41: Pre-Transplant Administration of Keratinocyte Growth Factor Affects Peripheral T-cell Homeostasis Through Increased Recent Thymic Emigrant Export and Affects the Course of Murine Chronic Graft-Vs.-Host Disease

Accelerated recovery of thymic function following allogeneic hematopoietic stem cell transplantation (allo-HSCT) not only provides a sufficiently broad repertoire of T-cell responses to pathogens, but also is thought to play a role in affecting the outcome of graft-vs.-host disease (GVHD) through the restoration of central tolerance and/or the production of regulatory cell populations that may blunt the effect of donor-derived alloreactive T-cell populations. Keratinocyte growth factor (KGF) has been shown in murine models to accelerate thymic function and ameliorate acute GVHD, but it is unclear whether the latter involves a thymic-dependent mechanism of increased T-cell production and/or cytoprotection of epithelial cells in target organs of GVHD. We examined the effect of pre-transplant administration of KGF in the B10.D2 into BALB/c murine model of chronic GVHD (cGVHD). KGF treated mice had significantly increased thymic function as assessed by enumeration of thymocyte populations, analysis of thymic cytoarchitecture, and enumeration of peripheral T-cell subsets and recent thymic emigrants (RTE). Significantly, enhanced export of RTE by KGF decreased peripheral T-cell homeostatic expansion and downregulated expression of activation markers, suggesting that RTE effectively compete with post-thymic T-cells for limited cytokines and contact-dependent niches post-allo-HSCT. Parallel experiments in thymectomized recipients receiving KGF exhibited no changes in cell cycle profiles or activation profiles of peripheral T-cells. Pre-transplant KGF administration improved clinical cGVHD outcomes in both thymus-intact and thymectomized recipients. However, there were no observable differences in the course of cGVHD between KGF treated thymus intact and thymectomized mice, suggesting that enhanced thymic function by KGF did not provide for any additional benefit to the cytoprotective effects of KGF. One contributing factor for this observation was the inability of KGF treatment to increase peripheral regulatory T-cell numbers. In summary, pre-transplant administration of KGF can accelerate thymic recovery post allo-HSCT and that the increased export of newly generated T-cells can blunt peripheral expansion of post-thymic T-cells. However, this thymus-dependent effect of KGF is insufficient to further ameliorate cGVHD. Nevertheless, the results suggest a potentially important role of KGF in immune reconstitution and modulation of cGVHD post-allo-HSCT.