Donor Lymphocyte Infusion–Mediated Graft-versus-Host Responses in a Preclinical Swine Model of Haploidentical Hematopoietic Cell Transplantation

• Published in: Biology of blood and marrow transplantation Vol. 22; no. 11; pp. 1953 - 1960
• Main Authors: Duran-Struuck, Raimon, Matar, Abraham J., Crepeau, Rebecca L., Teague, Alexander G.S., Horner, Benjamin M., Pathiraja, Vimukthi, Spitzer, Thomas R., Fishman, Jay A., Bronson, Roderick T., Sachs, David H., Huang, Christene A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2016
• Subjects: Animals; Blood Donors; Cyclosporine - therapeutic use; Donor leukocyte infusion; Graft vs Host Disease - etiology; Graft vs Host Disease - prevention & control; Graft-versus-leukemia and graft-versus-host disease; Hematopoietic Stem Cell Transplantation - methods; Lymphocyte Depletion; Lymphocyte Transfusion - adverse effects; Lymphohematopoietic graft-versus- host responses; MHC defined miniature swine; Mixed chimerism; Swine; Transplantation Chimera; Transplantation Conditioning; Transplantation, Haploidentical - methods; Whole-Body Irradiation; Mixed chimerism; Donor leukocyte infusion; Graft-versus-leukemia and graft-versus-host disease; Lymphohematopoietic graft-versus- host responses; MHC defined miniature swine
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2016.08.011

•Mixed chimerism without GVHD across MHC barriers can be achieved in a RIC swine HCT model.•Mixed chimeras are highly resistant to delayed DLI GVH effects.•Pre-DLI leukodepletion overcomes resistance to conversion.•GVHD is often, but not always, observed after DLI conversion. We previously described successful hematopoietic stem cell engraftment across MHC barriers in miniature swine without graft-versus-host disease (GVHD) using novel reduced-intensity conditioning regimens consisting of partial transient recipient T cell–depletion, thymic or low-dose total body irradiation, and a short course of cyclosporine A. Here we report that stable chimeric animals generated with these protocols are strongly resistant to donor leukocyte infusion (DLI)–mediated GVH effects. Of 33 total DLIs in tolerant chimeras at clinical doses, 21 failed to induce conversion to full donor hematopoietic chimerism or cause GVHD. We attempted to overcome this resistance to conversion through several mechanisms, including using sensitized donor lymphocytes, increasing the DLI dose, removing chimeric host peripheral blood cells through extensive recipient leukapheresis before DLI, and using fully mismatched lymphocytes. Despite our attempts, the resistance to conversion in our model was robust, and when conversion was achieved, it was associated with GVHD in most animals. Our studies suggest that delivery of unmodified hematopoietic stem cell doses under reduced-intensity conditioning can induce a potent, GVHD-free, immune tolerant state that is strongly resistant to DLI.