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Clinical Trial
. 2011 Dec 1;365(22):2055-66.
doi: 10.1056/NEJMoa1108188.

Interleukin-2 and regulatory T cells in graft-versus-host disease

John Koreth  1 , Ken-ichi Matsuoka, Haesook T Kim, Sean M McDonough, Bhavjot Bindra, Edwin P Alyea 3rd, Philippe Armand, Corey Cutler, Vincent T Ho, Nathaniel S Treister, Don C Bienfang, Sashank Prasad, Dmitrios Tzachanis, Robin M Joyce, David E Avigan, Joseph H Antin, Jerome Ritz, Robert J Soiffer
Affiliations
Clinical Trial

Interleukin-2 and regulatory T cells in graft-versus-host disease

John Koreth et al. N Engl J Med. .

Abstract

Background: Dysfunction 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.

Methods: In 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.

Results: A 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).

Conclusions: Daily 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.).

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Figures

Figure 1 (facing page)
Figure 1 (facing page). Clinical and Regulatory T (Treg) Cell Responses to 8 Weeks of Daily Low-Dose Interleukin-2 Therapy in Individual Patients
Panels A and C show manifestations of sclerodermatous chronic GVHD in two patients at baseline; Panels B and D show partial responses, with decreased erythema, after 8 weeks of treatment with low-dose interleukin-2. Softening of sclerodermatous hidebound skin, which cannot be seen in the photographs, was also prominent. Panel E shows flow-cytometric plots, gated on CD4, of Treg cells (CD4+CD25med-highCD127low) during 8 weeks of interleukin-2 therapy in one patient with chronic GVHD. The percentage of total CD4+ cells that are Treg cells (shown in the truncated rectangle) is indicated in each plot. The fluorescence intensity of fluorophore-conjugated CD127 and CD25 monoclonal antibody–bound cells is indicated on the x and y axes, respectively.
Figure 2
Figure 2. Immunologic Effects of 8 Weeks of Low-Dose Interleukin-2 Therapy and of Extended Therapy
Panels A through D show the immunologic effects of 8 weeks of low-dose interleukin-2 (red line), followed by 4 weeks without interleukin-2. Medians and interquartile ranges are shown. Panel E shows the immunologic effects of extended treatment with interleukin-2 (red line) on regulatory T (Treg) cells. A sustained increase in CD4+CD25med-highCD127low Treg cells during 12-month treatment with interleukin-2 is shown. Medians and interquartile ranges are shown. NK denotes natural killer, and Tcon CD4+ conventional T.
Figure 3
Figure 3. Confirmatory Assays of FOXP3+ Expression and Functional Capacity of In Vivo Interleukin-2–Expanded Treg Cells
In Panel A, the lymphocyte gate for identification of CD4+ T-cell subsets is shown. Within the CD4+ T-cell gate, Treg cells are identified as CD25med-highCD127low in the ellipse shown. Gated Treg cells were examined for intracellular FOXP3 expression. FOXP3 enrichment is shown in one patient. Samples from all five patients had similar FOXP3 enrichment. Panel B shows the results of studies of in vivo interleukin-2–expanded Treg cells that were isolated from peripheral blood and cultured with autologous carboxyfluorescein diacetate succinimidyl ester (CFSE)–labeled Tcon responder cells in the presence of costimulatory anti-CD3 and anti-CD28 antibodies (anti-CD3/28). After 4 days, cells were harvested and cell-division analysis was performed. Data from one experiment are shown. In Panel C, the percentage of CFSE-labeled costimulated proliferated Tcon cells is shown for six patients. In all six patients, the Tcon cells showed strong proliferation after ex vivo stimulation with anti-CD3/28, which was efficiently suppressed by the interleukin-2–expanded Treg cells.
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