The thymus undergoes age-related atrophy, coincident with increased circulating sex steroids from puberty. The impact of thymic atrophy is most profound in clinical conditions that cause a severe loss in peripheral T cells with the ability to regenerate adequate numbers of naive CD4+ T cells indirectly correlating with patient age. The present study demonstrates that androgen ablation results in the complete regeneration of the aged male mouse thymus, restoration of peripheral T cell phenotype and function and enhanced thymus regeneration following bone marrow transplantation. Importantly, this technique is also applicable to humans, with analysis of elderly males undergoing sex steroid ablation therapy for prostatic carcinoma, demonstrating an increase in circulating T cell numbers, particularly naive (TREC+) T cells. Collectively these studies represent a fundamentally new approach to treating immunodeficiency states in humans.
Chronic thymus involution associated with aging results in less efficient T-cell development and decreased emigration of naïve T cells to the periphery. Thymic decline in the aged is linked to increased morbidity and mortality in a wide range of clinical settings. Negative consequences of these effects on global health make it of paramount importance to understand the mechanisms driving thymic involution and homeostatic processes across the lifespan. There is growing evidence that thymus tissue is plastic and that the involution process might be therapeutically halted or reversed. We present here progress on the exploitation of thymosuppressive and thymostimulatory pathways using factors such as keratinocyte growth factor, interleukin 7 or sex steroid ablation for therapeutic thymus restoration and peripheral immune reconstitution in adults.
IntroductionThus far, 3 subsets of proinflammatory helper T cells have been described: Th1, Th2, and Th17 cells. 1 Naive T cells exposed to interleukin-12 1 (IL-12) differentiate into Th1 cells, resulting in expression of Tbet and STAT4, and secretion of interferon (IFN)-␥. 2 Th1 cells are essential for the clearance of intracellular bacteria and negatively regulate the development of Th2 and Th17 cells. 2 IL-4 activates a Th2 program, characterized by expression of STAT6 and GATA3 and secretion of IL-4, IL-5, and IL-13, which is important for humoral immunity. 2 Finally, naive T cells exposed to TGF-, IL-6, and IL-21 differentiate into Th17 cells by activating ROR␥t, ROR␣, STAT3, STAT4, and IRF4 transcription factors. [3][4][5][6] Th17 cells produce high levels of IL-17A (IL-17), IL-17F, IL-21, and IL-22, and have been shown to contribute to mucosal immunity. [7][8][9] Specifically, IL-17 is important in the control or clearance of various pathogens, including Klebsiella pneumoniae, 10 Citrobacter rodentium, 3 Borrelia burgdorferi, 11 and Candida albicans. 12 In addition, Th17 cells have been implicated in allograft rejection of solid organs [13][14][15] and several autoimmune diseases. 1,[16][17][18][19] IL-17, otherwise known as IL-17A, is the bestcharacterized member of the IL-17 family (IL-17A through F). IL-17 is a disulfide-linked homodimeric glycoprotein consisting of 155 amino acids with a molecular weight of 35 kDa. 20 IL-17F shares the greatest homology with IL-17 (55%). Th17 cells produce IL-17 and IL-17F while innate immune cells produce other IL-17 family members. IL-17 and IL-17F can exist as homodimers or heterodimers. 21 IL-17 homodimers are efficient at inducing chemokine production by epithelial cells. The IL-17 receptor (IL-17RA) is a type 1 transmembrane protein, and its mRNA is expressed in the lungs, kidneys, liver, and spleen as well as in isolated fibroblasts, epithelial cells, mesothelial cells, and various myeloid cells in rats and mice. 20 Th17 cells have been identified as the primary source of IL-22, an IL-10 family member. 8,22 IL-22 can stimulate proliferation, abnormal differentiation, and migration of various epithelial cells. 23 Its up-regulation has been associated with several autoimmune diseases, including psoriasis, Crohn's disease, and ulcerative colitis, as well as murine models of inflammatory bowel disease. [24][25][26][27] Allogeneic bone marrow transplantation (BMT) is a potentially curative therapy for various hematopoietic malignancies and immunologic diseases. 28,29 GVHD is a major complication of allogeneic BMT and causes significant morbidity and mortality. GVHD is the result of alloreactive donor T cells recognizing alloantigens on normal host tissues and mounting an attack against the host. 28,30 During GVHD, donor T cells specifically target the intestines, skin, and liver, 28 however, alloreactive T cells also contribute to graft-versus-tumor (GVT) activity, which may prevent tumor relapse. 28 During the early stages after BMT, alloreactive CD4 ϩ T cells sec...
