Cyclosporine A but Not Corticosteroids Support Efficacy of Ex Vivo Expanded, Adoptively Transferred Human Tregs in GvHD.

Sybille Landwehr-Kenzel,Petra Reinke,Isabela Schmitt-Knosalla,Anne Forke,Anne Zobel,Robert Klopfleisch,Hans-Dieter Volk,Michael Schmueck-Henneresse,Henrike Hoffmann

doi:10.3389/fimmu.2021.716629

Abstract

Reshaping the immune balance by adoptive transfer of regulatory T-cells (Tregs) has emerged as a promising strategy to combat undesired immune reactions, including in Graft-versus-Host Disease (GvHD), which is the most lethal non-relapse complication of allogeneic hematopoietic stem cell transplantation. Currently however, little is known about the potentially inhibitory in vivo effects of conventional immunosuppressive drugs, which are routinely used to treat GvHD, on adoptively transferred Tregs. Here we demonstrate drug-specific effects of the conventional immunosuppressive drugs Cyclosporine A, Mycophenolate mofetil and methylprednisolone on adoptively transferred Tregs in a humanized NOD/SCID/IL2Rgamma-/- GvHD mouse model. The clinical course of GvHD and postmortem organ histology, including cellular organ infiltration, showed that co-administration of Cyclosporine A and Tregs is highly beneficial as it enhanced Treg accumulation at inflammatory sites like lung and liver. Similarly, co-administration of Mycophenolate mofetil and Tregs improved clinical signs of GvHD. In contrast, co-administration of methylprednisolone and Tregs resulted in reduced Treg recruitment to inflammatory sites and the fast deterioration of some animals. Consequently, when clinical trials investigating safety and efficacy of adjunctive Treg therapy in GvHD are designed, we suggest co-administering Cyclosporine A, whereas high doses of glucocorticosteroids should be avoided.

Highlights

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option for many patients with malignant and non-malignant diseases of the hematopoietic system
To investigate the clinical effect of conventional immunosuppressive drugs on adjunctive tTreg therapy, Graft-versus-Host Disease (GvHD) was induced in NOD/ SCID/IL-2Rgamma-/- mice by infusion of 3x106 human peripheral blood mononuclear cells (PBMCs) (Figure 1, Table 1 and Figures 2A–M)
The timing of clinical GvHD manifestation resembled the clinical course known from human HSCT, with disease onset usually occurring during the first 15 days after transplantation

Summary

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option for many patients with malignant and non-malignant diseases of the hematopoietic system. Graftversus Host-Disease (GvHD) still constitutes one of the most lethal post-transplant complications of HSCT [1]. The current paradigm holds that GvHD is primarily a T-cell mediated disease caused by donor effector-T-lymphocytes recognizing allogenic structures as non-self in the host, and thereby eliciting their proinflammatory and cytolytic program. Therapeutic benefits can be achieved by enrichment of circulating tTregs after HSCT [12,13,14,15,16,17,18,19] and in the context of solid organ transplantation [20,21,22] and autoimmune diseases such as hepatitis C vasculitis [23], systemic lupus erythematosus or Type 1 diabetes [24,25,26]

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