Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model

Sabrina Copsel, Dietlinde Wolf, Brandon Kale, Henry Barreras, Casey O. Lightbourn, Cameron S. Bader, Warren Alperstein, Norman H. Altman, Krishna V Komanduri, Robert B Levy

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach that induces the marked expansion and selective activation of Tregs in vivo by targeting tumor necrosis factor receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Tregs to ameliorate GVHD and other disorders would be the generation of more potent Treg populations. Here we wanted to determine if very low doses of Tregs generated using the “2-pathway” stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD. Analysis of such 2-pathway expanded Tregs identified higher levels of activation and functional molecules (CD103, ICOS-1, Nrp-1, CD39, CD73, il-10, and tgfb1) versus unexpanded Tregs. Additionally, in vitro assessment of 2-pathway stimulated Tregs indicated enhanced suppressor activity. Notably, transplant of extremely low numbers of these Tregs (1:6 expanded Tregs/conventional T cells) suppressed GVHD after an MHC-mismatched aHSCT. Overall, these results demonstrate that 2-pathway stimulated CD4+ FoxP3+ Tregs were quantitatively and qualitatively more functionally effective than unexpanded Tregs. In total, the findings in this study support the notion that such 2-pathway stimulated Tregs may be useful for prevention of GVHD and ultimately promote more widespread application of aHSCT in the clinic.

Original languageEnglish (US)
JournalBiology of Blood and Marrow Transplantation
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Graft vs Host Disease
Interleukin-2
Hematopoietic Stem Cell Transplantation
Tumor Necrosis Factor Receptors
Immune Tolerance
Regulatory T-Lymphocytes
Homeostasis
Maintenance
T-Lymphocytes
Transplants
Population
Proteins

Keywords

  • Graft-versus-host disease (GVHD)
  • Hematopoietic stem cell transplantation (HSCT)
  • Interleukin-2 (IL-2)
  • Regulatory T cells (Tregs)
  • Tumor necrosis factor receptor superfamily 25 (TNFRSF25)

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model. / Copsel, Sabrina; Wolf, Dietlinde; Kale, Brandon; Barreras, Henry; Lightbourn, Casey O.; Bader, Cameron S.; Alperstein, Warren; Altman, Norman H.; Komanduri, Krishna V; Levy, Robert B.

In: Biology of Blood and Marrow Transplantation, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach that induces the marked expansion and selective activation of Tregs in vivo by targeting tumor necrosis factor receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Tregs to ameliorate GVHD and other disorders would be the generation of more potent Treg populations. Here we wanted to determine if very low doses of Tregs generated using the “2-pathway” stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD. Analysis of such 2-pathway expanded Tregs identified higher levels of activation and functional molecules (CD103, ICOS-1, Nrp-1, CD39, CD73, il-10, and tgfb1) versus unexpanded Tregs. Additionally, in vitro assessment of 2-pathway stimulated Tregs indicated enhanced suppressor activity. Notably, transplant of extremely low numbers of these Tregs (1:6 expanded Tregs/conventional T cells) suppressed GVHD after an MHC-mismatched aHSCT. Overall, these results demonstrate that 2-pathway stimulated CD4+ FoxP3+ Tregs were quantitatively and qualitatively more functionally effective than unexpanded Tregs. In total, the findings in this study support the notion that such 2-pathway stimulated Tregs may be useful for prevention of GVHD and ultimately promote more widespread application of aHSCT in the clinic.",
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AU - Copsel, Sabrina

AU - Wolf, Dietlinde

AU - Kale, Brandon

AU - Barreras, Henry

AU - Lightbourn, Casey O.

AU - Bader, Cameron S.

AU - Alperstein, Warren

AU - Altman, Norman H.

AU - Komanduri, Krishna V

AU - Levy, Robert B

PY - 2018/1/1

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