Stefanie Sarantopoulos

Positions:

Associate Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Associate Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1998

Boston University

Ph.D. 1998

Boston University School of Medicine

Intern, Internal Medicine

Boston University School of Medicine

Resident, Internal Medicine

Boston University School of Medicine

Chief Resident, Internal Medicine

Boston University School of Medicine

Fellowship, Hematology/ Oncology

Dana Farber Cancer Institute

Grants:

BAFF Pathology: Novel Therapeutic Targets in Chronic Graft versus Host Disease

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Breaking B-Cell Tolerance to Produce Antibodies that Eradicate Leukemias and Lymphomas

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

The Notch2-BCR Axis: Targeting Drivers of B cell Fate in Chronic GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
End Date

Understanding Aberrant TLR7 Signaling in B Cells from Patients with Chronic GVHD

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
End Date

A Phase II of Entospletinib, a SYK Inhibitor, First line cGVHD patients

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

Publications:

Allogeneic HSCT for autoimmune disease: a shared decision.

MLA Citation
Sullivan, Keith M., and Stefanie Sarantopoulos. “Allogeneic HSCT for autoimmune disease: a shared decision..” Nat Rev Rheumatol, vol. 15, no. 12, Dec. 2019, pp. 701–02. Pubmed, doi:10.1038/s41584-019-0306-7.
URI
https://scholars.duke.edu/individual/pub1412070
PMID
31530942
Source
pubmed
Published In
Nat Rev Rheumatol
Volume
15
Published Date
Start Page
701
End Page
702
DOI
10.1038/s41584-019-0306-7

An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B-cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4-to-IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.
Authors
Poe, JC; Jia, W; Su, H; Anand, S; Rose, JJ; Tata, PV; Suthers, AN; Jones, CD; Kuan, PF; Vincent, BG; Serody, JS; Horwitz, ME; Ho, VT; Pavletic, SZ; Hakim, FT; Owzar, K; Zhang, D; Blazar, BR; Siebel, CW; Chao, NJ; Maillard, I; Sarantopoulos, S
MLA Citation
Poe, Jonathan C., et al. “An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD..” Blood, vol. 130, no. 19, Nov. 2017, pp. 2131–45. Pubmed, doi:10.1182/blood-2017-05-782466.
URI
https://scholars.duke.edu/individual/pub1273846
PMID
28851699
Source
pubmed
Published In
Blood
Volume
130
Published Date
Start Page
2131
End Page
2145
DOI
10.1182/blood-2017-05-782466

Monitoring the kinetics of B-cell recovery following rituximab may guide the management of steroid-refractory chronic GvHD.

Authors
DeFilipp, Z; Purcell, M; Harris, WAC; Chandra, DJ; Gleason, C; Wrammert, J; Sarantopoulos, S; Waller, EK
MLA Citation
DeFilipp, Z., et al. “Monitoring the kinetics of B-cell recovery following rituximab may guide the management of steroid-refractory chronic GvHD..” Bone Marrow Transplant, vol. 51, no. 4, Apr. 2016, pp. 607–09. Pubmed, doi:10.1038/bmt.2015.304.
URI
https://scholars.duke.edu/individual/pub1108149
PMID
26642338
Source
pubmed
Published In
Bone Marrow Transplant
Volume
51
Published Date
Start Page
607
End Page
609
DOI
10.1038/bmt.2015.304

Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans.

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD.
Authors
Flynn, R; Du, J; Veenstra, RG; Reichenbach, DK; Panoskaltsis-Mortari, A; Taylor, PA; Freeman, GJ; Serody, JS; Murphy, WJ; Munn, DH; Sarantopoulos, S; Luznik, L; Maillard, I; Koreth, J; Cutler, C; Soiffer, RJ; Antin, JH; Ritz, J; Dubovsky, JA; Byrd, JC; MacDonald, KP; Hill, GR; Blazar, BR
MLA Citation
Flynn, Ryan, et al. “Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans..” Blood, vol. 123, no. 25, June 2014, pp. 3988–98. Pubmed, doi:10.1182/blood-2014-03-562231.
URI
https://scholars.duke.edu/individual/pub1115014
PMID
24820310
Source
pubmed
Published In
Blood
Volume
123
Published Date
Start Page
3988
End Page
3998
DOI
10.1182/blood-2014-03-562231

Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease.

Investigation of the effects of rituximab (anti-CD20) on B-cell-activating factor of the tumor necrosis factor family (BAFF) and B cells would better define the significance of B-cell homeostasis in chronic graft-versus-host disease (cGVHD) pathophysiology. We studied 20 cGVHD patients at a median of 25 months after rituximab treatment when most patients had recovered total B-cell numbers. A total of 55% of patients had stable/improved cGVHD, and total B-cell numbers in these patients were significantly higher compared with rituximab-unresponsive patients. Although total B-cell number did not differ significantly between cGVHD groups before rituximab, there was a proportional increase in B-cell precursors in patients who later had stable/improved cGVHD. After rituximab, BAFF levels increased in all patients. Coincident with B-cell recovery in the stable/improved group, BAFF/B-cell ratios and CD27(+) B-cell frequencies decreased significantly. The peripheral B-cell pool in stable/improved cGVHD patients was largely composed of naive IgD(+) B cells. By contrast, rituximab-unresponsive cGVHD patients had persistent elevation of BAFF and a predominance of circulating B cells possessing an activated BAFF-R(Lo)CD20(Lo) cell surface phenotype. Thus, naive B-cell reconstitution and decreased BAFF/B-cell ratios were associated with clinical response after rituximab in cGVHD. Our findings begin to delineate B-cell homeostatic mechanisms important for human immune tolerance.
Authors
Sarantopoulos, S; Stevenson, KE; Kim, HT; Washel, WS; Bhuiya, NS; Cutler, CS; Alyea, EP; Ho, VT; Soiffer, RJ; Antin, JH; Ritz, J
MLA Citation
Sarantopoulos, Stefanie, et al. “Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease..” Blood, vol. 117, no. 7, Feb. 2011, pp. 2275–83. Pubmed, doi:10.1182/blood-2010-10-307819.
URI
https://scholars.duke.edu/individual/pub1115024
PMID
21097674
Source
pubmed
Published In
Blood
Volume
117
Published Date
Start Page
2275
End Page
2283
DOI
10.1182/blood-2010-10-307819