Christie Orschell

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Side effects of cancer chemotherapy and radiotherapy include destruction of bone marrow stem and progenitor cells. These cells help the body fight against life-threatening infection and hemorrhage. Exposure from radiological terrorism or accidents also leads to severe bone marrow damage. There are many FDA-approved medications to help bone marrow recovery after cancer treatment, but currently only two approved medical countermeasures (MCM) for individuals exposed to lethal doses of radiation. These medications, Neupogen and Neulasta, are “repurposed” from the cancer field.

Dr. Christie Orschell’s laboratory developed mouse models of the Hematopoietic-Acute Radiation Syndrome (H-ARS) and the Delayed Effects of Acute Radiation Exposure (DEARE) for efficacy testing of MCM against radiation according to the FDA Animal Rule. Under the Animal Rule, which guides drug development when human efficacy studies are unethical or unfeasible, development of radiation MCMs must first use animal models. Her models contributed to the approval of Neupogen and Neulasta, and have been promoted by the NIH to undergo qualification as a “drug development tool” by the FDA, which would allow the model to be publicly available for use in drug development programs and included in FDA submissions without the need to reconfirm suitability of the model.

Dr. Orschell’s work to develop animal models for radiation drug discovery is another example of how IUPUI faculty are TRANSLATING RESEARCH INTO PRACTICE.

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    Delayed effects of acute radiation exposure (DEARE) in a murine model of the hematopoietic acute radiation syndrome: Multiple-organ injury consequent to total body irradiation
    (Office of the Vice Chancellor for Research, 2015-04-17) Quickery, Ariel; Unthank, Joseph L.; Miller, Steven J.; Orschell, Christie M.
    Introduction. Victims of radiation exposure from terrorist activity, radiation accidents or radiologic warfare will face a variety of acute and chronic organ injuries requiring multi-faceted approaches to treatment. The hematopoietic system is the most sensitive tissue to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) after exposures of 2-10 Gy in mice. If untreated, H-ARS results in death within weeks from opportunistic infection and/or hemorrhage due to loss of neutrophils and platelets, respectively. However, survivors of ARS are plagued months to years later in life by delayed effects of acute radiation exposure (DEARE), a myriad of chronic illnesses affecting multiple organ systems believed to be due to persistent systemic oxidative stress, inflammation, fibrosis and loss of stem cell self-renewal. Fibrosis and collagen deposition disrupt both normal tissue structure and function and are common to organs with late radiation injury including the kidney and heart after radiation doses >15Gy, but have not been shown to exist after doses as low as those used in the H-ARS model (8Gy). The goal of this study was to determine the extent, if any, of heart and kidney DEARE in survivors of H-ARS. Methods. Mice (male and female C57BL/6) received total body irradiation (TBI; LD50/30 to LD70/30) and kidney and heart were harvested at 9 and 21 months from the H-ARS survivor mice. Tissues were fixed in neutral buffered formalin, paraffin embedded and sectioned, then stained with hematoxylin/eosin (H&E), trichrome, or picosirius red. Serum was collected at 4.3, 9, and 21 months post-TBI and analyzed for blood urea nitrogen (BUN) as an indicator of kidney function. Total RNA was purified from heart and relative changes in NADPH oxidase 2 (Nox2) mRNA expression were assessed by quantitative real-time PCR. Results/Significance. Compared to age-matched non-irradiated controls (NI), renal pathology at 9 months post-TBI was manifest primarily as enlargement of Bowman’s capsule and glomerosclerosis along with limited interstitial fibrosis. By 21 months there was progression of these pathologies as well as extensive interstitial fibrosis, tubular atrophy, cysts, and atubular glomeruli, all of which were more pronounced in TBI mice compared to NI. Consistent with the renal pathology, BUN in TBI mice was significantly increased at 9 and 21 months post-TBI vs. 4.3 months, but normal in NI mice at all time points. In the heart, pericardial, perivascular and interstitial fibrosis were observed at 9 months with increased severity at 21 months post-TBI compared to NI. The perivascular fibrosis was associated with increased medial layer collagen and apparent loss of vascular smooth muscle cells. Nox2 mRNA in heart was increased at 9 and 21 months post-TBI, indicating an increase in oxidant stress. To our knowledge, such striking heart and kidney damage has not been documented after radiation doses as low as those in our H-ARS model (~8Gy) and indicate that DEARE is a concern for individuals exposed to radiation doses previously thought to not elicit late effects.
