Barry, Simon Mark Elliot; (2003) Lymphocyte responses in the lung in patients with respiratory disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The initial promise generated by earlier studies of bronchoalveolar lavage (BAL) in the differential diagnosis of lung disease has generally failed to be translated to routine clinical practice. The reasons for this delay stem largely from the fact that the cytospin techniques used to differentiate BAL leukocyte subpopulations are cumbersome, time- consuming and imprecise. Nevertheless, flow cytometry (FCM) offers an alternative technology that is rapid, precise and well suited to document complex changes in cellular phenotype in fresh and cultured specimens. The patients included in this thesis were all investigated for suspected respiratory disease and FCM was undertaken in addition to routine diagnostic tests on the BAL specimens. Three key findings were observed. First, a simple single four-colour panel has been developed that enables the rapid enumeration of the major clinically relevant leukocyte components in BAL, including the CD4/CD8 lymphocyte ratio. This technology is shown to be superior to cytospin techniques in terms of precision and speed, and should be adopted for routine clinical investigation. Second, it has been demonstrated that the lung is a distinct immunological site when compared to the blood. CDS T lymphocytes have been investigated using the discriminatory markers, CD27 and CD45RA, and it has been shown that there is a preferential accumulation of mature memory CDS cells in the lung. Lastly, the differences between the lung and the blood have been further evaluated by analysing antigen-specific responses in patients with tuberculosis. It has been shown that powerful CD4 interferon-y and tumour necrosis factor-a synthetic responses to short term incubation with purified protein derivative (PPD) in BAL, but not blood, can be used for the rapid diagnosis of acute tuberculosis. This test is a candidate for routine clinical application, particularly because patients with extra-pulmonary tuberculosis also respond. Most importantly, this thesis has demonstrated that the focused investigation of BAL using a powerful tool such as FCM can deliver important immunological information with direct clinical relevance. It therefore highlights the vital link between medicine and laboratory services in order to define optimal diagnostic technologies on the basis of modern research.

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