Background: Early pulmonary rehabilitation (PR) is recommended following hospitalised exacerbations of COPD as it improves exercise capacity and health related quality of life, and reduces readmissions and mortality. However little data exist for early PR following hospitalisation for other respiratory conditions, including bronchiectasis. Methods: In an exploratory feasibility study, eighteen individuals with a primary diagnosis of bronchiectasis, recently discharged following a hospitalised exacerbation, were referred for early PR comprising two supervised sessions per week for eight weeks. They were propensity matched 1:2 with a control group of 36 individuals with COPD undergoing the same early PR programme. Results: Baseline characteristics are outlined in Table 1. Completion rate was similar in both groups (56 versus 61%). Improvements in exercise capacity, health related quality of life, anxiety and depression, or disease knowledge following early PR were similar between the bronchiectasis and COPD groups (Table 2). Conclusions: Post-hospitalisation PR in individuals with bronchiectasis appears feasible with similar completion rates and improvements in clinical outcomes as observed in propensity-matched patients with COPD. Further studies, including randomised clinical trials, are needed to explore the efficacy of early PR following hospitalised exacerbations of bronchiectasis.

Bacterial pneumonia is the most common infectious cause of death worldwide, disease burden is increasing and antibiotic resistance continues to escalate.[1,2][1] Novel therapies are needed. Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells which reside in bone marrow and

IL-8-dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels of IL-8 in the lung. To better understand the duality of IL-8-dependent host immunity to bacterial infection and lung pathology, we expressed human IL-8 transgenically in murine bronchial epithelium, and investigated the impact of overexpression on lung bacterial clearance, host immunity, and lung pathology and function. Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation and activation, and chemotaxis. There was enhanced protection against challenge with Pseudomonas aeruginosa, and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL-2, and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen OprF, indicating a regulatory T-cell phenotype. However, this enhanced bacterial immunity came at a high price of progressive lung remodeling, with increased inflammation, mucus hypersecretion, and fibrosis. There was increased expression of Ccl3 and reduced expression of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all of which resulted in impaired lung function with reduced compliance, increased resistance, and bronchial hyperreactivity as measured by whole-body plethysmography. These results show that IL-8 overexpression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodeling, and damaged tight junctions, leading to impaired lung function.

Background: Human natural killer (NK) cell activity is regulated by a family of killer cell immunoglobulin-like receptors (KIRs) that bind human leukocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys(80)). KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn(80)). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes.Results: The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2,C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLAC*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross- reactive binding.conclusion: KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, providing an explanation for KIR2DL3-C1 interactions appearing weaker than KIR2DL1-C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR-HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition.

Background Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys 80 ) and KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn 80 ). However, this model does not capture allelic diversity in HLA-C or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes. Results The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides, or predicted HIV Gag peptides, by HLA-C can promote KIR cross-reactive binding. Conclusions KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, which provides an explanation for why KIR2DL3–C1 interactions appear weaker than KIR2DL1–C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR–HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition.

Killer cell immunoglobulin-like receptor/HLA class I (KIR/HLA-I) combinations are associated with disease risk, implicating functional roles for NK cells (NKCs) or KIR(+) T cells. KIR/HLA-I interactions can act through inhibition of NKC activation by target cells and NKC licensing for greater intrinsic responsiveness. We compared licensing conferred by the weaker, HLA-C group 1/KIR2DL3, and the stronger, HLA-C group 2/KIR2DL1, inhibitory combinations. The "rheostat model" predicts weaker licensing by HLA-C1/KIR2DL3 interactions than HLA-C2/KIR2DL1. We analyzed degranulation in NKC subsets expressing single and multiple receptors for HLA-I. NKG2A had the strongest licensing impact, while KIR2DL3, KIR2DL1, and KIR3DL1 were weaker, and not significantly different to each other. Presence of one or two matched HLA-C allotypes did not alter licensing of KIR2DL3(+) and KIR2DL1(+) NKC. Coexpression of activating KIR2DS1 disarmed KIR2DL3(+) and KIR2DL1(+) NKC to a similar extent. KIR3DL1 and NKG2A combined for more enhanced licensing of double-positive NKC than the combination of KIR2DL3 and KIR2DL1. Thus, KIR2DL3 and KIR2DL1 have similar capacity to license NKC, suggesting that inhibitory signal strength and amount of available HLA-C ligands do not correlate with NKC licensing. Altogether, our results show that the basis for disease associations of HLA-C and KIR2DL likely encompasses factors other than licensing.

BACKGROUND: Mesenchymal stem cells (MSCs) regulate lung inflammation, and enhance bacterial clearance and survival in preclinical models of pneumonia and sepsis 1-3 ,making them a possible treatment for bacterial lung infection resistant to antibiotic therapy. AIM: We set out to study how MSCs interact with host immunity to reduce bacterial burden and enhance survival through their interaction with regulatory T-cells (Tregs). METHODS: Bacterial lung infection was studied in a Foxp3-DTR inducible Treg knockout model on a C57Bl/6 genetic background (Kim et al .(2007). Nature Immunol. 8(2):191). Foxp3-DTR inducible Treg knockouts carry a targeting construct encoding human diphtheria toxin receptor fused to sequences encoding GFP inserted into the Foxp3 gene. Treatment with diphtheria toxin leads to conditional depletion of Tregs. Age/sex matched groups of transgenics were infected intranasally with either Streptococcal pneumonia e or Pseudomonas aeruginosa. Bone marrow-derived murine MSCs were injected i.v. Mice were monitored for 24 hours before being sacrificed and analysed. RESULTS: Bacterial clearance was enhanced in MSC-treated mice. Treg depletion impeded the enhanced bacterial clearance seen in MSC treated mice. CONCLUSIONS: This study shows that MSCs enhance bacterial clearance in the lung and that this effect is Treg dependent. REFERENCES: 1) Mei S.H.J., et al . (2010). Am J Resp Crit Care Med 182:1047. 2) Krasnodembskaya A., et al . (2012). Am J Physiol Lung Cell Mol Physiol 302:1003. 3) Gupta N., et al . (2012). Thorax. 67(6): 533-539.