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    Increased Incidence of Lymphosarcoma in Long-Term Murine Survivors of Lethal Radiation: A Classification of Subtypes
    (Office of the Vice Chancellor for Research, 2013-04-05) Spencer, Cleandrea; Chua, Hui Lin; Plett, Arthur; Sampson, Carol; Joshi, Mandar; Roberts, Christopher S.; Lipking, Kelsey; Orschell, Christie M.; Sandusky, George E.
    Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is thought to be due to decreased self-renewal of hematopoietic stem cells (HSC). We previously examined RBMD in murine survivors of lethal radiation modeling a terrorist event [800cGy total-body irradiation (TBI)]. We reported severely deficient HSC potential up to 20mo post-TBI compared to non-TBI age-matched controls, evidenced by minimal engraftment skewed to myeloid cells. CBC and BM cellularity were decreased in TBI mice, most dramatically in old age (>16mo). The percentage of some hematopoietic progenitors was consistently increased in TBI mice (~1.4x higher than non-TBI) possibly due to an increased cell cycling rate compared to non-TBI cells. Of interest, we now report the occurrence of a thymic mass developing in 13-24% of TBI mice 2-19 months post-TBI, compared to <1% of non-TBI. We characterized the Lymphosarcoma into the following groups based on the St. Jude pathology subclassification: Diffuse Lymphosarcoma involving multiple organs, Thymic lymphoma (usually associated with thymic and around the heart), Lymphosarcoma (potentially starting in the spleen and peri-pancreatic lymph nodes (Ab=abdomen)), and follicular lymphoma seen as a diffuse proliferation of lymphocytes in the white pulp area in the spleen. Thymic lymphomas were the most common, followed by Lymphosarcoma (Ab), follicular lymphoma (restricted to white pulp area in the spleen) and diffuse Lymphosarcoma. Immunostain markers revealed the thymic lymphomas were from T-cell lineage and the abdominal Lymphosarcoma were mainly from B-cell lineage. A few mice had disease involving the bone marrow. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to stem cell exhaustion and subsequent RBMD, as well as predispose survivors to hematopoietic neoplasias.
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    Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells
    (Elsevier, 2008-05) Orschell, Christie M.; Borneo, Jovencio; Munugalavadla, Veerendra; Ma, Peilin; Sims, Emily; Ramdas, Baskar; Yoder, Mervin C.; Kapur, Reuben; Department of Medicine, IU School of Medicine
    OBJECTIVE: Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells. RESULTS: Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1(+)Lin(-) cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK(-/-) cells, although, this increase did not affect the homing potential of more primitive Lin(-)Sca-1(+) SFK(-/-) cells. The stem cell-repopulating defect observed in mice transplanted with SFK(-/-) bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK(-/-) bone marrow cells. CONCLUSIONS: Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells.
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    PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), and IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-01) Plett, Paul Artur; Chua, Hui Lin; Sampson, Carol H.; Katz, Barry P.; Fam, Christine M.; Anderson, Lana J.; Cox, George N.; Orschell, Christie M.; Department of Medicine, IU School of Medicine
    Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76-8.72 Gy, Cs, 0.62-1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24-28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24-28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT's PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event.
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    Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-01) Chua, Hui Lin; Plett, P. Artur; Sampson, Carol H.; Katz, Barry P.; Carnathan, Gilbert W.; MacVittie, Thomas J.; Lenden, Keith; Orschell, Christie M.; Department of Medicine, IU School of Medicine
    In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation.
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    Delayed effects of acute radiation exposure on the cardiovascular system using a murine model of the hematopoietic acute radiation syndrome
    (Office of the Vice Chancellor for Research, 2016-04-08) Thungu, Beatrice; Ortiz, Miguel; Unthank, Joseph L.; Orschell, Christie M.; Miller, Steven J.
