@article{Brian C. Betts_Joseph Pidala_Jongphil Kim_Asmita Mishra_Taiga Nishihori_Lia Perez_Jose Leonel Ochoa-Bayona_Farhad Khimani_Kelly Walton_Ryan Bookout_Michael Nieder_Divis K. Khaira_Marco Davila_Melissa Alsina_Teresa Field_Ernesto Ayala_Frederick L. Locke_Marcie Riches_Mohamed Kharfan-Dabaja_Hugo Fernandez_Claudio Anasetti_2017, place={Pavia, Italy}, title={IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation}, volume={102}, url={https://haematologica.org/article/view/8075}, DOI={10.3324/haematol.2016.153072}, abstractNote={Graft-<em>versus</em>-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16<sup>th</sup> April 2014 and 19<sup>th</sup> December 2015, 20 patients received IL-2 (200,000 IU/m<sup>2</sup> thrice weekly, days 0 to +90) with SIR (5–14 ng/mL) and tacrolimus (TAC) (3–7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% <em>vs.</em> 16.0%, <em>P</em>=0.0016; 0.052 k/uL <em>vs.</em> 0.037 k/uL, <em>P</em>=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% <em>vs.</em> 50%, <em>P</em>=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3<sup>+</sup> CD4<sup>+</sup> T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (<em><a href="http://clinicaltrials.gov">clinicaltrials.gov</a> identifier: 01927120</em&gt;).}, number={5}, journal={Haematologica}, author={Brian C. Betts and Joseph Pidala and Jongphil Kim and Asmita Mishra and Taiga Nishihori and Lia Perez and Jose Leonel Ochoa-Bayona and Farhad Khimani and Kelly Walton and Ryan Bookout and Michael Nieder and Divis K. Khaira and Marco Davila and Melissa Alsina and Teresa Field and Ernesto Ayala and Frederick L. Locke and Marcie Riches and Mohamed Kharfan-Dabaja and Hugo Fernandez and Claudio Anasetti}, year={2017}, month={Apr.}, pages={948-957} }