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.
(Sarott RC, Westphal M, Pfaff P, Korn C, Sykes DA, Gazzi T, Brennecke B, Atz K, Weise M, Mostinski Y, Hompluem P, Koers E, Miljus T, Roth NJ, Asmelash H, Vong MC, Piovesan J, Guba W, Rufer A, Kusznir EA, Huber S, Raposo C, Zirwes EA, Osterwald A, Pavlovic A, Moes S, Beck J, Benito-Cuesta I, Grande T, Ruiz de Martin S, Yeliseev AA, Drawnel F, Widmer G, Holzer D, van der Wel T, Mandhair H, Yuan CY, Drobyski W, Saroz Y, Grimsey NL, Honer M, Fingerle J, Gawrisch K, Romero J, Hillard C, Varga Z, van der Stelt M, Pacher P, Gertsch J, McCormick P, Ullmer C, Oddi S, Maccarrone M, Veprintsev D, Nazaré M, Grether U, Carreira EM.) J Am Chem Soc. 2020 Sep 09 PMID: 32902974 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 Jul 09 PMID: 32653622 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 May;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
(Guru Murthy GS, Hari PN, Szabo A, Pasquini M, Narra R, Khan M, Abedin S, Chhabra S, Dhakal B, D'Souza A, Drobyski WR, Rizzo JD, Runaas L, Shah NN, Shaw B, Saber W, Fenske T, Hamadani M.) Biol Blood Marrow Transplant. 2019 04;25(4):827-833 PMID: 30572109 SCOPUS ID: 2-s2.0-85059680507 12/21/2018
(Yeshurun M, Weisdorf D, Rowe JM, Tallman MS, Zhang MJ, Wang HL, Saber W, de Lima M, Sandmaier BM, Uy G, Kamble RT, Cairo MS, Cooper BW, Cahn JY, Ganguly S, Camitta B, Verdonck LF, Dandoy C, Diaz MA, Savani BN, George B, Liesveld J, McGuirk J, Byrne M, Grunwald MR, Drobyski WR, Pulsipher MA, Abdel-Azim H, Prestidge T, Wieduwilt MJ, Martino R, Norkin M, Beitinjaneh A, Seo S, Nishihori T, Wirk B, Frangoul H, Bashey A, Mori S, Marks DI, Bachanova V.) Blood Adv. 2019 02 26;3(4):670-680 PMID: 30808685 PMCID: PMC6391668 SCOPUS ID: 2-s2.0-85062250569 02/28/2019
(Ganetsky A, Frey NV, Hexner EO, Loren AW, Gill SI, Luger SM, Mangan JK, Martin ME, Babushok DV, Drobyski WR, Smith J, Timlin C, Freyer CW, Stadtmauer EA, Porter DL.) Bone Marrow Transplant. 2019 02;54(2):212-217 PMID: 29795429 SCOPUS ID: 2-s2.0-85047331089 05/26/2018
(Piper C, Drobyski WR.) Front Immunol. 2019;10:163 PMID: 30853956 PMCID: PMC6395399 SCOPUS ID: 2-s2.0-85062722237 03/12/2019
(Voshtina E, Szabo A, Hamadani M, Fenske TS, D'Souza A, Chhabra S, Saber W, Drobyski WR, Hari P, Shah NN.) Biol Blood Marrow Transplant. 2019 01;25(1):e33-e38 PMID: 30244105 SCOPUS ID: 2-s2.0-85055445894 09/24/2018
(Xin G, Zander R, Schauder DM, Chen Y, Weinstein JS, Drobyski WR, Tarakanova V, Craft J, Cui W.) Nat Commun. 2018 11 28;9(1):5037 PMID: 30487586 PMCID: PMC6261948 SCOPUS ID: 2-s2.0-85057571059 11/30/2018