Non-myeloablative hematopoietic cell transplantation (HCT) followed by delayed donor leukocyte infusion(DLI) is a promising immunotherapeutic approach to treat hematologic malignancies including leukemias andlymphomas. Major limitations of this approach, however, include the risks of graft failure, graft-versus-hostdisease, (GVHD) and infection. MGH MHC-inbred miniature swine provide a pre-clinical model for studies oftransplantation biology with responses to HCT resembling those of humans. Preliminary data suggest that anovel, minimally myelosuppressive preparative regimen leads to stable multilineage chimerism following highdosehaploidentical HCT, without causing GVHD. In this proposal we aim to 1) determine the immunologicalmechanisms involved in controlling hbst-versus-graft (HVG) and GVH responses that allow engraftmentwithout GVHD across MHC barriers in this model. These studies will be performed in close collaboration withProjects 1 and 2 to extend the mechanistic studies in rodent models. We will then 2) optimize the swinemodel to facilitate translation of this protocol to the clinic and analyze the importance of specific geneticdisparities (haploidentical class I and II, class I only, class II only) on engraftment, GVHD and the effects ofsubsequent DLI. In collaboration with Project 4, we will test novel strategies to improve stem cell harvestsfollowing cytokine mobilization through parathyroid hormone (PTH) stimulation. Increased numbers of stemcells in the leukapheresis product following PTH stimulation and cytokine mobilization may enable stableengraftment using lower doses of cells more easily attainable in the clinic. It is hoped that results of thesestudies will permit the development of tailored approaches to the use of DLI in chimeric patients dependingon their HLA disparities from the donor. In addition, we plan to 3) further develop the swine model to allowdirect assessment of graft-versus-tumor effects of HCT and DLI. For this purpose, we will establish tumor celllines derived from inbred miniature swine and adapt these tumor lines for in vivo growth in pigs. With therecent availability of histocompatible miniature swine, and tumor lines derived from these highly inbredanimals, we have the unique opportunity to develop transplantable tumors in a preclinical large animal model.These studies could provide a foundation for future immunotherapeutic approaches for the treatment ofhematological malignancies that may be translated toward treatment of human disease.
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