Expansion Of Regulatory T Cells With Ultra Low-Dose Il-2 After Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) are of increasing interest in hematopoietic stem cell transplantation (HSCT) since they may help prevent graft-versus-host disease (GvHD). Murine models demonstrate that infusion of donor-derived Tregs to HSCT recipient mice can prevent GvHD by suppressing alloreactive T cell responses, while human recipients of allografts with low Treg numbers have increased rates of GvHD. We and others have previously given low-dose IL-2 to HSCT recipients in an attempt to enhance antitumor immunity. Although no definitive antitumor effects were observed, the patients were noted to have low rates of GvHD. Retrospectively, it has been demonstrated that patients who received IL-2 therapy had higher levels of FoxP3+ T cells (i.e., Tregs) than controls, suggesting that IL-2 preferentially expands Tregs in vivo, thereby preventing GvHD. We have therefore initiated a phase I/II clinical trial to evaluate the efficacy and toxicity of low-dose IL-2 injections following allogeneic HSCT. The intent is to promote Treg expansion in vivo and prevent acute GvHD. Thus far, 5 patients who received a HSCT for hematologic malignancies have been treated with ultra low-dose IL-2 (100,000 to 200,000 units/m2 subcutaneously three times weekly) beginning day +7 to day +28 after HSCT, for 6 to 12 weeks. Median age at time of transplant was 21 years (range, 9 to 56 years). Two patients received matched sibling donor transplants and three received alternative donor transplants with Campath 1-H for in vivo T-cell depletion. Flow cytometric analysis of blood from all patients demonstrated a rise in the percentage of CD4+ CD25+ FoxP3+ Tregs by 6 weeks following initiation of IL-2 therapy with mean of 4.7% (range, 0 to 9.8%) pre IL-2 to a mean of 17.7% (range, 7.8 to 31.1%) after IL-2 treatment. Functional analyses of these CD4+ CD25bright cells showed suppression of thymidine uptake in mixed lymphocyte cultures. No grade 3 or 4 toxicities occurred while on IL-2. No patient developed > grade I acute GvHD. One patient who did not complete the full 12 weeks of IL-2 therapy developed extensive, chronic GvHD two months after stopping IL-2. In conclusion, low-dose IL-2 is relatively well tolerated and may expand a CD4+ CD25+ FoxP3+ Treg population in vivo. Their effects on GvHD and relapse remain to be determined.