TRAIL/DR5 Interactions Are Important For Mediating Thymic Damage After Allogeneic Bone Marrow Transplantation
Year: 2010
Type: article
Abstract: Thymic GVHD (tGVHD) is associated with prolonged immunodeficiency. We previously found that thymic output after allo-BMT is directly related to thymus size, and inversely related to donor T cell dose and GVHD severity. Additionally, radiation-containing preparative regimens upregulate the death receptors Fas and DR5 on thymic stroma and decrease expression of cFLIP, thus sensitizing the thymus to GVHD. Finally, very few donor alloreactive T cells are sufficient to cause tGVHD via the Fas/Fas ligand (FasL) and TRAIL/DR5 pathways. Here, we performed allo-BMT in MHC-mismatched and MHC-matched minor antigen-disparate model systems, and demonstrated the exquisite sensitivity of the thymus to as few as 1-2.5×105 donor T cells, which mediated tGVHD without significant clinical GVHD. Additionally, tGVHD is partially reversible in our models (contingent on low T cell dose), such that mice with tGVHD exhibit a partial recovery in thymic cellularity late (day 60) post-transplant. We further studied the role of TRAIL in tGVHD, by asking whether alloreactive T cells and GVHD or conditioning-associated inflammation were strictly required for TRAIL/DR5-mediated damage. We treated recipients of T cell-depleted allo-BMT with mDR5-1 agonistic antibody either in the “early” peri-transplant period, or “late,” in the second week post-transplant. Allo-BMT recipients treated “early” with mDR5-1 had significantly decreased thymic cellularity and splenic BM-derived T cells as compared with controls. Furthermore, we observed similar BM cellularity and BM-derived lineage- sca-1+ckit+ (LSK), all in the absence of donor alloreactive T cells or GVHD. We observed similar results with mice treated with “late” mDR5-1, indicating the continued sensitivity of the thymus to TRAIL throughout the post-transplant period, and that GVHD and/or conditioning-associated cytokines are not required to enable TRAIL-mediated damage to the thymus. Furthermore, we observed that on day 28 after T cell-depleted allo-BMT, only 1-2% of donor thymocytes expressed DR5, suggesting that mDR5-1 (and potentially TRAIL) mediate their effects on thymic cellularity and function primarily via an indirect mechanism. We conclude that the thymus is highly sensitive to GVHD and endures severe damage at low levels of systemic GVHD. Furthermore, we provide significant additional mechanistic insight into the temporal, cellular, and inflammatory requirements for TRAIL/DR5 mediated damage to the thymus.
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2084943172