Chest
Volume 129, Issue 3, March 2006, Pages 527-535
Journal home page for Chest

Original Research: COPD
Treatment With AM3 Restores Defective T-Cell Function in COPD Patients

https://doi.org/10.1378/chest.129.3.527Get rights and content

Background

Lymphocyte alterations have been associated with an increased prevalence of acute respiratory infections in COPD patients. AM3 is an oral immunomodulator that normalizes the defective functions of peripheral blood natural killer and phagocytic cells in COPD patients and improves their health-related quality of life.

Objectives

To characterize putative systemic abnormalities of the T-cell compartment in COPD patients, and to investigate whether AM3 can restore such abnormalities.

Design

The study was a randomized, prospective, double-blind, placebo-controlled trial in a cohort of COPD patients. The results were also compared to those of nonsmoker and ex-smoker healthy control subjects.

Setting

Outpatient departments of four hospitals.

Patients

Seventy COPD patients were randomized to receive either AM3 or a placebo orally for 90 consecutive days. Populations of 36 healthy nonsmokers and 36 healthy ex-smokers were used as control subjects.

Measurements

Peripheral blood mononuclear cell (PBMC) proliferation and production of interleukin (IL)-2, IL-4, IL-12p40, tumor necrosis factor-α, and interferon (IFN)-γ proteins in response to the T-cell polyclonal mitogens were assessed at baseline and at the end of treatment.

Results

The proliferative response was significantly decreased in COPD patients. Decreased production of IFN-γ was the only defect in the profiles of the cytokine measures, and was selectively observed in COPD patients, but not in nonsmoker and ex-smoker healthy control subjects. Treatment with AM3 significantly restored the PBMC proliferative response to polyclonal mitogens and significantly promoted stimulated IFN-γ production in these patients. The normalization of these proliferative responses was not related to significant variations in the numbers of peripheral blood monocytes, CD3+, CD4+, CD8+ cells or of any major naïve/memory/activated T-cell subset. The increased IFN-γ production in the AM3 study arm was associated with an increase in the mean of number of IFN-γ molecules produced per CD8+ T cells.

Conclusions

PBMCs of COPD patients showed clear functional T-lymphocyte abnormalities that are rescued by AM3 treatment.

Section snippets

Study Subjects

Seventy patients with COPD were randomized to receive AM3 (n = 35) or an indistinguishable placebo (n = 35). Subject characteristics are shown in Table 1. All subjects received extensive information about the study and gave informed, witnessed consent to participate. Neither patients nor control subjects were unavailable for follow-up.

Two groups of age- and sex-matched control subjects were included for immunologic comparison: one group was comprised of 36 healthy nonsmokers (mean age, 61 ± 8

PBMCs From COPD Patients Show Defects in Proliferation and IFN-γ Production in Response to T-Lymphocyte Mitogens

The proliferative response of PBMCs from COPD patients, as well as those of nonsmoker and ex-smoker healthy control subjects, to stimulation with phytohemagglutinin and anti-CD3 monoclonal antibodies was investigated. The kinetics of the proliferative response of PBMCs to the mitogens were analyzed at 3 days, 5 days, and 7 days of culture. The maximum response was found at 5 days of culture for both sets of control subjects and patients (data not shown); this culture period was therefore used

Discussion

This article shows that COPD patients have a defective PBMC proliferative response to polyclonal T-lymphocyte mitogens and that the percentage of CD4 and CD8 T-lymphocytes producing IFN-γ is reduced compared to nonsmoker and ex-smoker healthy subjects. The treatment with the immunomodulator AM3 is able to restore these defects.

We and others8, 11, 16 have previously reported decreased natural killer cell activity and impaired monocyte and polymorphonuclear chemotactic and phagocytic activities

ACKNOWLEDGMENT

The placebo and AM3 used in this study were provided by the manufacturer (I. F. Cantabria; Madrid, Spain). The authors thank the Immune System Involvement in Respiratory Disease Research Group (J. Jareño, Hospital Del Aire, Madrid; J. M. Rodriguez, Hospital Universitario Gregorio Marañon, Madrid; M. Calle, Hospital Universitario Clinico San Carlos, Madrid; J.L. Izquierdo, Pulmonary Unit, Hospital General Universitario, Guadalajara; and E. Sanz, Department of Medicine, University of Alcalá,

References (45)

  • de la Iglesia MartinezF et al.

    Chronic obstructive pulmonary disease and the seasons of the year

    Arch Bronconeumol

    (2000)
  • WileyJA et al.

