William R. Drobyski, MD
Mariette C. and Philip W. Orth/Tom Anderson Chair of Oncology; Co-Leader, Discovery and Developmental Therapeutics Program, Cancer Center; Professor, Medicine (Hematology/Oncology), Pediatrics, Microbiology & Immunology
William Drobyski, MD, Professor of Medicine, Pediatrics and Microbiology & Immunology, obtained his medical degree from the University of Rochester where he also received residency training in Internal Medicine. He subsequently completed Hematology and Bone Marrow Transplantation fellowships at the University of Rochester and Medical College of Wisconsin (MCW), respectively. His research during his BMT fellowship focused on strategies to preserve the graft versus leukemia effect in patients receiving T cell depletion to prevent graft versus host disease (GVHD). He subsequently joined the faculty at MCW in 1990 and has had ongoing clinical responsibilities caring for patients on the Bone Marrow Transplant Unit along with directing a basic science research lab that is focused on understanding immunological aspects of allogeneic hematopoietic stem cell transplantation. For the past three decades, his research has specifically focused on understanding the pathophysiology of GVHD and graft versus leukemia effects conferred by the allogeneic graft using pre-clinical murine models of transplantation. He has also sought to translate basic research findings into the clinic in order to optimize patient outcomes.
Current research activities are supported by four NIH R01 grants as well as the Mariette C. and Philip W. Orth/Tom Anderson Endowed Chair in Oncology. Dr. Drobyski is also the Scientific Director of the Bone Marrow Transplantation Program and Leader of the Discovery and Developmental Therapeutics Program of the MCW Cancer Center.
- Bone Marrow Transplantation
- Graft vs Host Disease
- Hematopoietic Stem Cell Transplantation
- Graft vs Host Disease
- Hematopoietic Stem Cell Transplantation
- Leader, Discovery and Developmental Therapeutics Program, MCW Cancer Center
- Scientific Director Bone Marrow Transplant Program
Specific areas of interest and ongoing projects include:
Interleukin 23 (IL-23) and Granulocyte-Macrophage (GM-CSF) as critical mediators of inflammation during GVHD
Studies in the lab have shown that IL-23 plays a pivotal role in inducing inflammation within the GI tract during GVHD. To that end, we have identified a novel CD4+ IL-23R+ T cell population that constitutively expresses the β2 integrin, CD11c, has a biased central memory phenotype and memory T cell transcriptional profile, possesses innate-like properties by gene expression analysis, and has increased expression of the gut-homing molecules, α4β7 and CCR9. Using a number of complementary GVHD mouse models, we have shown that adoptive transfer of these cells results in TH1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality due to early accumulation of these cells in the GI tract. We have also recently identified that GM-CSF appears to have similar pro inflammatory effects within the GI tract and are actively investigating the role of these cytokine pathways in the biology of this disease.
Role of endocannabinoids in the pathophysiology of inflammation
Endocannabinoids are endogenously produced, arachidonic acid-containing bioactive lipids which play an important role in the modulation of anxiety, reward, stress responses, and memory. In addition, endocannabinoids have important immune modulatory effects in both inflammation and cancer. Ongoing studies in the lab are investigating how endocannabinoids regulate inflammation through the type 2 cannabinoid receptor. We have shown that inhibition of this signaling pathways exacerbates GVHD-associate inflammation and are currently examining agonist-based strategies to enhance immune regulation and mitigate the severity of this disease. Additionally, since GVHD is characterized by the development of fibrosis in the more chronic stage of the disease, we are investigating how endocannabinoids can be employed to mitigate this complication and prevent fibrotic-induced tissue damage.
We have identified that GVHD can also induce inflammation in the brain and that this is accompanied by neuro cognitive deficits which is analogous to what occurs in patients. Ongoing studies in the lab are examining neural pathways that are affected by GVHD-associated inflammation in collaboration with Dr. Cecilia Hillard who is the Director of the Neuroscience Research Center. Areas of focus include the role of host microglial cells, the contribution of endocannabinoids and inflammatory cytokines, and the effect of inflammation on tryptophan and dopamine metabolism which are critical neurotransmitters.
Translational Research using blockade of Interleukin 6 signaling to prevent GVHD
Interleukin 6 (IL-6) is produced by a number of cell types and is a primary mediator of inflammation. We observed that inhibition of IL-6 significantly reduced the severity of GVHD in animal models in part due to augmented reconstitution of regulatory T cells. We have subsequently translated these findings into a clinical trial in which patients were treated with Tocilizumab, a humanized form of the same antibody we used in our mouse models. The results of this study showed that patients treated with the antibody has a significant reduction in moderate to severe GVHD when compared to a cohort of patients that were treated with standard prophylactic therapy. This work indicated that our pre-clinical modeling and basic science investigations have direct clinical relevance.
Mitigation of gastrointestinal graft-versus-host disease with tocilizumab prophylaxis is accompanied by preservation of microbial diversity and attenuation of enterococcal domination.
(Chhabra S, Szabo A, Clurman A, McShane K, Waters N, Eastwood D, Samanas L, Fei T, Armijo G, Abedin S, Longo W, Hari P, Hamadani M, Shah NN, Runaas L, Jerkins JH, Van den Brink M, Peled JU, Drobyski WR.) Haematologica. 2023 Jan 01;108(1):250-256 PMID: 36106394 PMCID: PMC9827178 SCOPUS ID: 2-s2.0-85145424654 09/16/2022
Corrigendum to 'Ixazomib for chronic Graft-Versus-Host Disease prophylaxis following allogeneic hematopoietic cell transplantation' [Biology of Blood and Marrow Transplantation 26/10 (2020) 1876-1885].
