tregs have been developed to prevent rejection of skin allograft in humanized mouse models.

A FITC-targeted CAR on Tregs called mAb-directed CAR (mAbCAR) allows Tregs to be activated in a controllable way using various monoclonal antibodies (mAbs) that are covalently conjugated to FITC. The mAbCARs could be targeted to specific tissue sites to mitigate graft-versus-host disease.

CAR-Tregs and autoimmunity

TNP-CAR Tregs target an antigen commonly used in a mouse model of colitis, 2,4,6-trinitrophenol. Research in mouse models show this immunotherapy treatment may be protective against the disease and TNP-CAR Tregs localized to inflamed colonic mucosa.

MOG-CAR Tregs which target myelin oligodendrocyte glycoprotein (MOG) have been shown in mouse multiple sclerosis models to suppress autoimmune encephalomyelitis (EAE).

CEA-CAR Tregs have been shown to target lung epithelia in a mouse model of allergic asthma and reduce airway hyperactivity and reduce eosinophilic airway inflammation.

Hemophilia patients receiving factor VIII (FVIII) replacement drugs can develop anti-drug antibodies. FVIII-specific Tregs (ANS8-CAR Tregs) have been shown to suppress anti-FVII antibody responses in mouse models.




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