The Next Frontier of Regulatory T Cells: Promising Immunotherapy for Autoimmune Diseases and Organ Transplantations

Abstract

Regulatory T cells (Tregs) are crucial in maintaining tolerance. Hence, Treg immunotherapy is an attractive therapeutic option in autoimmune diseases and organ transplantations. Currently, autoimmune diseases do not have a curative treatment and transplant recipients require life-long immunosuppression to prevent graft rejection. There has been significant progress in understanding polyclonal and antigen-specific Treg biology over the last decade. Clinical trials with good manufacturing practice (GMP) Treg cells have demonstrated safety and early efficacy of Treg therapy. GMP Treg cells can also be tracked following infusion. In order to improve efficacy of Tregs immunotherapy, it is necessary that Tregs migrate, survive and function at the specific target tissue. Application of antigen specific Tregs and maintaining cells' suppressive function and survival with low dose interleukin-2 (IL-2) will enhance the efficacy and longevity of infused GMP-grade Tregs. Notably, stability of Tregs in the local tissue can be manipulated by understanding the microenvironment. With the recent advances in GMP-grade Tregs isolation and antigen-specific chimeric antigen receptor (CAR)-Tregs development will allow functionally superior cells to migrate to the target organ. Thus, Tregs immunotherapy may be a promising option for patients with autoimmune diseases and organ transplantations in near future.

Keywords: antigen specific; autoimmune liver diseases; liver transplant; polyclonal; recruitment; regulatory T cell; tolerance.

Figure 1

Autoimmune diseases in multiple organs in humans. e.g. autoimmune diseases that can co-exist in multiple tissues are: brain (multiple sclerosis), eye (autoimmune iritis and episcleritis), lung (autoimmune idiopathic pulmonary fibrosis), gut (Coeliac disease, pernicious anemia, inflammatory bowel disease), liver—autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis), kidneys (autoimmune glomerulonephritis), skin (psoriasis, pemphigus), endocrine (autoimmune thyroid disease such as Hashimoto thyroiditis, Graves' disease, type 1 diabetes, Addison's disease), and multi-organ involvement, such as systemic lupus erythematosus.

Figure 2

Regulatory T cells in live and cadaveric liver transplant. Liver transplantation can be a living-related (right lobe graft- upper figure) or a cadaveric transplant (whole liver transplant—lower figure). Renal transplantation can also be cadaveric or a live donor allograft. If it is a living donor transplantation, antigen-specific Treg cells can be generated and expanded before transplantation whereby recipient Treg cells are co-cultured with donor dendritic cells, which are primed with donor antigens (yellow dots). Both polyclonal and antigen-specific Treg cells proliferate and function via utilizing interleukin-2 as Treg highly express IL-2 receptor, CD25. These generated Treg cells are applied in both autoimmune disease and transplantation clinical trials.

Figure 3

Microenvironmental factors in different organs. Local tissue microenvironmental factors in organ (heart, liver, kidney, bone marrow, islet cells) transplantation. Infused Treg cells arrive to local tissue where they crosstalk with innate immune cells (macrophage, dendritic cells, monocyte, natural killer cells, neutrophils) and adaptive immune cells (NKT, Mucosa associated invariant T cells, Treg, Th1, Th17 cells) in the local tissue. Treg cells localize in tissue with pro-inflammatory cytokines (interleukin 1, 6 and 12, tumor necrosis factor (TNF) and interferon (IFN)), chemokines (CXCL and CCL) and local metabolites (carbohydrate, fatty acid, peptides and vitamins). Infused Treg cell plasticity and their function in the local tissue microenvironment is dependent on these factors.

Figure 4

Schematic illustration of large scale GMP Treg production. Leukapharesis procedures are performed to those patients with either autoimmune diseases or those who will undergo transplantations. GMP Treg will be cell sorted using surface markers to obtain highly pure CD4⁺ CD25^high CD127^low cells population. Then, cells will be expanded in GMP culture media with GMP-grade IL-2 cytokines, GMP-grade rapamycin (to prevent effector T cells outgrowth) and GMP-grade CD3, CD28 Treg expander beads (with or without known antigen). These cells will then undergo quality assessment process and will be frozen until infusion back to patients.