Graft-versus-host disease (GVHD) remains a devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT), and little progress has emerged since the introduction many years ago of calcineurin inhibitors (cyclosporine and tacrolimus) as prophylaxis. When it develops, treatment with steroids is efficacious in only 40 to 50 percent of the cases, and the prognosis of steroid-resistant GVHD remains very poor with less than 30 percent long-term survivors. There is thus a desperate need to improve understanding of this complex disease.
One major paper was published by Zhang and colleagues in the fall of 2005. In this study, the authors identify in a mouse model a new subset of CD8+ T lymphocytes that generate and sustain all allogeneic T-cell subsets in GVHD reactions, while self-renewing themselves (inducing GVHD upon transfer into secondary recipients). These CD8+T cells persist throughout the course of GVHD, are generated in the initial phase in response to alloantigen and dendritic cells, and require IL-15. Their long life, ability to self-renew, and multi-potentiality define these cells as being memory stem cells.
In Brief
Why is this study not just another rodent model with poor clinical implications? Two main reasons, at least from my point of view:
Identification of selective drug targets within the GVHD memory stem cell could be used for eradicating ongoing GVHD,and thus break the deadly circle of donor T-cell activation against the host target cells, while sparing a T-cell subset engaged against infectious agents (viral and fungal, in particular).
Discovery of such a cell subset has much broader applications and implications beyond just GVHD. Memory stem cells will be important targets for understanding and influencing diverse chronic immune reactions, including autoimmune diseases and solid organ transplant rejection.
So now what are the obstacles to overcome from a clinical perspective before moving from the bench to the bedside?
The first objective must surely be to identify and characterize whether these memory stem cells actually do exist in humans.
The relationship of this subset of cells to other cells responsible for the graft-versus-leukemia (GVL) observed after allogeneic HSCT is of major importance. Does the memory stem cell identified in this model setting differ from the cell that is responsible for the GVL effect both in rodent models and, most importantly, in human beings?
These questions aside, this paper nevertheless opens the door of a new and highly exciting era in the field of GVHD in particular, and in the world of immunology in general.
Competing Interests
Dr. Socié indicated no relevant conflicts of interest.
