Chronic GVHD (cGVHD) is the most important adverse long-term consequence of allogeneic hematopoietic cell transplantation (HCT) and represents the most frequent cause of mortality occurring after 1-2 years from HCT. In previous studies supported by this Program Project, we made the novel observation that donor B cells played a critical role in the pathophysiology of cGVHD. This was demonstrated in patients with cGVHD as well as in murine models and this led us to undertake a series of clinical trials that demonstrated the clinical efficacy of B cell-directed therapy in the treatment and prevention of cGVHD. The overarching goal of this Program Project in this renewal is to identify optimal strategies for the application of B cell-directed therapies for the treatment and prevention of cGVHD. In this collaborative effort, we incorporate novel pivotal multi-center clinical trials, preclinical models of cGVHD to identify more effective B cell targeting strategies for future clinical studies and detailed analysis of patients receiving novel therapies. This is a highly integrated Program Project where the new clinical trials in Project 1 have been informed by previous pre-clinical murine studies in Project 2 and laboratory studies demonstrating the role of B cells in patients with cGVHD in Project 3. Project 1, Targeting B Cells in Chronic Graft-versus-Host Disease Prevention and Treatment, is dedicated to clinical trials of anti-B cell therapy that address the unmet need during three phases of cGVHD: pre-clinical presentation, initial therapy and late stage disease. These trials are the next phase of studies leading from our prior work, and are informed by the preclinical studies of Project 2. Project 2, Preclinical Drug Approaches to Chronic GVHD Prevention and Treatment is dedicated to the identification and testing of new drug and peptide therapies of cGVHD in a robust mouse model of cGVHD associated with fibrosis. Project 3, Humoral Targets and B Cell Biology in Chronic Graft-vs.-Host Disease is dedicated to understanding the immunologic effects of B cell-directed therapies in patients treated on clinical trials in Project 1, and potential mechanisms by which these new treatments alter B cell function in vivo. Novel discovery in Project 3 may lead to new biomarkers of cGVHD. Supported by unique and highly integrated cores, we have the opportunity to build on our previous discoveries and improve outcomes for patients with cGVHD.
Chronic GVHD (cGVHD) is the most important adverse long-term consequence of allogeneic hematopoietic cell transplantation. This Program Project addresses the unmet need in cGVHD with novel biological studies designed to better understand the role of the B cell in cGVHD pathophysiology, preclinical studies to test new B cell strategies in cGVHD therapy, and pivotal clinical trials to improve patient outcomes.
|Wu, Yongxia; Schutt, Steven; Paz, Katelyn et al. (2018) MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood 131:1974-1986|
|Gartlan, Kate H; Bommiasamy, Hemamalini; Paz, Katelyn et al. (2018) A critical role for donor-derived IL-22 in cutaneous chronic GVHD. Am J Transplant 18:810-820|
|Hippen, Keli L; Loschi, Michael; Nicholls, Jemma et al. (2018) Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease. Front Immunol 9:57|
|Koreth, John; Kim, Haesook T; Lange, Paulina B et al. (2018) Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results. Haematologica 103:522-530|
|Chen, Liying; Alexe, Gabriela; Dharia, Neekesh V et al. (2018) CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2. J Clin Invest 128:446-462|
|Kolupaev, Oleg V; Dant, Trisha A; Bommiasamy, Hemamalini et al. (2018) Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD. Blood Adv 2:2307-2319|
|Du, Jing; Flynn, Ryan; Paz, Katelyn et al. (2018) Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients. Blood 131:1743-1754|
|Zeiser, Robert; Sarantopoulos, Stefanie; Blazar, Bruce R (2018) B-cell targeting in chronic graft-versus-host disease. Blood 131:1399-1405|
|Blazar, Bruce R; MacDonald, Kelli P A; Hill, Geoffrey R (2018) Immune regulatory cell infusion for graft-versus-host disease prevention and therapy. Blood 131:2651-2660|
|Lu, Yunjie; Gao, Ji; Zhang, Shaopeng et al. (2018) miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg). Cell Death Dis 9:290|
Showing the most recent 10 out of 207 publications