    Introduction. Exposure to high level radiation from accidents or belligerent activities results in acute and chronic organ damage. The hematopoietic system is the most sensitive organ to radiation damage (2-10 Gy) and results in the hematopoietic acute radiation syndrome (H-ARS). Survivors of H-ARS are plagued months to years later with delayed effects of acute radiation exposure (DEARE), characterized by chronic illnesses affecting multiple organ systems. Previous results using the murine H-ARS model showed numerous kidney and heart DEARErelated pathologies similar to humans, including tissue fibrosis and elevated blood urea nitrogen. The goal of this study was to utilize the murine H-ARS model to determine possible roles for abnormal iron metabolism, inflammation, oxidant stress, and senescence in the development of cardiac DEARE. Methods. Mice (C57BL/6; 12 week-old) received total body irradiation (TBI: ~8.5-8.7 Gy, 137Cs, LD50to LD70) and hearts were harvested at various times post-TBI from H-ARS survivors. Paraffin tissue sections were stained with hematoxylin/eosin or Perls Prussian Blue, or reacted with a macrophage-specific antibody (F4/80). Total RNA was purified from fresh tissue and changes in mRNA expression were assessed by real-time PCR for the senescence marker p16 and NADPH oxidase subunits Nox2, Nox4, or p47phox. Results/Significance. Compared to age-matched non-irradiated controls (NI), tissue iron deposits were increased in irradiated (IR) hearts at 4 months, and progressively declined with time post-TBI. Numbers of macrophages were greater in IR vs. NI sections at all time points and decreased with time post-TBI. Nox2 and Nox4 mRNA expression was increased at both 9 and 21 months post-TBI, but p47phox increased only at 21 months. Expression of p16 in IR heart was increased at 7, but not at 22 months post-TBI. Taken together, the results indicate abnormal iron metabolism, inflammation, oxidant stress, and early senescence may contribute to development of cardiac DEARE.
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    Relationships between renal parameters and serum and urine markers of inflammation in those with and without HIV infection
    (Mary Ann Liebert, 2015-04) Shinha, Takashi; Mi, Deming; Liu, Ziyue; Orschell, Christie M.; Lederman, Michael M.; Gupta, Samir K.; Department of Medicine, IU School of Medicine
    We sought to determine the relationships among intrarenal and systemic inflammation and renal disease in HIV. We compared paired serum and urinary levels (normalized to urine creatinine) of monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), interferon-γ-induced protein-10 (IP-10), interleukin-8 (IL-8), and β2-microglobulin (B2M) between two groups of HIV-infected subjects not receiving antiretroviral therapy (ART) [A: not expecting to initiate ART immediately due to having CD4 cell counts ≥350/μl, N=26; B: about to initiate ART, N=19], a group of HIV-infected subjects receiving virologically suppressive antiretroviral therapy [C, N=30], and a group of HIV-uninfected, healthy volunteers [D, N=45]. We then correlated these inflammatory biomarker levels with urine protein/creatinine ratios (uPCR), urine albumin/creatinine ratios (uACR), and estimated glomerular filtration rates (eGFR). Urine inflammatory biomarker levels were highest in Group B. When combining all four study groups, statistically significant positive correlations included uPCR with urine IL-8, urine MCP-1, urine IP-10, and serum IP-10 and uACR with urine IL-8, urine B2M, serum IP-10, and serum B2M. eGFR was statistically significantly negatively correlated with serum MCP-1 and serum B2M. Paired serum and urine levels of IP-10 and B2M (but not IL-8, RANTES, or MCP-1) were significantly correlated with each other in the overall group. The levels of urine inflammatory markers tested differed by HIV status and use of virologically suppressive ART. These urine and serum inflammatory markers were differentially correlated with uPCR, uACR, and eGFR, suggesting that different intrarenal and systemic inflammatory pathways may contribute to different measures of nephropathy.
