IL-7 Blockade Prevents Graft-Versus-Host Disease and Improves T Cell Reconstitution Following Allogeneic Bone Marrow Transplantation.

Interleukin 7 (IL-7) promotes both thymopoiesis and mature T lymphocyte survival and proliferation. In experimental murine models of hematopoietic stem cell transplantation (HSCT), reconstitution of the naïve T cell population from donor-derived HSC is enhanced by IL-7 treatment. Since HSC products for transplantation may also contain IL-7-responsive mature T lymphocytes, IL-7 treatment in allogeneic BMT could lead to exacerbation of graft-versus-host disease (GVHD). Using IL-7 deficient murine models, we have previously shown that IL-7 mediates survival of mature T lymphocytes and is necessary for pathogenesis of GVHD. In the present study, we determined whether GVHD could be prevented by blockade of IL-7 signaling with an anti-murine IL-7 receptor alpha chain (IL-7Rα ) antibody. In order to induce GVHD, C57/BL6 (H2K^b) recipient mice were lethally irradiated (1300 cGy) and co-transplanted with 4x10⁶ lymph node (LN) and 1x10⁶ T cell depleted (TCD) BM cells from MHC-mismatched allogeneic Balb/C (H2K^d) donor mice. Following transplantation, the allogeneic BMT recipients were intraperitonally injected with either the anti-murine IL-7Rα antibody, SB14 (100μg/mouse/week) or PBS for 5 weeks. GVHD-related mortality and morbidity were decreased in allogeneic recipients treated with anti-IL-7Rα anti-body compared to the PBS treated groups. Anti-IL-7Rα antibody treatment significantly increased survival in the B6 mice (70%, n=20) for up to 5 months when compared to the PBS treated B6 recipients (20%, n=20 [p<0.005]). Histological examination of the anti-IL-7Rα anti-body treated B6 mice showed no evidence of GVHD in the skin, gut, or thymus. The overall GVHD clinical index of anti-IL-7Rα antibody treated allogeneic recipients was significantly lower than that of the PBS treated animal (p<0.05). The recovery of donor CD4⁺ or CD8⁺ T cells in the spleen and lymph nodes of the antibody treated recipients was significantly lower than the PBS treated animals by day 30 post-transplantation. Even though IL-7 signaling is essential for the development of T lymphocytes in the thymus, anti-IL-7Rα antibody treatment did not prevent donor-derived thymopoiesis. Histological analysis of thymic tissues revealed that anti-IL-7Rα antibody treated recipients have normal thymic cortical and medullary microenvironments whereas PBS recipients displayed a lack of cortical and medullary distinction and decreased thymic cellularity at day 30 and 250 following transplantation. Furthermore, anti-IL-7Rα antibody treated recipients were able to generate naïve T lymphocytes (CD62⁺ CD44⁻) whereas most donor T cells in the periphery of PBS treated recipients with GVHD had a memory phenotype (CD62⁻ CD44⁺). Collectively, these findings suggest that the blockade of IL-7 signaling by anti-IL-7Rα antibody treatment not only inhibits occurrence of GVHD in the early phase of post-allogeneic BMT but also maintains host thymic capacity and improves T cell reconstitution.