The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-␥ (IFN-␥), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-␥-receptor-deficient (IFN-␥RKO) MHCmatched C57BL/6 recipients. In IFN-␥RKO recipients, host cells were unresponsive to IFN-␥, whereas wt donor cells were exposed to exceptionally high levels of IFN-␥. From an IFN-␥ perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-offunction on donor cells. We found that lack of IFN-␥R prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-␥RKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-␥: Ccnd1 and Myc. We conclude that IFN-␥ produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD. IntroductionInterferon-␥ (IFN-␥) is a master regulator of adaptive immune responses. 1 IFN-␥ modulates hundreds of genes, regulating apoptosis and cell proliferation, antigen processing and presentation, and leukocyte trafficking and effector function. Although our comprehension of the molecular bases of IFN-␥ signaling in the immune system has evolved rapidly, our understanding of how IFN-␥ signals in various cell types are integrated in vivo and impinge on systemic immunopathologic conditions is still rudimentary.GVHD is the most important complication of allogeneic hematopoietic cell transplantation, accounting for most treatmentrelated morbidity and mortality. 2 It is a systemic disease affecting mostly the liver, intestine, skin, and lymphoid organs. [3][4][5] Studies in mouse models of GVHD have reported increased serum levels of IFN-␥ and induction of IFN-␥ transcriptional target genes in the skin and liver. 6,7 However, IFN-␥ was reported to have predominantly a protective influence on GVHD lethality in most though not all studies using IFN-␥-deficient donors, antibody-mediated depletion, or injection of IFN-␥. 4 Use of IFN-␥ receptor 1 chaindeficient (IFN-␥RKO) mice in MHC-mismatched transplants has further shown that the impact of IFN-␥ on GVHD lethality resulted from effects on both donor T cells and host nonhematopoietic cells. 8,9 Thus, alloreactive CD8 T cells from IFN-␥RKO and IFN-␥ deficient donors expand more extensively than CD8 T cells from wt donors. 8 Furthermore, lack of IFN-␥R on host pulmonary parenchyma enhances donor cell migration and expansion within the lu...

Age-related thymic involution severely impairs immune responsiveness. Strategies to generate T cells extrathymically are therefore being explored with intense interest. We have demonstrated that T cells produced extrathymically were functionally deficient relative to thymus-derived T cells. The main limitation of extrathymic T cells is their undue susceptibility to apoptosis; they thus do not expand properly when confronted with pathogens. Using oncostatin M-transgenic mice, we found that in the absence of lymphopenia, T cells of extrathymic origin constitutively undergo excessive homeostatic proliferation that leads to overproduction of IL-2 and IFN-γ. IFN-γ up-regulates Fas and FasL on extrathymic CD8 T cells, thereby leading to their demise by Fas-mediated apoptosis. Moreover, IFN-γ and probably IL-2 curtail survival of extrathymic CD4 T cells by down-regulating IL-7Rα and Bcl-2, and they support a dramatic accumulation of FoxP3+ T regulatory cells. Additionally, we show that wild-type thymus-derived T cells undergoing homeostatic proliferation in a lymphopenic host shared key features of extrathymic T cells. Our work explains how excessive lymphopenia-independent homeostatic proliferation renders extrathymic T cells functionally defective. Based on previous work and data presented herein, we propose that extrathymic T cells undergo constitutive homeostatic proliferation because they are positively selected by lymph node hemopoietic cells rather than by thymic epithelial cells.

The ability of 17 Actinobacillus pleuropneumoniae isolates representing serotypes 1, 2, 5, and 7, to adhere in vitro to porcine respiratory tract mucus was examined. Adherence of bacteria to crude mucus preparations was evaluated by use of a dot-blot assay and an enzyme immunoassay. Seventy per cent (12/17) of the isolates of A. pleuropneumoniae had affinity, to various degrees, for porcine respiratory tract mucus. No relationship was found between affinity for respiratory mucus and serotype, haemagglutination, lipopolysaccharide (LPS) profiles, or adherence to porcine tracheal rings. However, a correlation was found between affinity for respiratory mucus and capsular material thickness; heavily encapsulated isolated showed no or less affinity for mucus than isolates with a thinner layer of capsular material. Moreover, two encapsulated isolates showed less affinity for mucus than their acapsulated variant. Finally, the affinity of A. pleuropneumoniae for respiratory mucus was heat- and proteinase-K-resistant. Our data suggest that capsular material of A. pleuropneumoniae could mask a surface component, possibly LPS, which has affinity for porcine respiratory mucus.

Background: Metabolic syndrome (MetS) is a health disorder characterized by metabolic abnormalities that predict an increased risk to develop cardiovascular disease (CVD) and type 2 diabetes (T2DM). It can be resolved, and its complications reduced, by lifestyle interventions offered in primary care. The objectives of this study were to evaluate the impact of the exercise program of the CHANGE feasibility study on physical fitness and physical activity habits, and assess associations between changes in MetS components and cardiorespiratory fitness (CRF). Methods: In this analysis of 192 of the 293 adults with MetS in the overall study, the impact on physical fitness [aerobic capacity, muscular fitness and flexibility], and non-supervised physical activities was investigated over 12 months. In the CHANGE program, aerobic capacity, muscular fitness and flexibility were assessed at baseline, after 3 months of weekly supervised exercise, and following 9 additional months during which participants had one monthly session of supervised exercise. Additionally, CRF response was also examined in relation to changes in MetS components [fasting glucose, highdensity lipoprotein (HDL) cholesterol, triglycerides, blood pressure, waist circumference (WC)]. Results: Fitness variables were significantly increased at 12 months with most of the improvements reached by 3 months (estimated VO 2 max: 6 and 12%; partial curl-ups: 55 and 80%; push-ups: 50 and 100%; flexibility: 22 and 10% in men and women, respectively, p < 0.001). As expected, the duration and intensity of supervised aerobic physical activity increased during the first 3 months of supervision in both men and women, and remained unchanged for the duration of the program. The duration of non-supervised physical activities did not change during the program in men whereas an increase in manual work of moderate intensity was recorded in women between 3 and 12 months. In women, mean changes in WC were significantly greater among high VO 2 max responders than low responders, between 0 and 12 months, as well as between 3 and 12 months (− 3.42 cm and − 4.32 cm, respectively, p < 0.05). No associations were seen with MetS components in men. Higher intensity activities were maintained by both sexes at one year.