Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia

doi:10.1073/pnas.062056099

Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia

^*Center for Blood Research, Harvard Medical School, Boston, MA 02115; Departments of ^†Pathology and ^**Medicine, Brigham and Women's Hospital, Boston, MA 02115; ^§Stanford Medical Center, Palo Alto, CA 94303; ^¶Cambodian Health Committee and ^‡‡Institut Pasteur du Cambodge, Phnom-Penh, Cambodia; Divisions of ^‖Adult Oncology and ^§§Cancer Immunology, Dana–Farber Cancer Institute, Boston, MA 02115; and ^††Institut Pasteur de Madagascar, Antananarivo, Madagascar

Communicated by Robert A. Good, University of South Florida, St. Petersburg, FL (received for review October 24, 2001)

Abstract

Purified protein derivative (PPD) skin testing is used to identify persons infected with Mycobacterium tuberculosis (Mtb) and to assess cell-mediated immune responses to Mtb. However, lack of skin induration to intradermal injection of PPD or PPD anergy is observed in a subset of patients with active tuberculosis (TB). To investigate the sensitivity and persistence of PPD reactivity and its in vitro correlates during active TB disease and after successful chemotherapy, we evaluated the distribution of skin size induration after intradermal injection of PPD among 364 pulmonary TB patients in Cambodia. A subset of 25 pulmonary TB patients who had a positive skin reaction to mumps and/or candida antigens showed persistent anergy to PPD after successful completion of TB therapy. Strikingly, in vitro stimulation of T cells from persistently anergic TB patients with mumps but not PPD resulted in T cell proliferation, and lower levels of IL-2 and IFN-γ and higher levels of IL-10 were detected in PPD-stimulated cellular cultures from PPD-anergic as compared with PPD-reactive pulmonary TB patients. These results show that anergy to PPD is antigen-specific and persistent in a subset of immunocompetent pulmonary TB patients and is characterized by antigen-specific impaired T cell proliferative responses and a distinct pattern of cytokine production including reduced levels of IL-2.

Footnotes

↵ ‡ J.C.D. and E.Y.T. contributed equally to this work.
↵ ¶¶ To whom reprint requests should be addressed at: Center for Blood Research, 800 Huntington Avenue, Boston, MA 02115. E-mail: goldfeld{at}cbr.med.harvard.edu.
Abbreviations:

Mtb,

Mycobacterium tuberculosis;

TB,

tuberculosis;

DTH,

delayed-type hypersensitivity;

PPD,

purified protein derivative;

PBMC,

peripheral blood mononuclear cells;

AFB,

acid-fast bacilli;

APC,

antigen presenting cell;

TCR,

T cell receptor