Browsing by Subject "Graft-versus-host disease"
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Item Addition of Infliximab to Standard Acute Graft-versus-Host Disease Prophylaxis following Allogeneic Peripheral Blood Cell Transplantation(Elsevier, 2008-07-01) Hamadani, Mehdi; Hofmeister, Craig C.; Jansak, Buffy; Phillips, Gary; Elder, Patrick; Blum, William; Penza, Sam; Lin, Thomas S.; Klisovic, Rebecca; Marcucci, Guido; Farag, Sherif S.; Devine, Steven M.; Medicine, School of MedicineInfliximab, a chimeric monoclonal antibody (mAb) against tumor necrosis factor (TNF)-α, has shown activity against steroid refractory acute graft-versus-host disease (aGVHD). We conducted a prospective trial of infliximab for the prophylaxis of aGVHD. Patients older than 20 years undergoing myeloablative allogeneic stem cell transplantation (SCT) for hematologic malignancies were eligible. GVHD prophylaxis consisted of infliximab given 1 day prior to conditioning and then on days 0, +7, +14, +28, and +42, together with standard cyclosporine (CSA) and methotrexate (MTX). Nineteen patients with a median age of 53 years were enrolled. All patients received peripheral blood allografts from matched sibling (n = 14) or unrelated donors (n = 5). Results were compared with a matched historic control group (n = 30) treated contemporaneously at our institution. The cumulative incidences of grades II-IV aGVHD in the infliximab and control groups were 36.8% and 36.6%, respectively (P = .77). Rates of chronic GVHD were 78% and 61%, respectively (P = .22). Significantly more bacterial and invasive fungal infections were observed in the infliximab group (P = .01 and P = .02, respectively). Kaplan-Meier estimates of 2-year overall survival (OS) and progression free survival (PFS) for patients receiving infliximab were 42% and 36%, respectively. The corresponding numbers for patients in the control group were 46% and 43%, respectively. The addition of infliximab to standard GVHD prophylaxis did not lower the risk of GVHD and was associated with an increased risk of bacterial and invasive fungal infections.Item Biomarkers for Allogeneic HCT Outcomes(Frontiers Media, 2020-04-21) Adom, Djamilatou; Rowan, Courtney; Adeniyan, Titilayo; Yang, Jinfeng; Paczesny, Sophie; Pediatrics, School of MedicineAllogeneic hematopoietic cell transplantation (HCT) remains the only curative therapy for many hematological malignant and non-malignant disorders. However, key obstacles to the success of HCT include graft-versus-host disease (GVHD) and disease relapse due to absence of graft-versus-tumor (GVT) effect. Over the last decade, advances in “omics” technologies and systems biology analysis, have allowed for the discovery and validation of blood biomarkers that can be used as diagnostic test and prognostic test (that risk-stratify patients before disease occurrence) for acute and chronic GVHD and recently GVT. There are also predictive biomarkers that categorize patients based on their likely to respond to therapy. Newer mathematical analysis such as machine learning is able to identify different predictors of GVHD using clinical characteristics pre-transplant and possibly in the future combined with other biomarkers. Biomarkers are not only useful to identify patients with higher risk of disease progression, but also help guide treatment decisions and/or provide a basis for specific therapeutic interventions. This review summarizes biomarkers definition, omics technologies, acute, chronic GVHD and GVT biomarkers currently used in clinic or with potential as targets for existing or new drugs focusing on novel published work.Item Characterization of Hepatic Dysfunction in subjects diagnosed with Chronic GVHD by NIH Consensus Criteria(Elsevier, 2022) Yang, Alexander H.; Han, Ma Ai Thanda; Samala, Niharika; Rizvi, Bisharah S.; Marchalik, Rachel; Etzion, Ohad; Wright, Elizabeth C.; Cao, Liang; Hakim, Frances T.; Jones, Elizabeth; Kapuria, Devika; Hickstein, Dennis D.; Fowler, Daniel; Kanakry, Jennifer A.; Kanakry, Christopher G.; Kleiner, David E.; Koh, Christopher; Pavletic, Steven Z.; Heller, Theo; Medicine, School of MedicineHepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality.Item Clinical Proteomics for Post-Hematopoeitic Stem Cell Transplantation Outcomes(Wiley, 2019-03) Paczesny, Sophie; Metzger, Jochen; Pediatrics, School of MedicineAllogeneic hematopoietic stem cell transplantation (HSCT) is the most effective form of tumor immunotherapy available to date. However, while HSCT can induce beneficial graft-versus-leukemia (GVL) effect, the adverse effect of graft-versus-host disease (GVHD), which is closely linked to GVL, is the major source