Donor Lymphocyte Infusion–Mediated Graft-Versus-Host Responses In A Preclinical Swine Model Of Haploidentical Hematopoietic Cell Transplantation

Keywords

Donor leukocyte infusion; Graft-versus-leukemia and graft-versus-host disease; Lymphohematopoietic graft-versus- host responses; MHC defined miniature swine; Mixed chimerism

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.

Publication Date

11-1-2016

Publication Title

Biology of Blood and Marrow Transplantation

Volume

22

Issue

11

Number of Pages

1953-1960

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.bbmt.2016.08.011

Socpus ID

84992396672 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84992396672

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