Interleukin 7 worsens graft-versus-host disease

Abstract

Impaired immune reconstitution has moved to the forefront of clinical problems limiting progress in allogeneic bone marrow transplantation (BMT). The identification of therapies that can enhance immune reconstitution by increasing thymopoiesis is critical to solving this problem. Interleukin 7 (IL-7) is the most potent thymopoietic cytokine identified thus far. To study the effects of IL-7 on immune reconstitution and graftversus-host disease (GVHD) following allogeneic BMT, we administered recombinant human IL-7 (rhIL-7) in a murine parent into an F1 model. Results showed that rhIL-7 therapy lowered the "threshold" T-cell dose required to induce both clinical signs of GVHD as well as lethal GVHD. Histologic analysis of GVHD target tissues revealed that rhIL-7 increased the degree of inflammation and tissue damage observed at all T-cell doses studied, but did not change the pattern of organs affected or the histologic appearance of the GVHD within target organs. In addition, we evaluated the capacity for rhIL-7 to enhance thymopoiesis in the setting of allogeneic T cell-depleted (TCD) and T-cell-replete BMT. We observed that rhIL-7 therapy enhanced thymic function in TCD allogeneic BM transplant recipients, but not in animals that received even modest doses of T cells presumably due to thymic toxicity of the graft-versus-host reaction. Thus, caution must be exercised as IL-7 is developed clinically as an immunorestorative agent for use in the setting of allogeneic BMT. These results suggest that use of IL-7 should be limited to the setting of TCD BMT to obtain the greatest benefit on immune competence with the least toxicity.

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

“…Furthermore, plasma IL-7 levels measured early after HSCT were predictive biomarkers of acute GvHD (20). Administration of recombinant human IL-7 (CYT107) was reported to increase circulating CD4 + and CD8 + T cell numbers (23,34); however, several studies recommended careful consideration because of the potential promotion of GvHD with the use of IL-7 after HSCT (19,20,35). Our findings support these concerns, because IL-7 impairs DN T cell-mediated suppression of alloreactive T cell responses.…”

Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future

“…As might be predicted therefore, IL-7-mediated augmentation of antigen-specific proliferation reduces the T-cell threshold at which GVHD is observed in murine models. 30 Indeed, although augmented immune reconstitution is observed in mice treated with T-cell-depleted progenitor cell transplants and IL-7, this does not occur when T cells are present in the graft. 30 Thus, while IL-7 remains the most potent immunorestorative described thus far, clinical use of IL-7 following allogeneic progenitor cell transplantation will likely be most effective when GVHD is prevented through T-cell depletion.…”

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

“…81,82 In mice transplanted with T-cell depleted marrow grafts, IL-7 enhanced thymopoiesis, though this resulted in increased toxicity from GVHD if the graft contained T cells. 83 In a primate transplant model, IL-7 induced a marked increase in peripheral T-cell numbers. In these studies, the effect of IL-7 on thymopoiesis was unclear and therefore the effects on long-term immune reconstitution are uncertain.…”