of morbidity and mortality following HSCT. Until recently, available diagnostic and staging tools frequently fail to identify those at higher risk of disease progression or death. Furthermore, there are shortcomings in the prediction of the need for therapeutic interventions or the response rates to different forms of therapy. The past decade has been characterized by an explosive evolution of proteomics technologies, largely due to important advances in high-throughput MS instruments and bioinformatics. Building on these opportunities, blood biomarkers have been identified and validated both as promising diagnostic tools, prognostic tools that risk-stratify patients before future occurrence of GVHD and as predictive tools for responsiveness to GVHD therapy and non-relapse mortality. These biomarkers might facilitate timely and selective therapeutic intervention. This review summarizes current information on clinical proteomics for GVHD as well as other complications following HSCT. Finally, it proposes future directions for the translation of clinical proteomics to discovery of new potential therapeutic targets to the development of drugs.Item Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology(Springer Nature, 2021) Fujiwara, Hideaki; Seike, Keisuke; Brooks, Michael D.; Mathew, Anna V.; Kovalenko, Ilya; Pal, Anupama; Lee, Ho-Joon; Peltier, Daniel; Kim, Stephanie; Liu, Chen; Oravecz-Wilson, Katherine; Li, Lu; Sun, Yaping; Byun, Jaeman; Maeda, Yoshinobu; Wicha, Max S.; Saunders, Tom; Rehemtulla, Alnawaz; Lyssiotis, Costas A.; Pennathur, Subramaniam; Reddy, Pavan; Microbiology and Immunology, School of MedicineIntestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis. But little is known about the target cell intrinsic features that influence disease severity. Herein we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified disruption of IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.Item Post-haematopoietic cell transplantation outcomes: why ST2 became a ‘golden nugget’ biomarker(Wiley, 2021-03) Paczesny, Sophie; Pediatrics, School of MedicineImmunotherapies have emerged as highly promising approaches to treat cancer patients. Allogeneic haematopoietic cell transplantation (HCT) is the most validated tumour immunotherapy available to date but its clinical efficacy is limited by toxicities, such as graft-versus-host disease (GVHD) and treatment resistance leading to relapse. The problems with new cellular therapies and checkpoint inhibitors are similar. However, development of biomarkers post-HCT, particularly for toxicities, has taken off in the last decade and has expanded greatly. Thanks to the advances in genomics, transcriptomics, proteomics and cytomics technologies, blood biomarkers have been identified and validated in promising diagnostic tests, prognostic tests stratifying for future occurrence of GVHD, and predictive tests for responsiveness to GVHD therapy and non-relapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention. This review outlines a path from biomarker discovery to first clinical correlation, focusing on soluble STimulation-2 (sST2) – the interleukin (IL)-33-decoy receptor – which is the most validated biomarker.Item ST2/MYD88 signaling is a therapeutic target alleviating murine acute graft-versus-host disease sparing T regulatory cell function(2018-01-10) Griesenauer, Brad; Paczesny, Sophie; Dent, Alexander L.; Kaplan, Mark H.; Kapur, ReubenAcute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble serum stimulation-2 (sST2) are elevated during human and murine aGVHD and are correlated to a type 1 T cell response. Membrane-bound ST2 (ST2) on donor T cells has been shown to be protective against aGVHD. ST2 signals through the adapter protein myeloid differentiation primary response 88 (MyD88). The role of MyD88 signaling in donor T cells during aGVHD remains unknown. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of interleukin 1 receptor (IL-1R) and toll-like receptor 4 (TLR4) signaling, both of which also signal through MyD88, in two murine HCT models. This protection was entirely driven by MyD88-/- CD4 T cells, leading to a decreased type 1 response without affecting T cell proliferation, apoptosis, or migration. In our aGVHD models, loss of intrinsic MyD88 signaling is not responsible for the observed protection. However, transplanting donor MyD88-/- T conventional cells (Tcons) with wild type (WT) or MyD88-/- T regulatory cells (Tregs) ameliorated aGVHD severity and lowered aGVHD mortality. Transcriptome analysis of sorted MyD88-/- CD4 T cells from the intestine ten days post-HCT showed lower levels of Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, and