Long-Term Homeostatic Effects of Daily Low-Dose IL-2 on CD4+ FoxP3+ Regulatory T Cells in Patients with Active Chronic Graft-Versus-Host Disease

• Published in: Blood 2015-12, Vol.126 (23), p.3133-3133
• Main Authors: Whangbo, Jennifer, Koreth, John, Kim, Haesook T., Dusenbury, Katharine, Alho, Ana Cristina, Reynolds, Carol G, Chammas, Marie J, Jones, Kyle T, Nikiforow, Sarah, Cutler, Corey S, Ho, Vincent T., Armand, Philippe, Alyea, Edwin P., Soiffer, Robert J., Antin, Joseph H., Ritz, Jerome
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.3133.3133

Patients with active chronic graft-versus-host disease (cGVHD) have poor reconstitution of CD4+ CD25+ FOXP3+ regulatory T cells (Tregs), which have broad suppressive activity and are required for the maintenance of peripheral tolerance after allogeneic hematopoietic stem cell transplant. Interleukin-2 (IL-2) is a key growth factor for the development, expansion and function of Tregs in vivo. Phase 1 (DFCI 07-083) and phase 2 (DFCI 11-149) studies of daily subcutaneous low-dose IL-2 in patients with refractory cGVHD demonstrated preferential Treg expansion in all patients and objective clinical responses in approximately 50% of participants. In the phase 2 study, 23 participants with clinical benefit (PR or SD with minor response) continued on extended IL-2 therapy, with 6 and 8 patients receiving over 1 and 2 years of low-dose IL-2, respectively. Analysis of phase 1 study patients indicated that IL-2 restored Treg homeostasis through rapid induction of Treg proliferation, increase in thymic Treg neogenesis and increased Treg expression of the anti-apoptotic Bcl-2 protein. Here, we provide novel insights into the immune homeostatic impact of low-dose IL-2 in phase 2 study patients during the initial 12 week treatment period and during extended therapy. Proliferation within the Treg compartment, measured by Ki67 expression, rapidly increased and peaked within 1 week of IL-2 initiation. Memory Tregs contained a higher fraction of proliferating cells and correspondingly, a rise in central memory (CM) and effector memory (EM) Tregs preceded an increase in naïve Tregs during the initial 12 week treatment period (Figure 1A and 1B). This is consistent with the observation that memory Tregs are more responsive than naive Tregs to activation by IL-2 in vitro. Although CM and EM Tregs continue to represent the predominant subsets of Tregs, there is a brisk expansion of the naïve Treg subset that coincides with increased thymic output of Tregs during extended IL-2 therapy. Consistent with their greater proliferative potential, CM and EM Tregs expressed lower levels of Bcl-2 compared with naïve Tregs. However, IL-2 promoted higher Bcl-2 expression in all Treg subsets to similar magnitudes during both the initial 12 week treatment period and extended therapy (Figure 2A). Bcl-2 was preferentially increased in Tregs and not in conventional CD4 (Tcon) or CD8 T cells (Figure 2B). As expected, naïve Tregs expressed very low levels of the pro-apoptotic CD95/Fas receptor prote