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
- 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.
(Yuan CY, Zhou V, Sauber G, Stollenwerk T, Komorowski R, López A, Tolón RM, Romero J, Hillard CJ, Drobyski WR.) Blood. 2021 Mar 04;137(9):1241-1255 PMID: 33027805 PMCID: PMC7933769 SCOPUS ID: 2-s2.0-85101859000 10/08/2020
(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 01 18;11(1):58 PMID: 33462203 PMCID: PMC7812704 SCOPUS ID: 2-s2.0-85100097244 01/20/2021
(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
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] (Biology of Blood and Marrow Transplantation (2020) 26/10(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. 2021 SCOPUS ID: 2-s2.0-85101258094 01/01/2021
(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 12 15;205(12):3480-3490 PMID: 33158956 PMCID: PMC7955895 SCOPUS ID: 2-s2.0-85097490484 11/08/2020
(Sarott RC, Westphal MV, Pfaff P, Korn C, Sykes DA, Gazzi T, Brennecke B, Atz K, Weise M, Mostinski Y, Hompluem P, Koers E, Miljuš T, Roth NJ, Asmelash H, Vong MC, Piovesan J, Guba W, Rufer AC, Kusznir EA, Huber S, Raposo C, Zirwes EA, Osterwald A, Pavlovic A, Moes S, Beck J, Benito-Cuesta I, Grande T, Ruiz de Martı N Esteban S, Yeliseev A, Drawnel F, Widmer G, Holzer D, van der Wel T, Mandhair H, Yuan CY, Drobyski WR, Saroz Y, Grimsey N, Honer M, Fingerle J, Gawrisch K, Romero J, Hillard CJ, Varga ZV, van der Stelt M, Pacher P, Gertsch J, McCormick PJ, Ullmer C, Oddi S, Maccarrone M, Veprintsev DB, Nazaré M, Grether U, Carreira EM.) J Am Chem Soc. 2020 10 07;142(40):16953-16964 PMID: 32902974 SCOPUS ID: 2-s2.0-85092682450 09/10/2020
(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, Douglas Rizzo J, Runaas L, Saber W, Shah NN, Shaw BE, Horowitz MM, Hari PN, Hamadani M.) Biol Blood Marrow Transplant. 2020 10;26(10):1876-1885 PMID: 32653622 PMCID: PMC7571859 SCOPUS ID: 2-s2.0-85089134303 07/13/2020
(Chhabra S, Narra RK, Wu R, Szabo A, George G, Michaelis LC, D'Souza A, Dhakal B, Drobyski WR, Fenske TS, Jerkins JH, Pasquini MC, Rizzo RD, Saber W, Shah NN, Shaw BE, Hamadani M, Hari PN.) Biol Blood Marrow Transplant. 2020 05;26(5):893-901 PMID: 31982543 SCOPUS ID: 2-s2.0-85080146585 01/27/2020
(Piper C, Zhou V, Komorowski R, Szabo A, Vincent B, Serody J, Alegre ML, Edelson BT, Taneja R, Drobyski WR.) Blood. 2020 02 20;135(8):568-581 PMID: 31880771 PMCID: PMC7033370 SCOPUS ID: 2-s2.0-85081142993 12/28/2019
(Badar T, Khan MA, Szabo A, Drobyski W, Chhabra S, Dhakal B, Fenske TS, Hamadani M, Hari P, Jerkins JH, Shah NN, Shaw BE, D'Souza A.) Amyloid. 2019 Dec;26(4):210-215 PMID: 31347424 SCOPUS ID: 2-s2.0-85074118154 07/28/2019
(Abedin S, McKenna E, Chhabra S, Pasquini M, Shah NN, Jerkins J, Baim A, Runaas L, Longo W, Drobyski W, Hari PN, Hamadani M.) Biol Blood Marrow Transplant. 2019 08;25(8):1689-1694 PMID: 30965140 SCOPUS ID: 2-s2.0-85065022222 04/10/2019
(Piper C, Drobyski WR.) Front Immunol. 2019;10:163 PMID: 30853956 PMCID: PMC6395399 SCOPUS ID: 2-s2.0-85062722237 03/12/2019