Donor Leukocyte Infusion Mediated Graft-Versus-Host Responses in a Pre-Clinical Swine Model of Haploidentical Hematopoietic Cell Transplantation

Abstract

The donor-anti-host cellular reactivity associated with allogeneic hematopoietic cell transplantation (HCT) is a powerful anti-leukemia treatment. However, graft-versus-host disease (GVHD) continues to limit HCT, especially across major histocompatibility (MHC) barriers. We previously described successful hematopoietic stem cell engraftment in MHC-mismatched swine without GVHD using novel reduced intensity conditioning (RIC) regimens consisting of partial, transient recipient T-cell depletion (with or without thymic or low-dose total body irradiation), and a short course of cyclosporine A (CyA). Here, we report that stable chimeric animals generated with these protocols are strongly resistant to donor leukocyte infusion (DLI) mediated GVH effects (n=17). Delayed DLI in tolerant chimeras at a dose consisting of 10-50X106 T cells /kg (Tc/kg) failed to induce conversion to full donor chimerism or cause GVHD. Sensitizing the donor with recipient skin prior to collecting donor cells for DLI did not have any demonstrable effect on DLI outcome (n=2). This resistance to DLI mediated GVH reactivity could be overcome in some cases (n=9) by either 1) increasing the dose of DLI, 2) removing chimeric host peripheral blood cell populations through extensive leukapheresis prior to DLI or 3) delivering lymphocytes fully mismatched to the host but not to the original HCT donor within the chimera. However, conversion to full donor chimerism in some recipients was associated with GVHD. Our studies suggest that delivery of non-manipulated HCT grafts under reduced intensity conditioning can induce a potent, GVHD free immune tolerant state that is strongly resistant to DLI. DLI induced conversion to full donor chimerism is often associated with GVHD despite full immune reconstitution of the host and lack of known inflammatory stimuli.