Age-associated thymic involution is accompanied by decreased thymic output. This adversely affects general immune competence and T cell recovery following cytoreductive treatments such as chemotherapy. A causal link between increasing sex steroids and age-related thymic atrophy is well established. Although castration has been demonstrated to regenerate the atrophied thymus, little is known about how this is initiated or the kinetics of thymocyte regeneration. The present study shows that although castration impacts globally across thymocyte development in middle-aged mice, the regenerative effects are initiated in the immature triple-negative compartment and early T lineage progenitors (ETP). Specifically, there was a reduction in number of ETP with age, which was restored following castration. There was, however, no change in ETP reconstitution potential in ETP at this age or following castration. Furthermore, in a chemotherapy-induced model of thymic involution, we demonstrate castration enhances intrathymic proliferation and promotes differentiation through the triple-negative program. Clinically, reversible sex steroid ablation is achieved hormonally, and thus presents a means of ameliorating immune inadequacies, for example, following chemotherapy for bone marrow transplantation. By improving our understanding of the kinetics of thymic recovery, this study will allow more appropriate timing of therapy to achieve maximal reconstitution, especially in the elderly.
Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF ؊/؊ mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF ؊/؊ , wildtype (WT), and KGF ؉/؊ mice were similar. However, KGF ؊/؊ mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF ؊/؊ recipients of syngeneic or allogeneic bone marrow transplant, but using KGF ؊/؊ mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. IntroductionKeratinocyte growth factor (KGF) is a 28-kDa fibroblast growth factor family member (FGF-7) that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the gut (gut epithelial cells), skin (keratinocytes), and thymus (thymic epithelial cells). [1][2][3] KGF is produced by mesenchymal cells and has a paracrine effect on epithelial cells 4,5 ; it binds FGFR2IIIb, a splice variant of FGF receptor 2, expressed predominantly on these cell types. FGFR2IIIb is activated by 4 known ligands: FGF-1, FGF3, 7 The heterogeneous stromal cell compartment of the thymus includes both cortical and medullary epithelial cells, as well as mesenchymal cells (including fibroblasts). Mesenchymal cells produce fibroblast growth factors and support thymocyte development, especially in cortical areas (reviewed in Anderson and Jenkinson 8 ). Jenkinson et al 9 reported that mesenchymal cells regulate the proliferation of thymic epithelial cells via the production of KGF (FGF-7) and fibroblast growth factor-10 (FGF-10) during fetal development, but the role of mesenchymal cells in regulating the composition of thymic stroma in the neonatal and postnatal period is unclear.Erikson et al 10 have demonstrated that KGF and FGFR2IIIb signaling can affect the development and function of thymic epithelium (TE). In the adult thymus, mature ␣ ϩ thymocytes are capable of producing KGF, which leads to the expansion of thymic medullary epithelial cells. 10 However, KGF expression is not detectable in the triple negative (CD3 Ϫ CD4 Ϫ CD8 Ϫ ) thymocyte precursors. 10 In contrast, peripheral ␣ Ϫ T cells do not secrete KGF, even in epithelial tissues that comprise the skin, intestine, and vagina. However, ␥␦ Ϫ T cells in epithelial tissues do produce KGF and may also regulate epithelial cell growth. 11 KGF can function as a growth factor for epithelial protection and repair, is found in a variety of tissues (extensively reviewed by Finch and Rubin 12 ), and is up-regulated after various ...
We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for 'off-the-shelf' immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy.
Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits α E and β 7 , CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors
G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. G-CSF- and G-CSF receptor-deficient mice are profoundly protected in several models of rheumatoid arthritis, and Ab blockade of G-CSF also protects against disease. To further investigate the actions of blocking G-CSF/G-CSF receptor signaling in inflammatory disease, and as a prelude to human studies of the same approach, we developed a neutralizing mAb to the murine G-CSF receptor, which potently antagonizes binding of murine G-CSF and thereby inhibits STAT3 phosphorylation and G-CSF receptor signaling. Anti-G-CSF receptor rapidly halted the progression of established disease in collagen Ab-induced arthritis in mice. Neutrophil accumulation in joints was inhibited, without rendering animals neutropenic, suggesting an effect of G-CSF receptor blockade on neutrophil homing to inflammatory sites. Consistent with this, neutrophils in the blood and arthritic joints of anti-G-CSF receptor-treated mice showed alterations in cell adhesion receptors, with reduced CXCR2 and increased CD62L expression. Furthermore, blocking neutrophil trafficking with anti-G-CSF receptor suppressed local production of proinflammatory cytokines (IL-1β, IL-6) and chemokines (KC, MCP-1) known to drive tissue damage. Differential gene expression analysis of joint neutrophils showed a switch away from an inflammatory phenotype following anti-G-CSF receptor therapy in collagen Ab-induced arthritis. Importantly, G-CSF receptor blockade did not adversely affect viral clearance during influenza infection in mice. To our knowledge, we describe for the first time the effect of G-CSF receptor blockade in a therapeutic model of inflammatory joint disease and provide support for pursuing this therapeutic approach in treating neutrophil-associated inflammatory diseases.
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