(Chhabra S, Visotcky A, Pasquini MC, Zhu F, Tang X, Zhang MJ, Thompson R, Abedin S, D'Souza A, Dhakal B, Drobyski WR, Fenske TS, Jerkins JH, Rizzo JD, Runaas L, Saber W, Shah NN, Shaw BE, Horowitz MM, Hari PN, Hamadani M.) Transplant Cell Ther. 2022 Oct;28(10):717 PMID: 36202527 SCOPUS ID: 2-s2.0-85101258094 10/07/2022
The effect of tocilizumab on patient reported outcomes and inflammatory biomarkers in hematopoietic cell transplantation.
(Taylor MR, Hillard CJ, Drobyski WR, Szabo A, Johnson BD, Zhu F, Raison CL, Cole SW, Knight JM.) Brain Behav Immun Health. 2022 Aug;23:100480 PMID: 35757656 PMCID: PMC9213229 SCOPUS ID: 2-s2.0-85133379996 06/28/2022
Single-cell immune profiling reveals a developmentally distinct CD4+ GM-CSF+ T-cell lineage that induces GI tract GVHD.
(Piper C, Hainstock E, Yin-Yuan C, Chen Y, Khatun A, Kasmani MY, Evans J, Miller JA, Gorski J, Cui W, Drobyski WR.) Blood Adv. 2022 May 10;6(9):2791-2804 PMID: 35015822 PMCID: PMC9092418 SCOPUS ID: 2-s2.0-85130140800 01/12/2022
Corrigendum to ‘Ixazomib for chronic Graft-Versus-Host Disease prophylaxis following allogeneic hematopoietic cell transplantation’ [Biology of Blood and Marrow Transplantation 26/10 (2020) 1876-1885, (S1083879120304146), (10.1016/j.bbmt.2020.07.005)]
(Chhabra S, Visotcky A, Pasquini MC, Zhu F, Tang X, Zhang MJ, Thompson R, Abedin S, D'Souza A, Dhakal B, Drobyski WR, Fenske TS, Jerkins JH, Rizzo JD, Runaas L, Saber W, Shah NN, Shaw BE, Horowitz MM, Hari PN, Hamadani M.) Transplantation and Cellular Therapy. October 2022;28(10):717 SCOPUS ID: 2-s2.0-85101258094 10/01/2022
Self-Renewing Islet TCF1+ CD8 T Cells Undergo IL-27-Controlled Differentiation to Become TCF1- Terminal Effectors during the Progression of Type 1 Diabetes.
(Ciecko AE, Schauder DM, Foda B, Petrova G, Kasmani MY, Burns R, Lin CW, Drobyski WR, Cui W, Chen YG.) J Immunol. 2021 Oct 15;207(8):1990-2004 PMID: 34507949 PMCID: PMC8492517 SCOPUS ID: 2-s2.0-85116529072 09/12/2021
Budesonide Prophylaxis Reduces the Risk of Engraftment Syndrome After Autologous Hematopoietic Cell Transplantation in Multiple Myeloma.
(Dhakal B, Thapa B, Dong H, Tarima S, Chhabra S, D'Souza A, Drobyski W, Abid M, Shah N, Fenske T, Longo W, Hari P, Hamadani M.) Clin Lymphoma Myeloma Leuk. 2021 Oct;21(10):e775-e781 PMID: 34257042 SCOPUS ID: 2-s2.0-85110347842 07/15/2021
Toll-like receptor-9 stimulated plasmacytoid dendritic cell precursors suppress autoimmune neuroinflammation in a murine model of multiple sclerosis.
(Letscher H, Agbogan VA, Korniotis S, Gastineau P, Tejerina E, Gras C, Mégret J, Moe A, Drobyski WR, Zavala F.) Sci Rep. 2021 Feb 26;11(1):4735 PMID: 33637789 PMCID: PMC7910458 SCOPUS ID: 2-s2.0-85101779771 02/28/2021
The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill.
(Knight JM, Costanzo ES, Singh S, Yin Z, Szabo A, Pawar DS, Hillard CJ, Rizzo JD, D'Souza A, Pasquini M, Coe CL, Irwin MR, Raison CL, Drobyski WR.) Transl Psychiatry. 2021 Jan 18;11(1):58 PMID: 33462203 PMCID: PMC7812704 SCOPUS ID: 2-s2.0-85100097244 01/20/2021
Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease.
(Rayasam A, Drobyski WR.) Front Immunol. 2021;12:779076 PMID: 34899738 PMCID: PMC8662938 SCOPUS ID: 2-s2.0-85121218490 12/14/2021
Toll-like receptor-9 stimulated plasmacytoid dendritic cell precursors suppress autoimmune neuroinflammation in a murine model of multiple sclerosis
(Letscher H, Agbogan VA, Korniotis S, Gastineau P, Tejerina E, Gras C, Mégret J, Moe A, Drobyski WR, Zavala F.) Scientific Reports. December 2021;11(1) SCOPUS ID: 2-s2.0-85101779771 12/01/2021
Kras-Deficient T Cells Attenuate Graft-versus-Host Disease but Retain Graft-versus-Leukemia Activity.
(Luo L, Chen Y, Chen X, Zheng Y, Zhou V, Yu M, Burns R, Zhu W, Fu G, Felix JC, Hartley C, Damnernsawad A, Zhang J, Wen R, Drobyski WR, Gao C, Wang D.) J Immunol. 2020 Dec 15;205(12):3480-3490 PMID: 33158956 PMCID: PMC7955895 SCOPUS ID: 2-s2.0-85097490484 11/08/2020