    Production of interferon-γ by influenza hemagglutinin-specific CD8 effector T cells influences the development of pulmonary immunopathology

    Am J Pathol

    (2001)
  • ChoJY et al.

    Immunostimulatory DNA sequences inhibit respiratory syncytial viral load, airway inflammation, and mucus secretion

    J Allergy Clin Immunol

    (2001)
  • HalpernMT et al.

    The economic impact of acute exacerbations of chronic bronchitis in the United States and Canada: a literature

    J Manag Care Pharm

    (2003)
  • JanewayCh et al.
    (2005)
  • AgustiAG et al.

    Systemic effects of chronic obstructive pulmonary disease

    Eur Respir J

    (2003)
  • SaettaM et al.

    Cellular and structural bases of chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2001)
  • VillarrubiaVG et al.

    The immunosenescent phenotype in mice and humans can be defined by alterations in the natural immunity reversal by immunomodulation with oral AM3

    Immunopharmacol Immunotoxicol

    (1997)
  • BarnesPJ

    Chronic obstructive pulmonary disease

    N Engl J Med

    (2000)
  • WedzichaJA et al.

    Exacerbations of chronic obstructive pulmonary disease

    Respir Care

    (2003)
  • ReynoldsHY

    Modulating airway defenses against microbes

    Curr Opin Pulm Med

    (2002)
  • ReidPT et al.

    Cytokines in the pathogenesis of chronic obstructive pulmonary disease

    Curr Pharm Des

    (2003)
  • Cited by (21)

    • Accelerated immunosenescence, oxidation and inflammation lead to a higher biological age in COPD patients

      2021, Experimental Gerontology
      Citation Excerpt :

      Regarding the proliferation of lymphocytes, a typical activity of the acquired immunity, in response to the T cell stimulator PHA, its values were lower in both groups of patients in comparison to controls. In this respect, an increased propensity to undergo apoptosis of T cells has been described in COPD patients (Hodge et al., 2003), which could affect the proliferation capacity of these cells (Reyes et al., 2006). The higher values of adhesion, and lower phagocytosis, proliferation capacity, and Natural Killer cytotoxic activity of leukocytes in COPD patients, especially those at severe stage, could be indicative of accelerated immunosenescence in comparison to the age-matched control group.

    • Enhanced activation of circulating plasmacytoid dendritic cells in patients with Chronic Obstructive Pulmonary Disease and experimental smoking-induced emphysema

      2018, Clinical Immunology
      Citation Excerpt :

      In agreement with a number of previous studies, we have shown here that increased proportions of Tc1 and Tc17 cells and higher levels of related cytokines (IFN-γ and IL-17A) in circulation of COPD patients, as compared with nonsmokers and healthy smokers. However, in contrast to our finding, Reyes and colleague [36] reported that decreased production of IFN-γ in CD8+ T cells from COPD patients and some other studies could not found any detectable difference in IFN-γ production by circulating CD8+ T-cells in patients with COPD [37,38]. The reasonable explanation for this discrepancy might be the differences severity of the disease and comorbidities.

    • Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells

      2013, Respiratory Medicine
      Citation Excerpt :

      Furthermore, our observation of a specific down-regulation of TCR ζ chain in peripheral lymphocytes of COPD is in keeping with previous studies in patients with autoimmune diseases [29], chronic infection [30], cancer[31–34] and in animal models of chronic inflammation [35,36]. This finding is consistent with a defective proliferative response to TCR specific activation signals previously described in peripheral T-cells of COPD patients [37]. To our knowledge, the role of MDSCs in COPD has not been investigated before.

    • Bacterial extracts for the prevention of acute exacerbations in chronic obstructive pulmonary disease: A point of view

      2008, Respiratory Medicine
      Citation Excerpt :

      CD8 T-cells also use IFN-γ as an antiviral effector moiety.15–17 It has been documented that percentage of T-cells secreting IFN-γ is reduced in both CD4 and CD8 subsets in COPD patients, compared to non-smoker and ex-smoker healthy control subjects.18 In vitro bacterial extracts exert immunomodulatory action via modulation of the signal transducer gp130 and gp130 binding cytokines, including IL-6 and IL-11.19

    View all citing articles on Scopus

    All of the data acquisition and analyses were completed in the Department of Medicine, Alcal´ University.

    This work was partially supported by grants from the Ministerio de Ciencía y Tecnología (FIT-2003–090000–0105, SAF-2004–08138), the Instituto de Salud Carlos III (PI021909 and GO3/075) and the Chronic Inflammatory Disease Group of Castilla-La Mancha, Spain.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

    View full text