Phenotypic characterization of T cells in bronchoalveolar lavage fluid (BALF) and peripheral blood of patients with diffuse panbronchiolitis; the importance of cytotoxic T cells

Abstract

SUMMARYWe investigated the contribution of T cells in diffuse panbronchiolitis (DPB) by identifying T cell subsets in BALF of 36 patients with DPB, before and after long-term treatment with macrolide antibiotics, and 16 healthy control subjects. The percentages of lymphocytes and CD3þ gd þ cells in BALF of DPB patients and control subjects were similar, but the absolute number of these cells was higher in DPB patients. Treatment resulted in a significant reduction in the absolute number of these cells. A further two-colour analysis of T cell subsets in BALF showed a significantly higher ratio and number of CD8 þ HLA-DR þ cells in DPB patients. Treatment resulted in a significant reduction of activated T cells. Most BALF CD8 þ cells were CD8The number of these cells in BALF of DPB patients (26 . 69 Ϯ 5 . 86 × 10 3 /ml) was higher than the control (2 . 02 Ϯ 0 . 38 × 10 3 /ml; P < 0 . 001), and a significant reduction was observed after treatment (7 . 69 Ϯ 2 . 59 × 10 3 /ml; P < 0 . 01). The number of CD4 þ cells was also higher in DPB patients than in controls, and most were CD4 þ CD29þ memory T cells. However, treatment did not influence the number of these cells. The number of lymphocytes, CD3 and CD4þ CD29 þ cells was higher in patients with bacterial infection than in those without bacterial infection, and interestingly, macrolide therapy reduced the number of lymphocytes,þ CD11b ¹ and CD8 þ HLA-DR þ cells, irrespective of bacterial infection. In peripheral blood, the percentage of CD8 þ HLA-DR þ cells was also higher in DPB patients than in healthy subjects, and significantly decreased after treatment. The percentage of CD8 þ CD11b ¹ cells in peripheral blood was similar in DPB patients and normal subjects, and treatment significantly reduced the percentage of these cells. Finally, the expression of the adhesion molecules CD11a/CD18 (a/b-chains of LFA-1) on lung CD3 þ cells and CD49d (a-chain of VLA) on lung CD4 þ cells was enhanced compared with that on peripheral blood in DPB patients. Our results suggest that elevation of memory T cells and activation of CD8 þ cells, mainly cytotoxic T cells, in the airway lumen of DPB patients may contribute to chronic bronchial inflammation, possibly through up-regulation of adhesion molecules. Our findings also indicate that macrolide antibiotics may have a direct or indirect suppressive effect on cytotoxic T cells, and as such, reduce inflammation and improve clinical condition.

Diffuse panbronchiolitis

“…In addition, a significant increase in the percentage and absolute number of activated cytotoxic (CD8+, HLA-DR+, CD11b+) cells has been observed [54,55]. The number of CD4+ cells is also increased, with a predominance of CD4+CD29+ memory T-cells [53].…”

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

“…ϩ CD11b Ϫ cytotoxic T cells in BAL fluid from subjects with DPB (131). Macrolide suppression of proinflammatory cytokine production may be the principal mechanism of action in DPB (71, 183,283).…”

Macrolide antibiotics induce apoptosis of human peripheral lymphocytes in vitro

“…We previously reported that long-term MCL treatment reduced the number of lymphocytes in bronchoalveolar lavage fluid (BALF) of patients with DPB [12,13]. In this regard, elimination of lymphocytes by apoptosis is important in the control of chronic pulmonary inflammation [14].…”