High-TECh thymus

In this issue of Blood, Kelly and colleagues provide a possible solution to poor thymic function and prolonged immune deficiency following allogeneic BMT by demonstrating the additive benefit of combining KGF with androgen blockade to speed recovery of thymic function and reconstitution of functional T cells after BMT.

The thymus is a dynamic organ with regard to both the lymphoid and stromal compartments. The 3-dimensional thymic stromal compartment, composed primarily of cortical and medullary thymic epithelial cells (TECs), fibroblasts, and endothelial cells, directly supports thymocyte development and selection.¹  Myeloablative conditioning prior to hematopoietic stem-cell transplantation (HSCT) damages and depletes TECs. Because T-cell reconstitution and the generation of a broad T-cell repertoire require factors supplied by TECs, prolonged T-cell immune deficiency due to TEC injury predisposes patients to infections. Adults who undergo allogeneic HSCT, and who typically have poor age- and chemotherapy-related TEC support of thymopoiesis, are especially vulnerable.²  Low TEC levels would impede T-cell reconstitution, regardless of the number of stem and thymic progenitor cells infused.

Hormonal factors can inhibit thymopoiesis. Androgens (eg, testosterone) strongly suppress thymopoiesis via effects on TECs and other androgen receptor–bearing cells in the thymus. Physical castration of old mice can reverse thymic atrophy linked to age-related increases in androgen levels.³  In addition, androgen ablation has been reported to enhance thymopoiesis and reduce costimulatory thresholds for peripheral T-cell activation, possibly resulting in enhanced host immunity.⁴  Consistent with this, initial clinical studies have indicated that pretransplant castration may improve patient thymopoiesis and T-cell recovery.^5,6  TECs also may be positively regulated by thymic proteins. Keratinocyte growth factor (KGF), also known under the generic drug name palifermin, is a member of the fibroblast growth factor family that binds FGFR2-IIIb expressed by TECs. Studies in mice and rhesus macaques have demonstrated that thymic injury and T-cell deficiency can be partially ameliorated by KGF pretreatment; however, maximal benefit was not observed until relatively long after bone marrow transplantation (BMT).^7,8 

The individual thymopoieitc effects of KGF and physical castration, and the broad distribution of cognate receptors for KGF as well as androgen within thymic tissues, led the authors to pretreat allo-BMT recipients with both KGF to induce TEC mitogenesis and a chemical luteinizing hormone-releasing hormone supra-agonist, leuprolide (Lupron; TAP Pharmaceutical Products, Lake Forest, IL), to block the androgen-inhibitory pathway. Prior to conditioning, these agents, when given together but not individually, normalized TEC subset numbers and thymic architecture, led to supranormal thymopoiesis and accelerated peripheral CD4/CD8 T-cell reconstitution, facilitated CD8 T cell–mediated clearance of a live pathogen, and augmented a CD4 T cell–dependent B-cell humoral response. Distinct TEC subsets were protected by each reagent. Importantly, palifermin is approved for use in HSCT patients to prevent mucositis, and various chemical luteinizing hormone-releasing hormone supra-agonists including leuprolide acetate (ie, Lupron) have been used for several decades to treat prostate cancer. Each agent is under separate investigation in clinical studies to determine its potential for enhancing T-cell reconstitution in patients undergoing HSCT. While future clinical trials arising from these provocative preclinical studies will need to be performed to determine whether the incidence of infectious complications can be diminished without adverse effects on graft-versus-host disease or tumor recurrence, it is likely that multimodal therapy targeting TEC subsets and other thymic stromal cells holds the key to reducing the profound immune deficiency that accompanies allogeneic HSCT.