Sophie Paczesny
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Translating Novel Biomarkers of Transplant Immunity and Tolerance
Allogeneic hematopoietic stem cell transplantation (HSCT) is a major therapy for malignant diseases of the blood and bone marrow and the most potent form of immune therapy against these diseases through its graft-versus-leukemia/tumor (GVL/GVT) effect. However, the efficacy of allogeneic HSCT has been impeded by frequent and severe graft-versus- host disease (GVHD) that is tightly linked to the GVL/GVT effect. Both acute and chronic forms of GVHD exist. The immunology of GVHD and GVL responses are complex and cytokines and cellular effectors are critical. Dr. Paczesy’s laboratory focuses on understanding the role of cytokines and cellular effectors in the biology of GVHD/GVL by discovering and investigating biomarkers in the blood and tissue of patients following allogeneic HSCT.
The goal of Dr. Paczesy’s laboratory is to develop tests to predict the risk of developing CVHD, responsiveness to treatment, and patient survival by integrating both proteomic and cellular biomarkers for the diagnosis and prognosis of GVHD. They are interested in both acute and chronic GVHD, which has overlapping features of immunodeficiency and symptoms of naturally occurring autoimmune disorders. Indeed, a prominent clinical feature of chronic GVHD is a debilitating fibrosing skin disease whose gross and histologic features resemble scleroderma (SSc) and, less commonly, morphea. Because of these potential biological similarities between chronic GVHD and autoimmune diseases, her work is also relevant.
Dr. Paczesy’s work to predict the risk of developing CVHD is another example of how IUPUI faculty are TRANSLATING RESEARCH INTO PRACTICE.
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Item Opportunities and challenges of proteomics in pediatric patients: circulating biomarkers after hematopoietic stem cell transplantation as a successful example(Wiley, 2014-12) Paczesny, Sophie; Duncan, Christine; Jacobsohn, David; Krance, Robert; Leung, Kathryn; Carpenter, Paul; Bollard, Catherine; Renbarger, Jamie; Cooke, Kenneth; Department of Medicine, IU School of MedicineBiomarkers have the potential to improve diagnosis and prognosis, facilitate-targeted treatment, and reduce health care costs. Thus, there is great hope that biomarkers will be integrated in all clinical decisions in the near future. A decade ago, the biomarker field was launched with great enthusiasm because MS revealed that blood contains a rich library of candidate biomarkers. However, biomarker research has not yet delivered on its promise due to several limitations: (i) improper sample handling and tracking as well as limited sample availability in the pediatric population, (ii) omission of appropriate controls in original study designs, (iii) lability and low abundance of interesting biomarkers in blood, and (iv) the inability to mechanistically tie biomarker presence to disease biology. These limitations as well as successful strategies to overcome them are discussed in this review. Several advances in biomarker discovery and validation have been made in hematopoietic stem cell transplantation, the current most effective tumor immunotherapy, and these could serve as examples for other conditions. This review provides fresh optimism that biomarkers clinically relevant in pediatrics are closer to being realized based on: (i) a uniform protocol for low-volume blood collection and preservation, (ii) inclusion of well-controlled independent cohorts, (iii) novel technologies and instrumentation with low analytical sensitivity, and (iv) integrated animal models for exploring potential biomarkers and targeted therapiesItem National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: III. The 2014 Biomarker Working Group Report(Elsevier B.V., 2015-05) Paczesny, Sophie; Hakim, Frances T.; Pidala, Joseph; Cooke, Kenneth; Lathrop, Julia; Griffith, Linda M.; Hansen, John; Jagasia, Madan; Miklos, David; Pavletic, Steven; Parkman, Robertson; Russek-Cohen, Estelle; Flowers, Mary E.D.; Lee, Stephanie; Martin, Paul; Vogelsang, Georgia; Walton, Marc; Schultz, Kirk R.; Department of Pediatrics, IU School of MedicineBiology-based markers to confirm or aid in the diagnosis or prognosis of chronic GVHD after allogeneic hematopoietic cell transplantation (HCT) or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include: a) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity, b) prognostic risk to develop chronic GVHD, and c) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well-documented following established quality control guidelines for sample acquisition, processing, preservation and testing, at intervals that are both calendar- and event-driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for utilization in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a four-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines.Item Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes(Nature Publishing Group, 2015-03) Gleimer, Michael; Li, Yumeng; Chang, Lawrence; Paczesny, Sophie; Hanauer, David A.; Frame, David G.; Byersdorfer, Craig A.; Reddy, Pavan R.; Braun, Thomas M.; Choi, Sung Won; Department of Pediatrics, IU School of MedicineObesity is an important public health problem that may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic hematopoietic stem cell transplants between 2004 and 2012. Pre-transplant body mass index (BMI) was classified as underweight, normal weight, overweight, or obese using the WHO classification, or age-adjusted BMI percentiles for children. The study population was predominantly Caucasian, and the median age was 51 years (5 months – 73 years). The cumulative 3-year incidence of non-relapse mortality (NRM) in underweight, normal weight, overweight, and obese patients was 20%, 19%, 20%, and 33%, respectively. Major causes of NRM were acute and chronic graft-versus-host disease (GVHD). The corresponding incidence of relapse was 30%, 41%, 37%, and 30%, respectively. Three-year overall survival was 59%, 48%, 47%, and 43%, respectively. Multivariate analysis showed that obesity was associated with higher NRM (HR 1.43, p=0.04), and lower relapse (HR 0.65, p=0.002). Pre-transplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese compared with normal weight patients (p=0.04 and p=0.05, respectively). The increase in NRM observed in obese patients was partially offset by lower incidence of relapse with no difference in overall survival.Item Various forms of tissue damage and danger signals following hematopoietic stem-cell transplantation(Frontiers Media S.A., 2015-01-28) Ramadan, Abdularouf; Paczesny, Sophie; Department of Pediatrics, IU School of MedicineHematopoietic stem-cell transplantation (HSCT) is the most potent curative therapy for many malignant and non-malignant disorders. Unfortunately, a major complication of HSCT is graft-versus-host disease (GVHD), which is mediated by tissue damage resulting from the conditioning regimens before the transplantation and the alloreaction of dual immune components (activated donor T-cells and recipient's antigen-presenting cells). This tissue damage leads to the release of alarmins and the triggering of pathogen-recognition receptors that activate the innate immune system and subsequently the adaptive immune system. Alarmins, which are of endogenous origin, together with the exogenous pathogen-associated molecular patterns (PAMPs) elicit similar responses of danger signals and represent the group of damage-associated molecular patterns (DAMPs). Effector cells of innate and adaptive immunity that are activated by PAMPs or alarmins can secrete other alarmins and amplify the immune responses. These complex interactions and loops between alarmins and PAMPs are particularly potent at inducing and then aggravating the GVHD reaction. In this review, we highlight the role of these tissue damaging molecules and their signaling pathways. Interestingly, some DAMPs and PAMPs are organ specific and GVHD-induced and have been shown to be interesting biomarkers. Some of these molecules may represent potential targets for novel therapeutic approaches.Item 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 MedicineFive 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.Item Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation.(Elsevier, 2015-10) Akil, Ayman; Zhang, Qing; Mumaw, Christen L.; Raiker, Nisha; Yu, Jeffrey; de Mendizabal, Nieves Velez; Haneline, Laura S.; Robertson, Kent A.; Skiles, Jodi; Diaz-Ricart, Maribel; Carreras, Enric; Renbarger, Jamie; Hanash, Samir; Bies, Robert R.; Paczesny, Sophie; Department of Pediatrics, IU School of MedicineReliable, non-invasive methods for diagnosing and prognosing sinusoidal obstruction syndrome (SOS) early after hematopoietic cell transplantation (HCT) are needed. We used a quantitative mass spectrometry-based proteomics approach to identify candidate biomarkers of SOS by comparing plasma pooled from 20 patients with and 20 patients without SOS. Of 494 proteins quantified, we selected six proteins [L-Ficolin, vascular-cell-adhesion-molecule-1 (VCAM1), tissue-inhibitor of metalloproteinase-1, von Willebrand factor, intercellular-adhesion-molecule-1, and CD97] based on a differential heavy/light isotope ratio of at least 2 fold, information from the literature, and immunoassay availability. Next, we evaluated the diagnostic potential of these six proteins and five selected from the literature [suppression of tumorigenicity-2 (ST2), angiopoietin-2 (ANG2), hyaluronic acid (HA), thrombomodulin, and plasminogen activator inhibitor-1] in samples from 80 patients. The results demonstrate that together ST2, ANG2,Item Early Th1 immunity promotes immune tolerance and may impair graft-versus-leukemia effect after allogeneic hematopoietic cell transplantation(European Hematology Association, 2016-05) Engelhardt, Brian G.; Paczesny, Sophie; Jung, Dae Kwang; Daguindau, Etienne; Jagasia, Madan; Savani, Bipin N.; Chinratanalab, Wichai; Cornell, Robert F.; Goodman, Stacey; Greer, John P.; Kassim, Adetola A.; Sengsayadeth, Salyka; Yoder, Sandra M.; Rock, Michael T.; Crowe Jr., James E.; Department of Pediatrics, IU School of MedicineItem Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease(Elsevier, 2017) Inamoto, Yoshihiro; Martin, Paul J.; Paczesny, Sophie; Tabellini, Laura; Momin, Amin A.; Mumaw, Christen L.; Flowers, Mary E. D.; Lee, Stephanie J.; Carpenter, Paul A.; Storer, Barry E.; Hanash, Samir; Hansen, John A.; Department of Pediatrics, IU School of MedicineChronic graft-versus-host disease (GVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic cell transplantation. To identify prognostic plasma proteins associated with de novo– or quiescent-onset chronic GVHD (cGVHD), we performed a discovery and validation proteomic study. The total study cohort included 167 consecutive patients who had no clinical evidence of GVHD under minimum glucocorticoid administration and had available plasma samples obtained at 80 ± 14 days after transplantation. We first used high-throughput mass spectrometry to screen pooled plasma using 20 cases with subsequent cGVHD and 20 controls without it, and we identified 20 candidate proteins. We then measured 12 of the 20 candidate proteins by ELISA on the same individual samples and identified 4 proteins for further verification (LGALS3BP, CD5L, CD163, and TXN for de novo onset, and LGALS3BP and CD5L for quiescent onset). The verification cohort included 127 remaining patients. The cumulative incidence of de novo–onset cGVHD was higher in patients with higher plasma soluble CD163 concentrations at day 80 than those with lower concentrations (75% versus 40%, P = .018). The cumulative incidence of de novo– or quiescent-onset cGVHD did not differ statistically according to concentrations of the 3 other proteins at day 80. CD163 is a macrophage scavenger receptor and is elevated in oxidative conditions. These results suggest that monocyte or macrophage activation or increased oxidative stress may contribute to the pathogenesis of cGVHD.Item Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post-allogeneic HCT.(American Society of Hematology, 2017-01-12) Zaid, Mohammad Abu; Wu, Juan; Wu, Cindy; Logan, Brent R.; Yu, Jeffrey; Cutler, Corey; Antin, Joseph H.; Paczesny, Sophie; Choi, Sung Won; Department of Pediatrics, IU School of MedicineA phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir = 104, Tac/Mtx = 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P = .0050, P = .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49-3.95], P = .0038 and 4.87 [2.53-9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P = .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P = .0053, AUC = 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study.Item Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease(American Society for Clinical Investigation, 2016-05-05) Li, Wei; Liu, Liangyi; Gomez, Aurelie; Zhang, Jilu; Ramadan, Abdulraouf; Zhang, Qing; Choi, Sung W.; Zhang, Peng; Greenson, Joel K.; Liu, Chen; Jiang, Di; Virts, Elizabeth; Kelich, Stephanie L.; Chu, Hong Wei; Flynn, Ryan; Blazar, Bruce R.; Hanenberg, Helmut; Hanash, Samir; Paczesny, Sophie; Department of Microbiology & Immunology, IU School of MedicineGastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+ T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+ T cell population toward CCL14. Mice that received CD146 shRNA-transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+ T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA- transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+ Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT.