Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease

转化新型药物靶向生物标志物来治疗移植物抗宿主病

• 批准号: 10618840
• 负责人: Sophie Paczesny
• 金额: $ 31.72万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-03 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618840
• 关键词: Acute Graft Versus Host Disease; Address; Allogenic; Antibodies; Appearance; Binding; Biological; Biological Assay; Biological Markers; Biological Products; CD28 gene; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Complication; Correlative Study; Cytoprotection; Data; Dendritic Cells; Detection; Development; Disease; Disease model; Effector Cell; Equilibrium; Fred Hutchinson Cancer Research Center; Future; Goals; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Human; Immune; Incidence; Indiana; Inflammation; Interleukin-2; Interleukins; Intervention; Intestines; Journals; Laboratories; MCAM gene; Malignant - descriptor; Measures; Mediating; Membrane; Molecular; Morbidity - disease rate; Multicenter Studies; Natural Immunity; Newly Diagnosed; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Plasma; Population; Pre-Clinical Model; Prognostic Marker; Prospective Studies; Proteome; Proteomics; Publishing; Recurrent disease; Regimen; Regulation; Regulatory T-Lymphocyte; Research; Risk; Safety; Sampling; Science; Severity of illness; Steroids; Stromal Cells; T-Lymphocyte; Testing; Therapeutic; Translating; Translational Research; Transplant Recipients; Universities; adaptive immunity; antagonist; cancer therapy; clinical investigation; clinically relevant; curative treatments; design; disorder prevention; effector T cell; efficacy testing; gastrointestinal; graft vs host disease; hematopoietic cell transplantation; innovation; insight; mortality; neutralizing antibody; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient stratification; post-transplant; predicting response; preemptive intervention; prevent; prophylactic; prospective; public health relevance; receptor; response; risk stratification; specific biomarkers; success; therapeutic target; therapy resistant; translational medicine; tumor

PROJECT SUMMARY/ABSTRACT Despite the high rates of acute graft versus host disease (aGVHD) (up to 50%) and their related mortality/morbidity following allogeneic hematopoietic cell transplantation (allo-HCT), there remains a paucity of therapies and biological correlative studies offered. Current therapies are limited to the nonspecific steroidal targeting of effector cells. Our long-term goal is to identify and validate GVHD biomarkers with the potential for risk stratification and therapeutic targeting. In the previous cycle, we discovered that: (1) soluble STimulation-2 (sST2), the interleukin-33 (IL-33) decoy receptor, as a biomarker for risk of therapy-resistant GVHD and death (N. Engl. J. Med, 2013); (2) Mechanistically, we have shown that during GVHD, sST2 was secreted earlier by intestinal stromal cells and later by cytopathic intestinal T effector cells (Teffs) (Science Translational Medicine, 2015); (3) Furthermore, we have shown that sST2 sequesters IL-33, limiting its availability to T cells expressing the transmembrane molecule form of ST2, mostly cytoprotective regulatory T cells (Tregs) (Science Translational Medicine, 2015; Journal of Clinical Investigation Insights, 2019); (4) Through another proteomics discovery comparing samples at 14 days post-transplantation in patients who develop gastrointestinal (GI) GVHD vs not, we found a T-cell population expressing CD146 that is Th17 prone and ICOS (Inducible T-cell COStimulator)-induced (Journal of Clinical Investigation Insights, 2016). Our new hypotheses address gaps remaining and will be tested with three specific aims: 1) Elucidate the cellular and molecular mechanisms of anti-ST2 neutralizing antibody mediated regulation of inflammation; 2) Implement a prospective multicenter study to determine ST2 threshold as a prognostic biomarker of aGVHD for enabling a biomarker-based preemptive trial; and 3) Inhibit the ICOS/ICOSL pathway with a dual ICOS/CD28 antagonist to prevent and treat aGVHD. The proposed research is significant because the impact of these studies will be 1) to risk stratify patients before initiating GVHD treatment, and 2) to develop entirely novel therapeutic strategies while simultaneously providing novel biological insights into a fatal condition, GVHD.

项目总结/文摘

项目成果

Graft-versus-host disease biomarkers: omics and personalized medicine.

• DOI: 10.1007/s12185-013-1406-9
• 发表时间: 2013-09
• 期刊: INTERNATIONAL JOURNAL OF HEMATOLOGY
• 影响因子: 2.1
• 作者: Paczesny, Sophie;Raiker, Nisha;Brooks, Sam;Mumaw, Christy
• 通讯作者: Mumaw, Christy

A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft-versus-host disease.

• DOI: 10.1111/bjh.18300
• 发表时间: 2022-08
• 期刊: BRITISH JOURNAL OF HAEMATOLOGY
• 影响因子: 6.5
• 作者: Pratta, Michael;Paczesny, Sophie;Socie, Gerard;Barkey, Natalie;Liu, Hao;Owens, Sherry;Arbushites, Michael C.;Schroeder, Mark A.;Howell, Michael D.
• 通讯作者: Howell, Michael D.

Regenerating islet-derived protein 3-α is a prognostic biomarker for gastrointestinal chronic graft-versus-host disease.

• DOI: 10.1182/bloodadvances.2021005420
• 发表时间: 2022-05-24
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: DePriest, Brittany Paige;Li, Hong;Bidgoli, Alan;Onstad, Lynn;Couriel, Daniel;Lee, Stephanie J.;Paczesny, Sophie
• 通讯作者: Paczesny, Sophie

Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation.

• DOI: 10.1016/j.bbmt.2015.07.004
• 发表时间: 2015-10
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Akil A;Zhang Q;Mumaw CL;Raiker N;Yu J;Velez de Mendizabal N;Haneline LS;Robertson KA;Skiles J;Diaz-Ricart M;Carreras E;Renbarger J;Hanash S;Bies RR;Paczesny S
• 通讯作者: Paczesny S

Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation.

蛋白质组学表征表明，在同种异体造血细胞和肺移植后，MMP-3与细支气管炎综合征相关。

• DOI: 10.1111/ajt.13750
• 发表时间: 2016-08
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Liu X;Yue Z;Yu J;Daguindau E;Kushekhar K;Zhang Q;Ogata Y;Gafken PR;Inamoto Y;Gracon A;Wilkes DS;Hansen JA;Lee SJ;Chen JY;Paczesny S
• 通讯作者: Paczesny S