title: Up-regulation of alternate co-stimulatory molecules on proinflammatory CD28null T cells in bronchiolitis obliterans syndrome.
abstract: Bronchiolitis obliterans syndrome (BOS) is associated with lack of immunosuppression of T cell proinflammatory cytokines and increased T cell granzyme B. Repeated antigen-driven proliferation down-regulates T cell CD28. We hypothesized that down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules (CD134, CD137, CD152 and CD154) on T cells may be associated with BOS. Co-stimulatory molecules, granzyme B, perforin and intracellular cytokines were measured by flow cytometry on T cells from stable lung transplant patients (n = 38), patients with BOS (n = 20) and healthy controls (n = 10). There was a significant increase in the percentage of CD4/28(null) and CD8/28(null) T cells producing granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α in BOS compared with stable patients. Down-regulation of CD28 was associated with steroid resistance and up-regulation of CD134, CD137, CD152 and CD154 on CD4(+) T cells and CD137 and CD152 on CD8(+) T cells. There was a significant correlation between increased CD28(null) /CD137 T cells producing IFN-γ, TNF-α with BOS grade (r = 0·861, P < 0·001 for CD28(null) /CD137 IFN-γ/CD8) and time post-transplant (r = 0·698, P < 0·001 for CD28(null) /CD137 IFN-γ/CD8). BOS is associated with down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules on steroid-resistant peripheral blood proinflammatory CD4(+) and CD8(+) T cells. Therapeutic targeting of alternate co-stimulatory molecules on peripheral blood CD28(null) T cells and monitoring response using these assays may help in the management of patients with BOS.
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Australia. greg.hodge@health.sa.gov.au
authors.forename: G
authors.initials: G
authors.lastname: Hodge
authors.forename: S
authors.initials: S
authors.lastname: Hodge
authors.forename: J
authors.initials: J
authors.lastname: Ahern
authors.forename: C-L
authors.initials: CL
authors.lastname: Holmes-Liew
authors.forename: P N
authors.initials: PN
authors.lastname: Reynolds
authors.forename: M
authors.initials: M
authors.lastname: Holmes
mesh_terms: D000328:Adult; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology*; D018106:CD28 Antigens / Q000032:analysis; D023201:CD40 Ligand / Q000096:biosynthesis / Q000235:genetics; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000235:genetics; D016022:Case-Control Studies; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000096:biosynthesis* / Q000235:genetics; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D053804:Granzymes / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016040:Lung Transplantation; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000032:analysis; D011183:Postoperative Complications / Q000209:etiology / Q000276:immunology*; D053262:Receptors, OX40 / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D016559:Tacrolimus / Q000627:therapeutic use; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D061025:Costimulatory and Inhibitory T-Cell Receptors; D007166:Immunosuppressive Agents; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D023201:CD40 Ligand; D007371:Interferon-gamma; D016572:Cyclosporine; C509213:GZMB protein, human; D053804:Granzymes; D016559:Tacrolimus