Abstract

Rabbit anti-human thymocyte globulins (ATG) (Thymoglobulin®) are widely used for treatment and prevention of solid organ transplant rejection. However, more recently these therapies have been shown to also reduce the severity of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. However, dose and schedule of ATG administration in the clinic has not been well defined, and thus, the studies reported here were undertaken to explore optimal dosing and timing regimens as well as possible mechanisms of action of anti-thymocyte globulin in an in vivo murine model of GVHD. We demonstrate that a murine version of ATG, rabbit anti-murine thymocyte globulin (mATG), completely inhibits the development of acute GVHD in a model of allosplenocyte transfer into immunodeficient recipient mice (C57BL/6→BALB/c RAG-2−/ −). This protection is observed even when mATG administration is delayed for up to three days following allosplenocyte transfer. Administration of mATG six or more days following induction of GVHD still ameliorates disease in up to 50% of the animals, depending on the timing of mATG treatment. Murine ATG also remains completely protective down to doses of 1mg/kg if administered at the time of allosplenocyte transfer. Although T cell depletion is still observed at this low, but efficacious dose of mATG, we also find significant increases in Foxp3+ CD4+ regulatory T cells in the spleen (30 fold over control) as well as increased Foxp3+ expression in liver and intestines (3 fold over control). These results demonstrate a potent protective effect of murine ATG in this model of acute GVHD and suggest that the induction of regulatory T cells may participate in the protective effects observed.

Author notes

Disclosure:Employment: All authors are employed by Genzyme Corp, whose commercial product is Thymoglobulin. Ownership Interests:; All authors have ownership interest in Genzyme Corp, whose commercial product is Thymoglobulin. Research Funding: Studies reported here were supported by Genzyme Corp. Off Label Use: Discussions will refer to the reported use of anti-thymocyte globulins (Thymoglobulin) in bone marrow transplantation for GVHD prophylaxis and/or prevention for which it is not approved in the US.