The role of lymphocytes in acute lung injury

Acute Respiratory Distress Syndrome (ARDS) is a significant problem in the critically ill. Early pathogenesis involves acute inflammation including neutrophil infiltration, the release of pro inflammatory cytokines and the influx of protein rich fluid due to the damage of the alveolar capillary barrier. Dysregulation of the inflammatory response is the main cause for lung pathology and to date there are no available pharmacological therapies. The role of myeloid cells has been described in great detail but this work represents the first detailed, systematic investigation of the role of lymphocytes during acute lung injury (ALl). Lymphocytes were shown to be present during the early development of lipopolysaccharide (LPS)-induced ALI Furthermore, elevation of lymphocyte-associated cytokines such as IL-2 was also observed; and these findings were validated in a human in vivo model and ALIl patients. Using an IL-17KO mouse model, a key role for IL-17 A in the recruitment of neutrophils to the airway was revealed. The main source of IL-17 A was attributed to the recently identified innate lymphoid cells (ILCs). It was shown that IL-17 A was produced in an IL-23-dependent manner augmented by IL-2. Detailed characterisation of the lung infiltrating ILCs suggested that they belonged to the recently classified ILC3s, previously described in the gut. Although regulatory T cells (Tregs) have been purported to play a role in the resolution phase of All, they were shown not to regulate early neutrophil recruitment, but had the capacity to downregulate cytokine-induced inflammation. Conversely, pan depletion of CD3+ T cells demonstrated a critical role for other populations of T cells in promoting pathogenesis during the acute phase of ALI; this effect is independent of IL-17 A. This work elucidates how the manipulation of lymphocyte populations may prove beneficial in developing therapeutics for the treatment of ALI patientsEThOS - Electronic Theses Online ServiceGBUnited Kingdo

IL-9 Regulates Pathology during Primary and Memory Responses to Respiratory Syncytial Virus Infection

IL-9 is a cytokine of great current interest associated with allergic/Th2 responses. High levels of IL-9 are present in bronchial secretions from infants with respiratory syncytial virus (RSV) bronchiolitis. To test its effects in RSV disease with a Th2 profile, BALB/c mice were vaccinated with recombinant vaccinia virus expressing the RSV G protein. On RSV challenge, immunized mice developed augmented disease characterized by enhanced pulmonary Th2 and local IL-9 production peaking on days 7-10 of RSV infection. Depletion with anti-IL-9 Ab at vaccination or RSV challenge enhanced viral clearance. Depletion only at challenge had no effect on disease severity, whereas depletion at immunization and challenge enhanced Th1 responses, inhibited virus-specific IgG1 production, and enhanced disease severity. By contrast, depletion of IL-9 at immunization boosted IgG2a and inhibited the Th2 response and disease during subsequent infection without a concomitant increase in type 1 cytokines. Adoptive transfer of secondary memory CD4 T cells from the spleens of IL-9-depleted mice into naive recipients replicated many of the effects of depletion, indicating that IL-9 acts via CD4 T cells. Therefore, IL-9 is a previously unknown but key modulator of antiviral immunity, regulating T and B cell responses and having potent and specific effects on viral lung disease. The Journal of Immunology, 2009, 183: 7006-7013

The nature of innate and adaptive interleukin-17A responses in sham or bacterial inoculation

Streptococcus pyogenes is the causative agent of numerous diseases ranging from benign infections (pharyngitis and impetigo) to severe infections associated with high mortality (necrotizing fasciitis and bacterial sepsis). As with other bacterial infections, there is considerable interest in characterizing the contribution of interleukin-17A (IL-17A) responses to protective immunity. We here show significant il17a up-regulation by quantitative real-time PCR in secondary lymphoid organs, correlating with increased protein levels in the serum within a short time of S. pyogenes infection. However, our data offer an important caveat to studies of IL-17A responsiveness following antigen inoculation, because enhanced levels of IL-17A were also detected in the serum of sham-infected mice, indicating that inoculation trauma alone can stimulate the production of this cytokine. This highlights the potency and speed of innate IL-17A immune responses after inoculation and the importance of proper and appropriate controls in comparative analysis of immune responses observed during microbial infection