BIOMARKERS FOR PROGNOSES OF PULMONARY DISEASES
The present invention relates to biomarkers that may be used to evaluate the prognoses of patients suffering from pulmonary diseases and assist in the determination of appropriate therapeutic regimens. It is based, at least in part, on the discovery that a number of T-cell antigens are differentially expressed in chronic lung disease patients depending on the prognosis of the patient. Non-limiting examples of these antigens include CD28, CD4, CD25, CD45, CD27 and CCR7 and combinations thereof. Use of these biomarker antigens, optionally in conjunction with pulmonary function tests, provides an indication of which patients are likely to suffer a severely adverse outcome within the year and/or be refractory to treatment.
1 . A method of determining the risk that a subject suffering from a chronic pulmonary disease will suffer a severe adverse event, comprising determining whether, in a sample comprising T-cells collected from the subject, one or more of the following is present:
the proportion of CD4+CD28null cells among the Cd4+ T-cell population is elevated, where said elevation indicates that the subject is at increased risk of suffering a severe adverse event;
the proportion of CD4+ cells among the peripheral blood mononuclear cell population is decreased, where said decrease indicates that the subject is at increased risk of suffering a severe adverse event;
the proportion of CD25+ cells among the CD4+ T-cell population is decreased, where said decrease indicates that the subject is at increased risk of suffering a severe adverse event;
the proportion of CD28+ cells among the CD8+ T-cell population is decreased, where said decrease indicates that the subject is at increased risk of suffering a severe adverse event;
the proportion of CD4+CD45+RO CD45RO+ cells among the CD4+ T-cell population is decreased, where said decrease indicates that the subject is at increased risk of suffering a severe adverse event;
the proportion of HLA-DR+ cells among the CD4+ T-cell population is increased, where said increase indicates that the subject is at increased risk of suffering a severe adverse event;
the proportion of CD27+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates that the subject is at increased risk of suffering an adverse event;
the proportion of CCR7+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates that the subject is at increased risk of suffering an adverse event;
the proportion of IL-7R+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates the subject is at increased risk of suffering an adverse event;
the proportion of CD3+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates the subject is at increased risk of suffering an adverse event;
the proportion of CD80+ cells among the CD4+ T-cell population is increased relative to a healthy control, where said decrease indicates the subject is at increased risk of suffering an adverse event;
the proportion of CTLA-4+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates the subject is at increased risk of suffering an adverse event;
the proportion of ICOS+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates the subject is at increased risk of suffering an adverse event;
the proportion of Itk+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates the subject is at increased risk of suffering an adverse event;
the proportion of Ltk+ cells among the CD4+ T-cell population is decreased relative to a healthy control, where said decrease indicates the subject is at increased risk of suffering an adverse event;
the proportion of granzyme B produced by CD4+ T-cells of the subject is increased relative to T-cells of a healthy control, where said increase indicates that the subject is at increased risk of suffering an adverse event;
the proportion of FoxP3 produced by CD4+ T cells of the subject is decreased relative to T cells of a healthy control, where said decrease indicates that the subject is at increased risk of suffering an adverse event; and
the proportion of perforin produced by CD4+ T-cells of the subject is increased relative to T-cells of a healthy control, where said increase indicates that the subject is at increased risk of suffering an adverse event.
2 . The method of claim 1 , where the chronic pulmonary disease is selected from the group consisting of chronic rejection following lung transplant, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary hypertension, inflammatory lung disease associated with an autoimmune disease, and lung disease associated with sarcoidosis and scleroderma.
3 . The method of claim 1 , where the chronic pulmonary disease is idiopathic pulmonary fibrosis.
4 . The method of claim 1 , where the chronic pulmonary disease is chronic rejection following lung transplant.
5 . The method of claim 1 , where the adverse event is selected from the group consisting of death within one year, lung transplant desirable or deemed necessary within one year, (in transplant patients) incidence of BOS, resistance to therapy with cyclosporine or other immunosuppressive agent, decrease in DLCO, or decrease in FVC, or decrease in FEV1
6 . The method of claim 1 , where if the percent of CD4+CD28+ of the CD4+ T-cell population is less than about 90 percent, the subject is at increased risk of suffering a severe adverse event.
7 . The method of claim 1 , where if the percent of CD4+ cells in the T cell population is less or equal to about 31.1 percent, the subject is at an increased risk of suffering a severe adverse event.
8 . The method of claim 1 , where if the percent of CD25+ cells in the T cell population is less than or equal to about 54 percent, then subject is at an increased risk of suffering a severe adverse event.
9 . The method of claim 1 , where if the percent of CD8+CD28+ cells in the CD8+ T cell population is less than or equal to about 21 percent, then subject is at an increased risk of suffering a severe adverse event.
10 . The method of claim 1 , where if the percent of CD45RO+ cells in the CD4+ T cell population is less than or equal to about 54 percent, then subject is at an increased risk of suffering a severe adverse event.
11 . The method of claim 1 , where if the percent of CD4+HLA−DR+ cells in the CD4+ T cell population is greater than about 87.1 percent, then subject is at an increased risk of suffering a severe adverse event.
12 . A kit comprising a capture agent directed to one or more of CD4, CD28, CD25, CD8, CD45, DR, Ro, CD27, CCR7, granzyme B, FoxP3, IL-7R, or perforin, optionally together with a detection agent, and optionally with a package insert describing one or more method according to claim 1 .