Anti-thymocyte globulin (ATG) prevents autoimmune encephalomyelitis by expanding myelin antigen-specific Foxp3+ regulatory T cells

Abstract

The T cell-depleting polyclonal antibody, anti-thymocyte globulin (ATG) has long been used in organ transplantation to treat acute rejection episodes. More recently, it is also being used as part of an induction regimen to protect allografts. It has been proposed that ATG might deplete effector T cells (T-effs) while sparing regulatory T cells (T-regs). In order to test whether ATG is effective in autoimmune disease, we used Foxp3gfp 'knock-in' mice in combination with a myelin oligodendrocyte glycoprotein (MOG)(35-55)/IA(b) tetramer to study more closely the effect of ATG treatment on antigen-specific T cell responses in vivo during MOG-induced experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple Sclerosis. ATG treatment enhanced the expansion of MOG-specific T-regs (CD4(+)Foxp3(+)) in MOG-immunized mice. T-effs were depleted, but on a single-cell basis, the effector function of residual T-effs was not compromised by ATG. Thus, ATG tipped the balance of T-effs and T-regs and skewed an auto-antigen-specific immune reaction from a pathogenic T cell response to a potentially protective T-reg response. In both acute and relapsing remitting disease models, ATG treatment resulted in the attenuation from EAE, both in a preventive and early therapeutic setting. We conclude that ATG treatment enforces the development of a dominant immunoregulatory environment which may be advantageous for the treatment of T cell-driven autoimmune diseases.

Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival

“…In fact, although T regulatory cells associated with transplantation tolerance (24,30,31,43) are induced by Thymoglobulin and mATG (23,25,26,32,33) and are responsible for mATGmediated prolonged graft survival (16), we did not see increases in T regulatory cells with the mATG and methotrexate combination over that of mATG alone. In addition, there was no evidence of enhanced depletion of T cells, and only a modest extension of mATG effects was observed as a result of blockade of anti-drug Ab responses by methotrexate.…”

“…In particular, as T regulatory cells have been associated with longterm graft survival in transplantation (23,24,30,31), are induced by Thymoglobulin and mATG (22,25,26,32,33), and have previously been demonstrated to be responsible for delayed graft rejection following mATG (16), CD3 + Foxp3 + cells, which bear a phenotype consistent with regulatory T cells, were evaluated. To assess histologic changes in long-surviving grafts, cardiac grafts were collected from the mATG and methotrexate combinationtreated group and the untreated syngeneic group at least 100 d after transplantation.…”

“…We explored whether the same regimen that is effective in reducing anti-drug Abs to the enzyme replacement therapy, Myozyme, or even fewer cycles of methotrexate, could reduce Ab responses that develop against mATG in the context of repeated administration. In addition, although T cell-directed therapies such as Thymoglobulin are efficacious, B cell and alloantibody responses also can contribute to chronic rejection as patients still can develop alloantibodies to their grafts (24)(25)(26). As a result, we investigated whether alloantibody responses in a fully mismatched allogeneic murine cardiac transplant model could also be controlled by methotrexate.…”

A new approach for treatment of type 1 diabetes: Phytotherapy and phytopharmacology of regulatory T cells

“…But, TGF-β plus IL-6 can abolish the generation of induced Treg cells (47,48). Using substances that induce immune tolerance via Treg cells activation or deletion of lymphocyte subsets have been suggested as immunoregulatory strategies for the disease (49). However, the efficiency of some of these approaches have been proved in clinical trials, the risks such as abnormal cytokine release render difficult its adoption (50).…”

The therapeutic potential of regulatory T cells for the treatment of autoimmune disease

“…Treatments such as anti-thymocyte globulin modulate autoimmunity, including EAE and spontaneous T1D in the NOD mouse model by both depleting Teff cells and inducing de novo pTregs [57][58][59][60]. The efficacy of these antibodies has led to clinical trials with Thymoglobulin, (Sanofi, Paris France) a drug approved for use in blocking graft versus host disease and kidney transplant rejection [61].…”