Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease

Katelyn Paz, Ryan Flynn, Jing Du, Stacey Tannheimer, Amy J. Johnson, Shuai Dong, Anne Katrien Stark, Klaus Okkenhaug, Angela Panoskaltsis-Mortari, Peter T. Sage, Arlene H. Sharpe, Leo Luznik, Jerome Ritz, Robert J. Soiffer, Corey S. Cutler, John Koreth, Joseph H. Antin, David B. Miklos, Kelli P. MacDonald, Geoffrey R. Hill & 10 others Ivan Maillard, Jonathan S. Serody, William J Murphy, David H. Munn, Colby Feser, Michael Zaiken, Bart Vanhaesebroeck, Laurence A. Turka, John C. Byrd, Bruce R. Blazar

Research output: Contribution to journalArticle

Abstract

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)-17 cells and germinal center (GC)–promoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ (PI3Kδ), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase-dead mutant donor bone marrow–derived GC B cells still supported BO cGVHD generation. A PI3Kδ-specific inhibitor, compound GS-649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1-dependent and Th17-associated scleroderma model, GS-649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)–approved PI3Kδ inhibitors for cGVHD therapy in patients.

Original languageEnglish (US)
JournalAmerican Journal of Transplantation
DOIs
StatePublished - Jan 1 2019

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1-Phosphatidylinositol 4-Kinase
Graft vs Host Disease
Germinal Center
Bronchiolitis Obliterans
B-Lymphocytes
Tissue Donors
Helper-Inducer T-Lymphocytes
T-Lymphocytes
Phosphotransferases
Th17 Cells
Regulatory T-Lymphocytes
United States Food and Drug Administration
Cell Survival
Cell Proliferation
Clinical Trials
Morbidity
Lipids
Bone and Bones
Survival
Mortality

Keywords

  • basic (laboratory) research/science
  • graft-versus-host disease (GVHD)
  • immunobiology
  • immunosuppressant - other

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease. / Paz, Katelyn; Flynn, Ryan; Du, Jing; Tannheimer, Stacey; Johnson, Amy J.; Dong, Shuai; Stark, Anne Katrien; Okkenhaug, Klaus; Panoskaltsis-Mortari, Angela; Sage, Peter T.; Sharpe, Arlene H.; Luznik, Leo; Ritz, Jerome; Soiffer, Robert J.; Cutler, Corey S.; Koreth, John; Antin, Joseph H.; Miklos, David B.; MacDonald, Kelli P.; Hill, Geoffrey R.; Maillard, Ivan; Serody, Jonathan S.; Murphy, William J; Munn, David H.; Feser, Colby; Zaiken, Michael; Vanhaesebroeck, Bart; Turka, Laurence A.; Byrd, John C.; Blazar, Bruce R.

In: American Journal of Transplantation, 01.01.2019.

Research output: Contribution to journalArticle

Paz, K, Flynn, R, Du, J, Tannheimer, S, Johnson, AJ, Dong, S, Stark, AK, Okkenhaug, K, Panoskaltsis-Mortari, A, Sage, PT, Sharpe, AH, Luznik, L, Ritz, J, Soiffer, RJ, Cutler, CS, Koreth, J, Antin, JH, Miklos, DB, MacDonald, KP, Hill, GR, Maillard, I, Serody, JS, Murphy, WJ, Munn, DH, Feser, C, Zaiken, M, Vanhaesebroeck, B, Turka, LA, Byrd, JC & Blazar, BR 2019, 'Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease', American Journal of Transplantation. https://doi.org/10.1111/ajt.15305
Paz, Katelyn ; Flynn, Ryan ; Du, Jing ; Tannheimer, Stacey ; Johnson, Amy J. ; Dong, Shuai ; Stark, Anne Katrien ; Okkenhaug, Klaus ; Panoskaltsis-Mortari, Angela ; Sage, Peter T. ; Sharpe, Arlene H. ; Luznik, Leo ; Ritz, Jerome ; Soiffer, Robert J. ; Cutler, Corey S. ; Koreth, John ; Antin, Joseph H. ; Miklos, David B. ; MacDonald, Kelli P. ; Hill, Geoffrey R. ; Maillard, Ivan ; Serody, Jonathan S. ; Murphy, William J ; Munn, David H. ; Feser, Colby ; Zaiken, Michael ; Vanhaesebroeck, Bart ; Turka, Laurence A. ; Byrd, John C. ; Blazar, Bruce R. / Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease. In: American Journal of Transplantation. 2019.
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AU - Flynn, Ryan

AU - Du, Jing

AU - Tannheimer, Stacey

AU - Johnson, Amy J.

AU - Dong, Shuai

AU - Stark, Anne Katrien

AU - Okkenhaug, Klaus

AU - Panoskaltsis-Mortari, Angela

AU - Sage, Peter T.

AU - Sharpe, Arlene H.

AU - Luznik, Leo

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AU - Antin, Joseph H.

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AU - MacDonald, Kelli P.

AU - Hill, Geoffrey R.

AU - Maillard, Ivan

AU - Serody, Jonathan S.

AU - Murphy, William J

AU - Munn, David H.

AU - Feser, Colby

AU - Zaiken, Michael

AU - Vanhaesebroeck, Bart

AU - Turka, Laurence A.

AU - Byrd, John C.

AU - Blazar, Bruce R.

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