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headshot

William R. Drobyski, MD

Professor

Locations

  • Froedtert Hospital
  • Cancer Center - Froedtert Hospital

Specialties

  • Hematology

Languages

  • English

Cancer Center - Froedtert Hospital

General Interests

Inflammation and Immunology, Transplantation Biology

Education

  • MD - Doctor of Medicine

Research Interests

The main focus of the lab is on understanding inflammatory pathways and the immune regulation of these pathways as they occur within the context of allogeneic hematopoietic stem cell transplantation (HSCT) and, more specifically, graft versus host disease (GVHD). Allogeneic HSCT is employed as life-saving treatment for patients with underlying hematological malignancies, but its efficacy is compromised by GVHD which is the major complication of this therapy. GVHD is a pro inflammatory syndrome that is initiated by T cells, but also is dependent upon the complex interaction between elements of both the innate (i.e. granulocytes, macrophages, dendritic cells) and adaptive (T cells, B cells, regulatory T cells) immune systems. Our lab employs a variety of approaches including genetically modified mouse models, flow cytometry, q-PCR, RNA-seq, western blot, and molecular cloning to study the complexity of this specific disorder and also as a model for understanding inflammation in a broader sense. We have a particular emphasis on the biology of inflammation as it occurs within the gastrointestinal (GI) tract as this is the primary target organ for GVHD pathogenesis. Also, the lab has a strong interest in translational studies in which we have applied basic science findings and translated these into novel therapeutic approaches for the treatment of this disease in patients.

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.

Immune-mediated neuroinflammation

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.

Publications

  • (Nguyen C, Kudek M, Zander R, Niu H, Shen J, Bauer A, Alson D, Khatun A, Chen Y, Sun J, Drobyski W, Edelson BT, Cui W.) J Immunol. 2024 Jun 01;212(11):1829-1842 PMID: 38619295 SCOPUS ID: 2-s2.0-85194012903 04/15/2024

  • (Moe A, Rayasam A, Sauber G, Shah RK, Doherty A, Yuan CY, Szabo A, Moore BM 2nd, Colonna M, Cui W, Romero J, Zamora AE, Hillard CJ, Drobyski WR.) J Clin Invest. 2024 Apr 25;134(11) PMID: 38662453 PMCID: PMC11142740 SCOPUS ID: 2-s2.0-85195012384 04/25/2024

  • (Chhabra S, Jerkins JH, Monahan K, Szabo A, Shah NN, Abedin S, Runaas L, Fenske TS, Pasquini MC, Shaw BE, Drobyski WR, Saber W, D'Souza A, Dhakal B, Mohan M, Longo W, Hamadani M.) Bone Marrow Transplant. 2024 Mar;59(3):373-379 PMID: 38177221 SCOPUS ID: 2-s2.0-85181508004 01/05/2024

  • (Yuan C, Rayasam A, Moe A, Hayward M, Wells C, Szabo A, Mackenzie A, Salzman N, Drobyski WR.) Nat Commun. 2023 Dec 02;14(1):7963 PMID: 38042840 PMCID: PMC10693577 SCOPUS ID: 2-s2.0-85178369915 12/03/2023

  • (Lin M, Estrada-Merly N, Eapen M, Zamora AE, Pezzin LE, Winn AN, Philip J, Schinke C, Drobyski WR, Anderson LD Jr, D'Souza A.) Bone Marrow Transplant. 2023 Dec;58(12):1400-1402 PMID: 37673983 SCOPUS ID: 2-s2.0-85170080925 09/07/2023

  • (Moe A, Rayasam A, Sauber G, Shah RK, Yuan CY, Szabo A, Moore BM, Colonna M, Cui W, Romero J, Zamora AE, Hillard CJ, Drobyski WR.) bioRxiv. 2023 Aug 14 PMID: 37645843 PMCID: PMC10462026 08/30/2023

  • (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

  • (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

  • (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

  • (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

  • (Rayasam A, Drobyski WR.) Front Immunol. 2021;12:779076 PMID: 34899738 PMCID: PMC8662938 SCOPUS ID: 2-s2.0-85121218490 12/14/2021

  • (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