The long-term objective of this project is to extend the application of stem cell transplants for use in patients with nonmalignant diseases by developing less toxic conditioning regimens that permit engraftment and prevent graft-versus-host disease. Included among these patients are those with hypocellular marrows who require immunosuppression only (e.g. aplastic anemia), those with genetic diseases in which 20-30% donor chimerism would relieve disease symptoms, and prospective solid organ transplant recipients who would become tolerized to their grafted organ. To address this goal, nonmyeloblative conditioning programs for hematopoietic allografts witch minimal graft-versus-host disease will be developed in a well-established preclinical model of random-bred dogs. The source of marrow repopulating cells used in these studies will be cytokine mobilized peripheral blood stem cells (PBSC) which enable earlier engraftment than does marrow. Specifically, we propose to explore regimens that will include monoclonal antibodies (MAbs) to lymphocyte surface determinants. Depending on the histocompatibility setting studied (DLA-identical vs. DLA-haploidentical littermates), MAbs to the TCR/CD3 complex, CD4, CD8, or certain adhesion molecules, e.g. CD44, may be used alone or in combination. The role of postgrafting immunosuppression, used to prevent GVHD, on engraftment will be defined. To address the issue of stem cell homing, as would be encountered in patients with cellular marrow, e.g. sickle cell disease, we shall determine how much marrow ablation in addition to immunosuppression is required for engraftment to be assured. This may be accomplished by very low-dose TBI, local marrow radiation, or the use of an MAb coupled to a short-lived alpha-emitting radionuclide, astatine-211. Finally, in DLA- haploidentical grafts, we will use a transient graft-versus-host effect to help with engraftment by transplanting """"""""lineage-depleted"""""""" PBSC along with in vitro expanded donor-anti host CTL that have been transduced with a herpes simplex virus thymidine kinase gene. Consequently, we shall exploit the CTL's acquired susceptibility to ganciclovir and eliminate the CTL after PBSC engraftment has occurred but before CVHD develops.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL036444-17
Application #
6241917
Study Section
Project Start
1997-08-01
Project End
1998-07-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
17
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
McCune, Jeannine S; Storer, Barry; Thomas, Sushma et al. (2018) Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients. Biol Blood Marrow Transplant 24:1802-1807
Thakar, M S; Bonfim, C; Walters, M C et al. (2017) Dose-adapted post-transplant cyclophosphamide for HLA-haploidentical transplantation in Fanconi anemia. Bone Marrow Transplant 52:570-573
Burroughs, Lauri M; Shimamura, Akiko; Talano, Julie-An et al. (2017) Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders. Biol Blood Marrow Transplant 23:1669-1677
Vaughn, J E; Anwer, F; Deeg, H J (2016) Treatment of refractory ITP and Evans syndrome by haematopoietic cell transplantation: is it indicated, and for whom? Vox Sang 110:5-11
Aki, S Z; Inamoto, Y; Carpenter, P A et al. (2016) Confounding factors affecting the National Institutes of Health (NIH) chronic Graft-Versus-Host Disease Organ-Specific Score and global severity. Bone Marrow Transplant 51:1350-1353
Khera, Nandita; Gooley, Ted; Flowers, Mary E D et al. (2016) Association of Distance from Transplantation Center and Place of Residence on Outcomes after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1319-1323
Karoopongse, Ekapun; Marcondes, A Mario; Yeung, Cecilia et al. (2016) Disruption of Iron Regulation after Radiation and Donor Cell Infusion. Biol Blood Marrow Transplant 22:1173-1181
Hoffmeister, P A; Storer, B E; Syrjala, K L et al. (2016) Physician-diagnosed depression and suicides in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up. Bone Marrow Transplant 51:153-6
Gallo, S; Woolfrey, A E; Burroughs, L M et al. (2016) Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD? Bone Marrow Transplant 51:1573-1578
Festuccia, Moreno; Deeg, H Joachim; Gooley, Theodore A et al. (2016) Minimal Identifiable Disease and the Role of Conditioning Intensity in Hematopoietic Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Evolving from Myelodysplastic Syndrome. Biol Blood Marrow Transplant 22:1227-1233

Showing the most recent 10 out of 788 publications