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    Prognostic biomarkers for acute graft-versus-host disease risk after cyclophosphamide-fludarabine nonmyeloablative allotransplantation
    (Elsevier, 2014-11) Nelson, Robert P.; Khawaja, Muhammad Rizwan; Perkins, Susan M.; Elmore, Lindsey; Mumaw, Christen L.; Orschell, Christie M.; Paczesny, Sophie; Department of Pediatrics, IU School of Medicine
    Five candidate plasma biomarkers (suppression of tumorogenesis 2 [ST2], regenerating islet-derived-3α [REG3α], elafin, tumor necrosis factor receptor 1 [TNFR1], and soluble IL-2 receptor-alpha [sIL2Rα]) were measured at specific time points after cyclophosphamide/fludarabine-based nonmyeloablative allotransplantation (NMAT) in patients who did or did not develop acute graft-versus-host disease (aGVHD). Plasma samples from 34 patients were analyzed at days +7, +14, +21, and +30. At a median follow-up of 358 days, 17 patients had experienced aGVHD with a median time to onset at day +36. Risk of aGVHD was associated with elevated plasma ST2 concentrations at day +7 (c-statistic = .72, P = .03), day +14 (c-statistic = .74, P = .02), and day +21 (c-statistic = .75, P = .02); elevated plasma REG3α concentrations at day +14 (c-statistic = .73, P = .03), day +21 (c-statistic = .76, P = .01), and day +30 (c-statistic = .73, P = .03); and elevated elafin at day +14 (c-statistic = .71, P = .04). Plasma concentrations of TNFR1 and sIL2Rα were not associated with aGVHD risk at any of the time points studied. This study identified ST2, REG3α, and elafin as prognostic biomarkers to evaluate risk of aGVHD after cyclophosphamide/fludarabine-based NMAT. These results need to be confirmed in an independent validation cohort.
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    The H-ARS Dose Response Relationship (DRR): Validation and Variables
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Jackson, William; Vemula, Sasidhar; Sellamuthu, Rajendran; Fisher, Alexa; Feng, Hailin; Wu, Tong; MacVittie, Thomas J.; Orschell, Christie M.; Department of Medicine, School of Medicine
    Manipulations of lethally-irradiated animals, such as for administration of pharmaceuticals, blood sampling, or other laboratory procedures, have the potential to induce stress effects that may negatively affect morbidity and mortality. To investigate this in a murine model of the hematopoietic acute radiation syndrome, 20 individual survival efficacy studies were grouped based on the severity of the administration (Admn) schedules of their medical countermeasure (MCM) into Admn 1 (no injections), Admn 2 (1-3 injections), or Admn 3 (29 injections or 6-9 oral gavages). Radiation doses ranged from LD30/30 to LD95/30. Thirty-day survival of vehicle controls in each group was used to construct radiation dose lethality response relationship (DRR) probit plots, which were compared statistically to the original DRR from which all LDXX/30 for the studies were obtained. The slope of the Admn 3 probit was found to be significantly steeper (5.190) than that of the original DRR (2.842) or Admn 2 (2.009), which were not significantly different. The LD50/30 for Admn 3 (8.43 Gy) was less than that of the original DRR (8.53 Gy, p < 0.050), whereas the LD50/30 of other groups were similar. Kaplan-Meier survival curves showed significantly worse survival of Admn 3 mice compared to the three other groups (p = 0.007). Taken together, these results show that stressful administration schedules of MCM can negatively impact survival and that dosing regimens should be considered when constructing DRR to use in survival studies.
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    Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS: Multiple-Organ Injury Consequent to <10 Gy Total Body Irradiation
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Unthank, Joseph L.; Miller, Steven J.; Quickery, Ariel K.; Ferguson, Ethan L.; Wang, Meijing; Sampson, Carol H.; Chua, Hui Lin; DiStasi, Matthew R.; Feng, Hailin; Fisher, Alexa; Katz, Barry P.; Plett, P. Artur; Sandusky, George E.; Sellamuthu, Rajendran; Vemula, Sasidhar; Cohen, Eric P.; MacVittie, Thomas J.; Orschell, Christie M.; Department of Surgery, School of Medicine
    The threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a Cs radiation source and studied 1-21 mo later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ∼22 to 34 ± 3.8 and 69 ± 6.0 mg dL, p < 0.01 vs. non-irradiated controls) and correlated with glomerosclerosis (29 ± 1.8% vs. 64 ± 9.7% of total glomeruli, p < 0.01 vs. non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peribronchial fibrosis/collagen deposition was observed from ∼9-21 mo post-TBI in kidney, heart, and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in the left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model, which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs.