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Acute graft-versus-host disease (aGVHD) is the most common complication for patients undergoing allogeneic stem cell transplantation. Despite extremely aggressive therapy targeting donor T cells, patients with grade III or greater aGVHD of the lower GI tract, who do not respond to therapy with corticosteroids, have a dismal prognosis. Thus, efforts to improve understanding of the function of local immune and non-immune cells in regulating the inflammatory process in the GI tract during aGVHD are needed. Here, we demonstrate, using murine models of allogeneic BMT, that type 2 innate lymphoid cells (ILC2s) in the lower GI tract are sensitive to conditioning therapy and show very limited ability to repopulate from donor bone marrow. Infusion of donor ILC2s was effective in reducing the lethality of aGVHD and in treating lower GI tract disease. ILC2 infusion was associated with reduced donor proinflammatory Th1 and Th17 cells, accumulation of donor myeloid-derived suppressor cells (MDSCs) mediated by ILC2 production of IL-13, improved GI tract barrier function, and a preserved graft-versus-leukemia (GVL) response. Collectively, these findings suggest that infusion of donor ILC2s to restore gastrointestinal tract homeostasis may improve treatment of severe lower GI tract aGVHD., Introduction Allogeneic stem cell transplant (allo-SCT) has the potential to provide curative therapy for patients with high-risk acute leukemia, lymphoid malignancies, and other malignant diseases (1-3). Despite improvements in HLA [...]

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/flIl7rCre/+ mice or induced ILC2 depletion in IcoS10™^Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild-type (WT) mice, but not ILC2 from Il5~/- mice induces EOS differentiation in bone-marrow cells from Rorafl/flIl7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5-/- and Il13-/- mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5-/- mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution ofWT EOS and ILC2 but not Il5-/- ILC2 slows AAA growth in Rorafl/flIl7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism. [ABSTRACT FROM AUTHOR]

Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may [...]

Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity--responsible for protective immune responses to helminth parasites (1,2) and the underlying cause of the pathogenesis of allergic asthma (3,4)--consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity., Type-2 immunity evolved to respond to parasitic helminth infections, with type-2 cytokines orchestrating eosinophilia, goblet cell hyperplasia, mucus secretion, and IgE production (5-7). These highly complex host responses involve the [...]

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q-syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q-syndrome., 5q-syndrome was first described in 1974 as a consistent association of the deletion of the long arm of chromosome 5 (del(5q)) with hematological abnormalities: macrocytosis, anemia, normal or high platelet [...]

ST2 is an IL-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. sST2 is a mechanically induced cardiomyocyte protein, and serum sST2 levels predict outcome in patients with [...]

The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, the primary cellular defect underlying impaired GCs in aging has not been identified. Here, we used heterochronic parabiosis to demonstrate that GC formation was dictated by the age of the lymph node (LN) microenvironment rather than the age of the immune cells. Lymphoid stromal cells are a key determinant of the LN microenvironment and are also an essential component underpinning GC structure and function. Using mouse models, we demonstrated that mucosal adressin cell adhesion molecule–1 (MAdCAM-1)–expressing lymphoid stromal cells were among the first cells to respond to NP-KLH + Alum immunization, proliferating and up-regulating cell surface proteins such as podoplanin and cell adhesion molecules. This response was essentially abrogated in aged mice. By targeting TLR4 using adjuvants, we improved the MAdCAM-1+ stromal cell response to immunization. This correlated with improved GC responses in both younger adult and aged mice, suggesting a link between stromal cell responses to immunization and GC initiation. Using bone marrow chimeras, we also found that MAdCAM-1+ stromal cells could respond directly to TLR4 ligands. Thus, the age-associated defect in GC and stromal cell responses to immunization can be targeted to improve vaccines in older people. MAdCAM-1 about aging: As people age, their immune responses to vaccines and infections diminish, increasing the risk for serious illness. These diminished immune responses have been tied to poor germinal center responses in older people, yet the exact mechanism for how this occurs is unclear. Here, Denton et al. vaccinated adult or aged mice with NP-KLH formulations to track germinal center responses overtime. They found that the microenvironment of the lymph node was impaired in older mice, defined by a poor response of MAdCAM-1+ stromal cells to vaccination. These MAdCAM-1+ stromal cells were partially rescued with a TLR4 agonist, which improved the initiation of germinal center immune responses. Together, these data suggest that targeting TLR4 might improve the efficacy of vaccination in older people. [ABSTRACT FROM AUTHOR]

Chromosomal translocations were studied by forming a fusion oncogene to mimic homologous recombination in embryonal stem cells. The fusion oncogene consisted of the human AF9 sequences which were mated into the mouse MII gene, which contains the transcription control elements similar to human leukemia. Expression of the fused genes produced tumors in chimeric mice. Prior to the development of tumors, the embryonal cell derivatives showed forms of expansion in peripheral blood.

The biological characterizations of the cDNA encoding interleukin 13 (IL-13), a T-cell-derived cytokine, were reported. It was shown that IL-13 induces IgG4 and IgE synthesis, CD23 expression and germ-line IgE heavy-chain gene transcription in human B cells. The activity of IL-13 is shown to be independent of IL-4. Together, the results indicate that IL-13 directs B cells to switch to IgG4 and IgE production.