Compartmentalization of intracellular proinflammatory cytokines in bronchial intraepithelial T cells of stable lung transplant patients

Allograft rejection remains a major cause of morbidity and mortality following lung transplantation and is associated with an increased expression of T cell proinflammatory cytokines. We have shown that CD4+ T cell proinflammatory cytokine production was significantly reduced in peripheral blood and bronchoalveolar lavage (BAL) of stable lung transplant patients, consistent with immunosuppression therapy. However, analysis of inflammatory cytokine profiles of intraepithelial T cells in bronchial brushing (BB) may be more relevant than peripheral blood or BAL T cells for assessing immune graft status. To investigate the immunomodulatory effects of currently used immunosuppressive regimens on bronchial intraepithelial T cell cytokine production, whole blood, BAL and BB from stable lung transplant patients and control volunteers were stimulated in vitro and cytokine production by CD8+ and CD4+ T cell subsets determined using multi‐parameter flow cytometry. In bronchial intraepithelial T cell subsets in control subjects and transplant patients there was compartmentalization of interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α production, a decrease in interleukin (IL)‐2 production by CD4+ T cells and CD4 : CD8 inversion compared with blood and BAL. Although there was a decrease in T cell proinflammatory cytokine production in blood of transplant patients, this was not found in BAL or bronchial intraepithelial CD8 T cell subsets, suggesting that the same level of immunosuppression may not occur in the lung of transplant recipients. Drugs that effectively reduce CD8 T cell proinflammatory cytokine production in the lung compartment may improve current protocols for reducing graft rejection in these patients.

[1]  S. Hodge,et al.  Increased Intracellular Pro- and Anti-inflammatory Cytokines in Bronchoalveolar Lavage T cells of Stable Lung Transplant Patients , 2005, Transplantation.

[2]  S. Hodge,et al.  Differential rates of apoptosis in bronchoalveolar lavage and blood of lung transplant patients. , 2005, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[3]  P. Corris,et al.  A role for cytokine measurement in therapeutic monitoring of immunosuppressive drugs following lung transplantation , 2005, Clinical and experimental immunology.

[4]  S. Hodge,et al.  Intracellular cytokines in blood T cells in lung transplant patients – a more relevant indicator of immunosuppression than drug levels , 2005, Clinical and experimental immunology.

[5]  R. Aris,et al.  Obliterative bronchiolitis or chronic lung allograft rejection: a basic science review. , 2005, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[6]  S. Hodge,et al.  Flow cytometric characterization of cell populations in bronchoalveolar lavage and bronchial brushings from patients with chronic obstructive pulmonary disease , 2004, Cytometry. Part B, Clinical cytometry.

[7]  J. Kirby,et al.  Post‐Transplant Renal Tubulitis: The Recruitment, Differentiation and Persistence of Intra‐Epithelial T Cells , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  D. Postma,et al.  Longitudinal profile of bronchoalveolar lavage cell characteristics in patients with a good outcome after lung transplantation. , 2002, American journal of respiratory and critical care medicine.

[9]  R. Mannon,et al.  Enhanced T cell cytokine gene expression in mouse airway obliterative bronchiolitis. , 2000, Transplantation.

[10]  P. Hasleton,et al.  Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation. , 1999, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[11]  S. Romagnani,et al.  The Th1/Th2 paradigm. , 1997, Immunology today.

[12]  G. Patterson,et al.  Cytokine gene transcripts for tumor necrosis factor-α, interleukin-2, and interferon-γ in human pulmonary allografts , 1995 .

[13]  G. Patterson,et al.  Cytokine gene transcripts for tumor necrosis factor-alpha, interleukin-2, and interferon-gamma in human pulmonary allografts. , 1995, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[14]  D. Erle,et al.  Lung epithelial lining fluid T cell subsets defined by distinct patterns of beta 7 and beta 1 integrin expression. , 1994, American journal of respiratory cell and molecular biology.

[15]  A. F. Wells,et al.  Cytokine Gene Expression: Analysis using Northern Blotting, Polymerase Chain Reaction and in situ Hybridization , 1991, Immunological reviews.

[16]  J. Kehrl Transforming growth factor-beta: an important mediator of immunoregulation. , 1991, International journal of cell cloning.