William R. Drobyski, MD
Mariette C. and Philip W. Orth/Tom Anderson Chair of Oncology
Co-Leader, Discovery and Developmental Therapeutics Program, Cancer Center
Microbiology and Immunology
Medical College of Wisconsin
Research Focus: Inflammation and Immunology, Transplantation Biology
MD: University of Rochester School of Medicine and Dentistry (1983)
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.
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 Neurosciences 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.
- Drobyski WR, Szabo A, Zhu F, Keever-Taylor CA, Hebert KM, Dunn R, Yim S, Johnson B, D’Souza A, Eapen M, Fenske TS, Hari P, Hamadani M, Horowitz MM, Rizzo JD, Saber W, Shah N, Shaw B, Pasquini M. Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft versus host disease: Low incidence of lower gastrointestinal tract disease. Haematologica 2018 (in press).
- Pan P, Oshima K, Huang YW, Agle KA, Drobyski WR, Chen X, Zhang J, Yearsley MM, Yu J, Wang LS. Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors. Int J Cancer 2018 (in press).
- Thompson J, Yin Z, D’Souza A, Fenske T, Hamadani M, Hari P, Rizzo JD, Pasquini M, Saber W, Shaw BE, Shahir K, Banerjee A, Drobyski WR. Etanercept and corticosteroid therapy for the treatment of late onset idiopathic pneumonia syndrome. Biol Blood Marrow Transplant 23(11): 1955-1960, 2017.
- Pan P, Skaer CW, Wang H-T, Oshima K, Huang Y-W, Yu J, Zhang J, Yearsley M, Agle K, Drobyski W, Chen X, Wang L-S. Loss of free fatty acid receptor 2 enhances colonic adenoma development and reduces the chemopreventive effects of black raspberries in ApcMin/+ mice. Carcinogenesis 38(1): 86-93, 2017.
- Belle L, Zhou V, Stuhr KL, Beatka M, Siebers EM, Knight JM, Lawlor MW, Weaver C, Hashizume M, Hillard CJ, Drobyski WR. Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD. JCI Insight 2(14) pii: 93726, 2017.
- Dodge J, Stephans A, Drobyski WR, Chen X. Effects of donor vitamin A deficiency and pharmacological modulation of donor T cell retinoic acid pathway on the severity of experimental graft versus host disease. Biol Blood Marrow Transplant 22(12): 2141-2148, 2016.
- Belle L, Agle K, Zhou V, Yin-Yuan C, Komorowski R, Eastwood D, Logan B, Sun J, Ghilardi N, Cua D, Williams CB, Gaignage M, Marillier R, van Snick J, Drobyski WR. Blockade of interleukin 27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression. Blood 128(16): 2068-2082, 2016.
- Zhou V, Agle K, Chen X, Beres A, Komorowski R, Belle L, Taylor C, Zhu F, Haribhai D, Williams CB, Verbsky J, Blumenschein W, Sadekova S, Bowman E, Ballantyne C, Weaver C, Serody DA, Vincent B, Serody J, Cua D, Drobyski WR. Identification of a colitogenic memory CD4+ T cell population that mediates gastrointestinal GVHD. J Clin Invest 126 (9): 3541-3555, 2016.
- Cornell RF, Hari P, Drobyski WR. Engraftment syndrome following autologous stem transplantation-an update unifying the definition and management approach. Biol Blood Marrow Transplant 21(12): 2061-2068, 2015.
Complete list of publications