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.

Cellular Therapies for the Treatment of Hematological Malignancies; Swine Are an Ideal Preclinical Model

“…Unfortunately, frequent complications of allogeneic bone marrow transplantation are infection and graft-vs.-host disease (GvHD), during which donor immune cells attack recipient cells. Swine (40–42), as well as other animal models (43, 44), have played an important role in the study and development of BMT and other cellular therapies for clinical application. Swine are an attractive model for the study and development of cellular immunotherapies due to the abundance of swine-specific reagents available (45–52).…”

“…Swine are an attractive model for the study and development of cellular immunotherapies due to the abundance of swine-specific reagents available (45–52). We have previously demonstrated the applicability of swine as a clinically-relevant model for the use of cellular therapies in inducing immunological tolerance via mixed chimerism (in which both recipient and donor cells co-exist) as well as for the treatment of GvHD in the form of donor leukocyte infusions (DLIs) (42, 53). In the following, we will recap some of these studies and touch on novel cellular therapies on the horizon.…”

“…This study and other similar studies in non-human primates laid the foundation for Sachs' pioneering study in humans using allogeneic BMT to simultaneously treat multiple myeloma and induce immune tolerance to MHC mismatched kidney allografts (57). Using the swine model described above, we attempted to leverage the alloreactive properties of DLIs to enhance donor chimerism, thereby maintaining or preventing graft loss, while at the same time avoiding GvHD (42). In our study of a total of 33 clinically dosed DLIs infused to immune tolerant swine chimeras, 21 failed to induce conversion to full donor hematopoietic chimerism or cause GvHD, demonstrating that our reduced intensity conditioning regimen for HCT promotes mixed chimerism and an immune tolerant state that is strongly resistant to DLI and GvHD.…”