Inflammation and Immunology, Transplantation Biology
MD, University of Rochester School of Medicine and Dentistry, 1983
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.
(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. 2018 Dec 18.
(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.
(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 Jan;25(1):e33-e38.
(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 Feb;54(2):212-217.
(Agle K, Vincent BG, Piper C, Belle L, Zhou V, Shlomchik W, Serody JS, Drobyski WR.) Blood. 2018 Jul 26;132(4):435-447.
(Jeschke JC, Mayne CG, Ziegelbauer J, DeCiantis CL, Singh S, Kumar SN, Suchi M, Iwakura Y, Drobyski WR, Salzman NH, Williams CB.) Mucosal Immunol. 2018 07;11(4):1127-1137.
(Raj RV, Hamadani M, Szabo A, Pasquini MC, Shah NN, Drobyski WR, Shaw BE, Saber W, Rizzo JD, Jerkins J, Fenske TS, D'Souza A, Dhakal B, Zhang C, Konings S, Hari PN, Chhabra S.) Biol Blood Marrow Transplant. 2018 Aug;24(8):1664-1670.
(Badar T, Hari P, Chhabra S, Dhakal B, Drobyski WR, Fenske TS, Hamadani M, Pasquini M, Saber W, Shah NN, Shaw BE, D'Souza A.) Bone Marrow Transplant. 2018 Sep;53(9):1210-1213.
(Pan P, Oshima K, Huang YW, Agle KA, Drobyski WR, Chen X, Zhang J, Yearsley MM, Yu J, Wang LS.) Int J Cancer. 2018 08 15;143(4):886-896.
(Drobyski WR, Szabo A, Zhu F, Keever-Taylor C, 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.) Haematologica. 2018 Apr;103(4):717-727.
(Thompson J, Yin Z, D'Souza A, Fenske T, Hamadani M, Hari P, Rizzo JD, Pasquini M, Saber W, Shah N, Shaw BE, Shahir K, Banerjee A, Drobyski WR.) Biol Blood Marrow Transplant. 2017 Nov;23(11):1955-1960.
(Belle L, Zhou V, Stuhr KL, Beatka M, Siebers EM, Knight JM, Lawlor MW, Weaver C, Hashizume M, Hillard CJ, Drobyski WR.) JCI Insight. 2017 Jul 20;2(14).