Human LAP + GARP + FOXP3 + regulatory T cells attenuate xenogeneic graft versus host disease.

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  • Additional Information
    • Source:
      Publisher: Ivyspring International Publisher Country of Publication: Australia NLM ID: 101552395 Publication Model: eCollection Cited Medium: Internet ISSN: 1838-7640 (Electronic) Linking ISSN: 18387640 NLM ISO Abbreviation: Theranostics Subsets: MEDLINE
    • Publication Information:
      Original Publication: Wyoming, N.S.W. : Ivyspring International Publisher, 2011-
    • Subject Terms:
      Adoptive Transfer/*methods ; Forkhead Transcription Factors/*metabolism ; Graft vs Host Disease/*therapy ; Peptides/*metabolism ; Protein Precursors/*metabolism ; Receptors, Antigen, T-Cell, alpha-beta/*metabolism ; T-Lymphocytes, Regulatory/*immunology ; Transforming Growth Factor beta/*metabolism; Animals ; Cells, Cultured ; Flow Cytometry/methods ; Humans ; Mice ; Mice, Inbred NOD ; T-Lymphocytes, Regulatory/transplantation
    • Abstract:
      Adoptive transfer of regulatory T cells (FOXP3 + Tregs) has been developed as a potential curative immune therapy to prevent and treat autoimmune and graft-versus-host diseases (GVHD). A major limitation that has hindered the use of Treg immunotherapy in humans is the difficulty of consistently isolating and obtaining highly purified Tregs after ex vivo expansion. Methods : We isolated bona fide Tregs from expansion cultures based on their selective surface expression of latency-associated peptide (LAP). The TCR Vβ diversity and intracellular cytokine production of Tregs were determined by flow cytometer. The TSDR methylation was determined by epigenetic human FOXP3 qPCR Assay. Their in vitro and in vivo potency was confirmed with suppression assay and humanized xenogeneic GVHD (xGVHD) murine model, respectively. Results : LAP + repurification results in >90% LAP + FOXP3 + Tregs, leaving behind FOXP3 - and FOXP3 + nonTregs within the LAP - population. After 4-week expansion, the LAP + Tregs were >1 billion cells, highly suppressive and anergic in vitro , >90% demethylated in the TSDR and able to maintain TCR Vβ diversity. In the xGVHD model, exogenous CD25 - PBMC administered alone results in a median survival of 32 days. The co-transfer of LAP + Tregs increased median survival to 47 days, while the LAP parent (CD25 + ) and LAP - nonTregs had median survival of 39 and 31 days, respectively. Conclusions : These preclinical data together provide evidence that LAP + Tregs are highly purified with fully suppressive function for cell therapy. This population results in a more effective and safer product for immunotherapy to treat GVHD and provides the necessary preclinical data for transition into a clinical trial with LAP + Tregs to prevent or treat GVHD and other autoimmune diseases.
      Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
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    • Grant Information:
      P30 CA016672 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: Graft-versus-host disease (GVHD); T cell receptor (TCR) repertoire; Treg-specific demethylated region (TSDR); latency-associated peptide (LAP); regulatory T cells (Tregs)
    • Accession Number:
      0 (FOXP3 protein, human)
      0 (Forkhead Transcription Factors)
      0 (Peptides)
      0 (Protein Precursors)
      0 (Receptors, Antigen, T-Cell, alpha-beta)
      0 (Transforming Growth Factor beta)
      0 (latency-associated propeptide, TGF-beta)
    • Publication Date:
      Date Created: 20190601 Date Completed: 20200629 Latest Revision: 20200629
    • Publication Date:
      20221213
    • Accession Number:
      PMC6531299
    • Accession Number:
      10.7150/thno.30254
    • Accession Number:
      31149046