Circulating T Helper 17 Cells (Th17) Increase at a Higher Rate than Tregs in Previously Untreated Patients with Severe Hemophilia A Who Develop Inhibitors During the First 50 Exposure Days to rFVIII

D. Brown¹, V. Berg², J. Blatny³, K. Fijnvandraat⁴, J. Klintman⁵, C. Male⁶, C. McGuinn⁷, S. Meeks⁸, E. Mullins⁹, V. Radelescu¹⁰, M. Ragni¹¹, M. Recht¹², E. Santagostino¹³, A. Shapiro¹⁴, J. Staber¹⁵, H. Yaish¹⁶, P. LeBeau¹⁷, J. Bowen¹⁷, B. Gangadharan¹⁸, B. Reipert¹⁸

¹University of Texas Health Science Center at Houston and McGovern Medical School, Houston, United States, ²Institute Krems Bioanalytics MC FH Krems, University of Applied Sciences Krems, Krems, Austria, ³University Hospital Brno, Masaryk University, Department of Paediatric Haematology, Brno, Czech Republic, ⁴Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Pediatric Hematology, Meibergdreef 9, Amsterdam, the Netherlands, ⁵Lund University, Clinical Coagulation Research Unit, Malmo, Sweden, ⁶Medical University of Vienna, Department of Paediatrics, Vienna, Austria, ⁷Weill Cornell Medicine, New York, United States, ⁸Emory University, Children's Healthcare of Atlanta, Aflac Cancer and Blood Disorders Center, Atlanta, United States, ⁹Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, United States, ¹⁰University of Kentucky, Lexington, United States, ¹¹University of Pittsburgh Medical Center, Pittsburgh, United States, ¹²Oregon Health & Science University, Portland, United States, ¹³Maggiore Hospital Policlinico and University of Milan, IRCCS Ca' Granda Foundation, Milan, Italy, ¹⁴Indiana Hemophilia and Thrombosis Center, Indianapolis, United States, ¹⁵University of Iowa, Stead Family Department of Pediatrics, Iowa City, United States, ¹⁶Univ of Utah School of Medicine, Salt Lake City, United States, ¹⁷Rho, Inc., Durham, United States, ¹⁸Baxalta Innovations GmbH, a Takeda Company, Drug Discovery Austria, Vienna, Austria

Abstract Number: PB0209

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors

Background: The Hemophilia Inhibitor PUPs study (HIPS) is a prospective longitudinal study of previously untreated patients with severe Hemophilia A during their first 50 exposure days (EDs) to a single source of recombinant FVIII, Advate. Among the 23 HIPS subjects who completed 50 EDs, 4 distinct antibody signatures were identified: Subgroup 1 (7) had no FVIII inhibitors or FVIII-specific antibodies, Subgroup 2 (7) had no inhibitors but had FVIII-Specific IgG1, Subgroup 3 (2) had low titer or transient FVIII inhibitors with FVIII specific IgG1 but without IgG3 or IgG4, and Subgroup 4 (7) had high titer inhibitors with high-affinity IgG1 and class-switched antibodies (IgG3, IgG4; rarely IgG2).

Aims: To compare T-cell subpopulations using highly sensitive epigenetic markers among the 4 subgroups at baseline and throughout the 1st 50 EDs.

Methods: HIPS subjects had blood samples drawn at baseline and after ED1, ED5, ED10, ED20, ED30, ED40, and ED50. Epigenetic studies using DNA markers which are unique and highly specific for CD3⁺ T cells, FOXP3⁺Tregs, IL-17A⁺ Th17 cells, follicular helper T cells (Tfh) were used to quantify each cell type (Precision for Medicine; Berlin, GE).

Results: 1. There was a significant difference in baseline % Tfh between subgroups 1, 2 and 4 (Figure 1).
2. There were no differences in baseline % of for total FOXP3⁺Tregs, IL-17A⁺ Th17 cells.
3. There was a significant difference in the rate of increase of % TH17/CD3 cells during 50 EDs between subgroups 1, 2, and 3 and subgroup 4 (Figure 2).

Conclusions: Proportion of Tfh cells is significantly higher at baseline in patients who develop high titer, high-affinity IgG class-switched antibodies. Proportion of Th17 cells increases at a higher rate than FOXP3⁺Tregs in patients who develop high titer, high affinity antibodies which likely reflects activation of adaptive immunity predisposing to inhibitor formation.

[Follicular Helper T-cells]

[TH17/CD3 Ratio]

To cite this abstract in AMA style:

Brown D, Berg V, Blatny J, Fijnvandraat K, Klintman J, Male C, McGuinn C, Meeks S, Mullins E, Radelescu V, Ragni M, Recht M, Santagostino E, Shapiro A, Staber J, Yaish H, LeBeau P, Bowen J, Gangadharan B, Reipert B. Circulating T Helper 17 Cells (Th17) Increase at a Higher Rate than Tregs in Previously Untreated Patients with Severe Hemophilia A Who Develop Inhibitors During the First 50 Exposure Days to rFVIII [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/circulating-t-helper-17-cells-th17-increase-at-a-higher-rate-than-tregs-in-previously-untreated-patients-with-severe-hemophilia-a-who-develop-inhibitors-during-the-first-50-exposure-days-to-rfviii/. Accessed September 29, 2023.

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