Bone marrow or stem cell transplantation
aGVHD is a frequent complication of bone marrow transplantation and there is need for new treatments. Transient anti-CD45RC MAb treatment induces tolerance in organ transplantation models through both depletion of CD45RChigh cells and activation of CD45RC-/low CD4+ and CD8+ Treg.
BN-LEW/F1 rats infused with LEW T cells showed a lethal aGVHD. Depletion of CD45RChigh cells from the T cell inoculum before infusion resulted in complete prevention of aGVHD (n=4). In vivo treatment after T cell infusion with anti-CD45RC MAb alone (0-30d, n=3) or a suboptimal dose of rapamycine (0-10d, n=3) did not prolong survival while combination of both anti-CD45RC and rapamycine were synergic (65 vs. 33d in controls, n=8) with 50% of the recipients showed indefinite survival. Long-term survivors rejected all third-party Sprague-Dawley but not BN or LEW skin grafts demonstrating donor-specific tolerance and preservation of other immune responses.
Administration of human PBMCs in NSG mice resulted in lethal aGVHD. Treatment with anti-CD45RC MAb alone (0-20d) or a suboptimal dose of rapamycine alone (0-10d) significantly prolonged survival (34d, n=9 and 30d, n=10 vs. 14d in controls, respectively) but all recipients died. In contrast, combination of both anti-CD45RC and rapamycine were synergic (84d, n=10) and 80% had indefinite survival. Human tumor cells implanted in immunodeficient NSG mice were rejected by hPBMCs infused 7d later. Treatment with anti-CD45RC MAb alone or in combination with rapamycine preserved elimination of tumor cells in all animals (n=4) demonstrating preservation of human immune responses.
Thus, treatment with anti-CD45RC in combination with rapamycine has a strong potential to prevent aGVHD.