Graft-versus-host-disease (GVHD)

GVHD is a common complication and cause of mortality after allogeneic blood and marrow transplant (AlloBMT). T cells present in the donor stem cell graft can target antigens present on the leukemia, termed the graft-versus-leukemia (GVL) effect, resulting in clinical remissions and cures. Unfortunately T cells can also target host tissues that express minor histocompatibility antigens (mHAs) that are mismatched to the donor, leading to GVHD.

GVHD pathogenesis can be divided into distinct phases. Inflammation from the conditioning regimen activates antigen presenting cells (APCs) in the host expressing mHAs that are foreign to the donor prime and activate donor T cells. Cytokines stimulated by the inflammation, such as gamma interferon (IFNg), enhance this activation. Donor T cells proliferate in response to being exposed to foreign mHAs present on APCs, and attack host organs like liver, gut and skin.

The activated T cells can also produce further cytokines that exacerbate GVHD further. Because GVHD can be a life threatening complication, it is typically treated with immunosuppressant drugs for weeks to months. The paradox is that GVHD, and the current drugs used for treating GVHD, inhibit the function of the donor T cells – simultaneously abrogating GVL. Therefore while GVHD may be controlled, the leukemia relapses. If GVHD is not treated, T cells may be intact to cause GVL but GVHD eventually kills the patient. Thus clinicians often allow a small amount of GVHD to occur, to reap any concurrent GVL effect, but then treat GVHD as it worsens before it becomes uncontrollable and lethal.

GVHD Pathogenesis

Thus, a paradigm shift in the field of alloHSCT is needed; namely prevention of GVHD while sparing the ability to maintain GVL. Our laboratory is focusing upon targeting non-T cell subsets to prevent GVHD while sparing T cells critical in mediating GVL. For example, Dr. Capitini has previously shown that

  • GVHD impairs responses to a tumor vaccine, but extracorporeal photopheresis (a therapy currently used in the clinic) can both prevent or treat GVHD through interleukin-10 production by dendritic cells, leading to improved vaccine responses in mice.
  • GVHD leads to decreased recovery of vaccine responding T cells in lymphoid organs, due to both diminished proliferation to the vaccine and increased apoptosisin mice. If the GVHD causing T cells were deficient in perforin, there was increased recovery of vaccine responding T cells, resulting in delayed tumor growth.
  • Using donor bone marrow deficient in the gamma interferon receptor (IFNgR) can prevent GVHD. Using this approach, the host can tolerate high doses of T cells without ever developing GVHD.

More recently, Dr. Capitini has shown that bone marrow deficient in STAT1, a downstream molecule of the interferon receptors, also prevents GVHD from delayed T cell infusions. These results informed work that led to FDA approval of the JAK1/JAK2 inhibitor ruxolitinib for treatment of GVHD.

Inhibiting STAT1