The role of the Sphingosine-1-Phosphate pathway in Graft-versus-Host disease (GVHD) and T-cell regeneration in murine allogeneic Hematopoietic stem cell transplantation

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the complication of acute graft-versus-host disease (aGVHD) which may develop to some degree in up to 80% of patients. Unfortunately, aGVHD and the immunosuppression needed to control disease slow down posttransplantation immune regeneration and consequently also hamper anti-tumor immunity. Tipping the balance towards efficient immune reconstitution but against the development of aGVHD remains a major goal in allo-HSCT. Furthermore, in clinical allo-HSCT, the development of aGVHD (that is initiated by alloreactive donor T cells) predisposes to chronic GVHD (cGVHD) with autoimmune manifestations.
It is currently unclear, however, how autoimmunity is linked to antecedent alloimmunity. Using murine models of allo-HSCT, I could show in a collaborative effort that autoreactive T cells can be generated de novo in the host thymus, implying an impairment in self-tolerance induction as a consequence of aGVHD. As a possible mechanism, we have published that loss of medullary thymic epithelium expressing the autoimmune regulator (Aire+mTEChigh) was essential for failure to clonally delete self-reactive T cells. Our data therefore indicated that functional compromise of the mTEC compartment links alloimmunity to the development of autoimmunity during cGVHD.
As a direct consequence of this work, I aimed to test in the second part of my PhD thesis project whether continuous blockade of donor T-cell trafficking from activation sites in secondary lymphoid organs (SLO) would prevent thymic injury and hence prevent the emergence of autoreactive T cells. Using different murine allo-HSCT models, I analyzed the effects of sphingosine-1-phosphate (S1P) pathway interference with the highly specific synthetic sphingosine-1-phosphate receptor 1 (S1PR1) agonist KRP203. I found that prophylactic but not therapeutic S1PR1 agonism reduced donor T-cell migration to the host thymus, thus significantly attenuating thymic aGVHD. Moreover, prophylactic KRP203 administration was found to allow for normal intrathymic T-cell maturation in the absence and presence of aGVHD. In consequence, the Aire+mTEChigh pool remained normal. Maintenance of the TEC compartment was indeed associated with the emergence of lower numbers of thymus-dependent autoreactive T cells in the periphery.
Lastly, my data confirmed that S1PR1 receptor agonism maintains the capacity to reject hematopoietic tumors that are retained in these sites. The present work closed gaps in knowledge with regard to the action profiles of S1PR1 agonism on two separate parameters that govern transplant outcome, i.e. posttransplantation T-cell neogenesis and anti-tumor immunity. It may hence accelerate clinical trials and the definitive implementation of S1PR1 receptor agonism as a principle for the prevention of aGVHD where the unmet medical need is high.