Sophie Paczesny

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https://hdl.handle.net/1805/11717

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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Browsing Sophie Paczesny by Author "Adeniyan, Titilayo"

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    Biomarkers for Allogeneic HCT Outcomes
    (Frontiers Media, 2020-04-21) Adom, Djamilatou; Rowan, Courtney; Adeniyan, Titilayo; Yang, Jinfeng; Paczesny, Sophie; Pediatrics, School of Medicine
    Allogeneic 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.
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    ICOSL+ plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist
    (American Association for the Advancement of Science, 2020-10-07) Adom, Djamilatou; Dillon, Stacey R.; Yang, Jinfeng; Liu, Hao; Ramadan, Abdulraouf; Kushekhar, Kushi; Hund, Samantha; Albright, Amanda; Kirksey, Maykala; Adeniyan, Titilayo; Lewis, Katherine E.; Evans, Lawrence; Wu, Rebecca; Levin, Steven D.; Mudri, Sherri; Yang, Jing; Rickel, Erika; Seaberg, Michelle; Henderson, Katherine; Gudgeon, Chelsea J.; Wolfson, Martin F.; Swanson, Ryan M.; Swiderek, Kristine M.; Peng, Stanford L.; Hippen, Keli L.; Blazar, Bruce R.; Paczesny, Sophie; Pediatrics, School of Medicine
    Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146+CCR5+ T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146+CCR5+ T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD.