title: Donor Lymphocyte Infusion-Mediated Graft-versus-Host Responses in a Preclinical Swine Model of Haploidentical Hematopoietic Cell Transplantation.
abstract: 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.
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania; Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts. Electronic address: Rduranst@gmail.com.
authors.forename: Raimon
authors.initials: R
authors.lastname: Duran-Struuck
authors.affiliation: Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts; College of Medicine, University of Central Florida, Orlando, Florida.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Matar
authors.affiliation: Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Crepeau
authors.affiliation: Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts.
authors.forename: Alexander G S
authors.initials: AGS
authors.lastname: Teague
authors.affiliation: Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Horner
authors.affiliation: Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts.
authors.forename: Vimukthi
authors.initials: V
authors.lastname: Pathiraja
authors.affiliation: Bone Marrow Transplant Program, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Spitzer
authors.affiliation: Massachusetts General Hospital, MGH Transplantation Center and Transplant Infectious Disease & Compromised Host Program, Boston, Massachusetts.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Fishman
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts.
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.affiliation: Massachusetts General Hospital, Transplantation Biology Research Center, Boston, Massachusetts.
authors.forename: Christene A
authors.initials: CA
authors.lastname: Huang
mesh_terms: D000818:Animals; D001782:Blood Donors; D016572:Cyclosporine / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000209:etiology* / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion / Q000009:adverse effects*; D013552:Swine; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical / Q000379:methods*; D014916:Whole-Body Irradiation
chemical_list: D016572:Cyclosporine
keywords: Donor leukocyte infusion; Graft-versus-leukemia and graft-versus-host disease; Lymphohematopoietic graft-versus- host responses; MHC defined miniature swine; Mixed chimerism