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Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.

ABSTRACT: Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3 × 10? cells), and therefore novel methods of Treg expansion to generate clinically relevant numbers are needed.Several methodologies are currently being used for ex vivo Treg expansion. We report a new approach to expand Treg from CB and demonstrate their efficacy in vitro by blunting allogeneic mixed lymphocyte reactions and in vivo by preventing GvHD through the use of a xenogenic GvHD mouse model.With the use of magnetic cell sorting, naturally occurring Treg were isolated from CB by the positive selection of CD25? cells. These were expanded to clinically relevant numbers by use of CD3/28 co-expressing Dynabeads and interleukin (IL)-2. Ex vivo-expanded Treg were CD4?25? FOXP3?127(lo) and expressed a polyclonal T-cell receptor, V? repertoire. When compared with conventional T-lymphocytes (CD4?25? cells), Treg consistently showed demethylation of the FOXP3 TSDR promoter region and suppression of allogeneic proliferation responses in vitro.In our NOD-SCID IL-2R?(null) xenogeneic model of GvHD, prophylactic injection of third-party, CB-derived, ex vivo-expanded Treg led to the prevention of GvHD that translated into improved GvHD score, decreased circulating inflammatory cytokines and significantly superior overall survival. This model of xenogenic GvHD can be used to study the mechanism of action of CB Treg as well as other therapeutic interventions.

SUBMITTER: Parmar S

PROVIDER: S-EPMC4124936 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.

Parmar Simrit S Liu Xiaoying X Tung Shawndeep S SS Robinson Simon N SN Rodriguez Gabriel G Cooper Laurence J N LJ Yang Hui H Shah Nina N Yang Hong H Konopleva Marina M Molldrem Jeffery J JJ Garcia-Manero Guillermo G Najjar Amer A Yvon Eric E McNiece Ian I Rezvani Katy K Savoldo Barbara B Bollard Catherine M CM Shpall Elizabeth J EJ

Cytotherapy 20131026 1

<h4>Background aims</h4>Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3 × 10⁶ cells), and therefore novel methods of Treg expansion to generate clinically relevant numbers are needed.<h4>Methods</h4>Several methodologies ar ...[more]

PMID: 24480547

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Project description:BackgroundDysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD.MethodsIn this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period.ResultsA total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100).ConclusionsDaily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana-Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.).

Dataset Information

Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.

Publications

Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.

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