Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients

The Journal of Immunology

Fujita

et al. 2013

Homeostatic proliferation of naive T cells in the spleen and cutaneous lymph nodes supplies memory–phenotype T cells. The “systemic” proliferative responses divide distinctly into fast or slow cell division rates. The fast proliferation is critical for generation of effector memory T cells. Because effector memory T cells are abundant in the lamina propria of the intestinal tissue, “gut-specific” homeostatic proliferation of naive T cells may be important for generation of intestinal effector memory T cells. However, such organ-specific homeostatic proliferation of naive T cells has not yet been addressed. In this study, we examined the gut-specific homeostatic proliferation by transferring CFSE-labeled naive CD4+ T cells into sublethally irradiated mice and separately evaluating donor cell division and differentiation in the intestine, mesenteric lymph nodes (MLNs), and other lymphoid organs. We found that the fast-proliferating cell population in the intestine and MLNs had a gut-tropic α4β7+ Th17 phenotype and that their production was dependent on the presence of commensal bacteria and OX40 costimulation. Mesenteric lymphadenectomy significantly reduced the Th17 cell population in the host intestine. Furthermore, FTY720 treatment induced the accumulation of α4β7+IL-17A+ fast-dividing cells in MLNs and eliminated donor cells in the intestine, suggesting that MLNs rather than intestinal tissues are essential for generating intestinal Th17 cells. These results reveal that MLNs play a central role in inducing gut-tropic Th17 cells and in maintaining CD4+ T cell homeostasis in the small intestine.

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

Kawabe

The Journal of Immunology

Fujita

et al. 2013

“…35 A second signal through T-cell co-stimulatory molecules and their ligands on APCs is required to achieve T-cell activation, proliferation, differentiation and survival. 36,37 An in vivo blockade of positive co-stimulatory molecules (CD28, ICOS, CD40, CD30, 4-1BB and OX40-those that activate T-cell response) reduces acute GVHD, [38][39][40][41][42][43] whereas a blockade of inhibitory signals (those that inhibit or exhaust T-cell response), such as programmed death-1 (PD-1) and CTLA-4, exacerbates acute GVHD in murine models. 44 Interactions that enhance or inhibit the function of APCs.…”

Section: Sensors Of Gvhdmentioning

confidence: 99%

New perspectives on the biology of acute GVHD

Paczesny

Hanauer

et al. 2009

Bone Marrow Transplant

158

126

The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as:(1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

“…Costimulatory pathways are now known to deliver both positive and negative signals and molecules from two major families, the B7 family and the TNF receptor (TNFR) family play pivotal roles in GVHD (97). Interruption of the second signal by blockade of various positive co-stimulatory molecules (CD28, ICOS, CD40, CD30, 4-1BB and OX40) reduces acute GVHD in several murine models while antagonism of the inhibitory signals (PD-1 and CTLA-4) exacerbates the severity of acute GVHD (2,(98)(99)(100)(101)(102)(103). The various T cell and APC costimulatory molecules and the impact on acute GVHD are summarized in Table 2.…”

Section: B Phase 2: Donor-t-cell Activation Differentiation and Migmentioning

confidence: 99%

Pathophysiology of acute graft-versus-host disease: recent advances

Tawara

Toubai

et al. 2007

Translational Research

118

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many malignant and non-malignant hematological diseases. Donor T cells from the allografts are critical for the success of this effective therapy. Unfortunately these T cells not only recognize and attack the disease cells/tissues but also the other normal tissues of the recipient as 'foreign' or 'nonself' and cause severe immune mediated toxicity, Graft-versus-Host Disease (GVHD). Several insights into the complex pathophysiology of GVHD have been gained from recent experimental observations, which show that acute graft-vs.-host disease (GVHD) is a consequence of interactions between both the donor and the host innate and adaptive immune systems. These insights have identified a role for a variety of cytokines, chemokines, novel T cell subsets (naïve, memory, regulatory and NKT cells) and also for non-T cells of both the donor and host (antigen presenting cells, γδ T cells, B cells and and NK cells) in modulating the induction, severity and maintenance of acute GVHD. This review will focus on the immunobiology of experimental acute GVHD with an emphasis on the recent observations.