Jak2, among others. Decreased sST2 was confirmed at the protein level with less secretion of sST2 and more expression of ST2 compared to WT T cells. Transplanting donor ST2-/- Tcons with WT or ST2-/- Tregs mirrored observations when using donor MyD88-/- Tcons. This suggests that Treg suppression from lack of MyD88 signaling in Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways. The results of our study confirm that ST2 represents an aGVHD therapeutic target that spares Treg function.Item The stimulatory role of ICOS in the development of CD146+CCR5+ T cells co-expressing IFN-γ and IL-17 during graft-versus-host disease(2015) Liu, Liangyi; Paczesny, Sophie; Broxmeyer, Hal E.; Blum, Janice S.; Haneline, Laura S.; Carlesso, NadiaGraft-versus-host disease (GVHD) remains the major complication after allogeneic hematopoietic stem cell transplantation (HSCT), resulting from immunological attack on target organs such as gastrointestinal (GI) tract, liver and skin from donor allogeneic T cells. The most common treatment for GVHD is immunosuppressive drugs such as corticosteroids, which may result in many side effects including the loss of the beneficial graft-versus-leukemia (GVL) effect and increased infection rates. However, GVHD-specific drugs have yet to be implemented. Here we show that by targeting on a novel pathogenic CD4+ T cell subpopulation that our lab previously found in patients with GI GVHD, we can develop new avenues to treat GVHD. This novel population is characterized as CD146+CCR5+ T cells, co-expressing IL-17A and IFN-γ. We found that the inducible T-cell costimulator (ICOS), which has been reported to be important for human Th17 differentiation in vitro, is critical for the development of this nonconventional T Helper 1 (Th1*)-polarized CD146+CCR5+ conventional T cells (Tconvs) population. Furthermore, we found that ICOS can induce the generation of Th1*-polarized CD146+CCR5+ regulatory T cells (Tregs) population, lowering the frequencies of phenotypic markers of functional Tregs. Our data also showed that inhibiting the major transcriptional factor of Th17, RAR-related orphan receptor gamma t (RORγt), could prevent the development of CD146+CCR5+ Tconvs in vitro. Our results demonstrate how pathogenic CD146+CCR5+ T cells are induced through ICOS or RORγt, suggesting new targets for GVHD treatment. We anticipate our assay to be a starting point for the development of novel GVHD-specific drugs. For example, the treatments that focus on inhibiting RORγ would have fewer side effects than general immunosuppressive drugs that GVHD patients use today and inhibit GVHD while sparing the GVL effect. Furthermore, we expect the CD146+CCR5+ Tconvs and/or Tregs can be used as GVHD biomarkers. These biomarkers may guide preemptive treatments such as RORγt inhibitor.Item The Impact of Cell-Intrinsic STAT6 Protein on Donor T Cell-Mediated Graft-Versus-Tumor Effect(MDPI, 2024-12-31) Guan, Xiaoqun; Fury, Hope; Issuree, Priya D.; Atagozli, Tyler; McManimon, Emory E.; Shao, Peng; Li, Yue; Chimenti, Michael; Butler, Noah S.; Kaplan, Mark H.; Elliott, David E.; Blazar, Bruce R.; Ince, M. Nedim; Pediatrics, School of MedicineBone marrow transplantation (BMT) is mainly performed to restore an anti-tumor immune response, called the graft-versus-tumor (GVT) effect, against leukemia, myeloma and lymphoma. This GVT reactivity is driven by donor T cells, and it can also cause lethal graft-versus-host disease (GVHD). We previously demonstrated that the colonization of mice with helminths preserves the GVT response while suppressing GVHD. As the T helper-2 (Th2) pathway is critical to helminthic immune regulation, we asked whether the genetic induction of Th2 signaling in donor T cells can restore helminthic immune regulation after BMT. Our studies utilized transgenic donor T lymphocytes that overexpress a constitutively active form of the Th2-associated transcription factor STAT6. Constitutively active STAT6 sustained the GVT response without causing severe acute GVHD, where transgenic T cells generated robust quantities of cytotoxic proteins important in GVT response, such as granzymes A and B, interferon-γ and Fas ligand, in addition to generating high quantities of Th2/regulatory cytokines. Bioinformatic analysis based on chromosome immune precipitation experiments indicated that STAT6 stimulates the expression of granzymes directly. Thus, in preserving the GVT response without causing GVHD mortality, our results indicate the therapeutic potential of restoring helminthic immune modulation by targeting STAT6 and STAT6-dependent T cell maturation.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.