Our major goal is to improve survival for all patients who require unrelated donor (URD) transplantation through a better understanding of the HLA barrier. HLA mismatching is associated with increased risks of GVHD and mortality. We recently found that survival after HLA-mismatched URD transplantation is superior when the mismatched alleles are evolutionarily related (clade-matched) and are expressed at low levels than when they are evolutionarily different (clade-mismatched) and expressed at high levels. These data suggest a novel approach for defining permissible HLA mismatches. At the same time, HLA matching does not guarantee that risks will never occur. We have new evidence that variation in the HLA-DP 3'untranslated region (UTR) may help explain risks of GVHD after HLA-matched transplantation, supporting a potential role for HLA-DP expression in the etiology of GVHD. Based on our novel findings, we will determine whether clade matching of HLA-A, C and B mismatches is tolerable, and if so, prospectively select clade-matched URDs when matched URDs are not available. We will elucidate the role of HLA-C expression in lowering risks among clade-matches. We furthermore will translate novel SNP information to URD selection to lower GVHD after HLA-matched transplantation, and determine the role for DP expression in GVHD.
The specific aims are to 1) determine the significance of clade-mismatching on clinical outcome after HLA-mismatched URD transplantation and 2) determine the role of HLA-DP 3'UTR variation on GVHD risk after HLA-matched URD transplantation. The exploration of permissible HLA mismatches by way of their evolutionary relatedness is a novel approach for understanding all recognition. The integration of MHC region variation into prospective URD selection is a unique approach to improve clinical outcome after transplantation. Elucidation of the role of HLA expression in defining transplant-associated risks will improve understanding of the mechanisms of all recognition. The selection of URDs to lower GVHD and mortality will directly benefit studies described in Project 2, and complement strategies developed by Projects 3 and 4 for lowering relapse.
When a patient does not have a matched donor for transplantation, we are developing ways to find mismatched donors who can be used safely. When a patient has a matched donor, we are developing ways to further lower risks after transplantation. We hope that these efforts will improve survival for all patients who need a transplant.
|Humbert, Olivier; Gisch, Don W; Wohlfahrt, Martin E et al. (2016) Development of Third-generation Cocal Envelope Producer Cell Lines for Robust Lentiviral Gene Transfer into Hematopoietic Stem Cells and T-cells. Mol Ther 24:1237-46|
|Mielcarek, Marco; Furlong, Terry; O'Donnell, Paul V et al. (2016) Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood 127:1502-8|
|Achille, Nicholas J; Othus, Megan; Phelan, Kathleen et al. (2016) Association between early promoter-specific DNA methylation changes and outcome in older acute myeloid leukemia patients. Leuk Res 42:68-74|
|Cheng, Guang-Shing; Campbell, Angela P; Xie, Hu et al. (2016) Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant 22:925-31|
|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 22:1227-33|
|Green, Margaret L; Leisenring, Wendy; Xie, Hu et al. (2016) Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 3:e119-27|
|Sedlak, Ruth Hall; Hill, Joshua A; Nguyen, Thuy et al. (2016) Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR. J Clin Microbiol 54:1223-7|
|Graf, Solomon A; Vaughn, Jennifer E; Chauncey, Thomas R et al. (2016) Comorbidities, Alcohol Use Disorder, and Age Predict Outcomes after Autologous Hematopoietic Cell Transplantation for Lymphoma. Biol Blood Marrow Transplant 22:1582-7|
|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|
|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|
Showing the most recent 10 out of 1809 publications