Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome.
BACKGROUND
HIV-tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy. Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear.


OBJECTIVE
To determine the effect of prednisone on the inflammatory response in TB-IRIS (antigen-specific effector T cells, cytokines, and chemokines).


METHODS
Blood was taken from participants in a randomized placebo-controlled trial of prednisone for TB-IRIS, at 0, 2, and 4 weeks. Participants received prednisone at a dosage of 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks, or placebo at identical dosages.


RESULTS
Analyses included IFN-γ enzyme-linked immunospot (ELISPOT), reverse transcription-polymerase chain reaction on peripheral blood mononuclear cells after restimulation with heat-killed Mycobacterium tuberculosis, Luminex multiplex cytokine analysis of corresponding tissue culture supernatants, and Luminex multiplex cytokine analysis of serum. Fifty-eight participants with TB-IRIS (31 receiving prednisone, 27 receiving placebo) were included. In serum, significant decreases in IL-6, IL-10, IL-12 p40, tumor necrosis factor-α, IFN-γ, and IFN-γ-induced protein-10 concentrations during prednisone, but not placebo, treatment were observed. No differences in ELISPOT responses comparing prednisone and placebo groups were shown in response to ESAT-6 (early secreted antigen target-6), Acr1, Acr2, 38-kD antigen, or heat-killed H37Rv M. tuberculosis. Purified protein derivative ELISPOT responses increased over 4 weeks in the prednisone group and decreased in the placebo group (P = 0.007).


CONCLUSIONS
The beneficial effects of prednisone in TB-IRIS appear to be mediated via suppression of predominantly proinflammatory cytokine responses of innate immune origin, not via a reduction of the numbers of antigen-specific T cells in peripheral blood.
Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa. graemein@mweb.co.za
Graeme
G
Meintjes
Keira H
KH
Skolimowska
Katalin A
KA
Wilkinson
Kerryn
K
Matthews
Rebecca
R
Tadokera
Anali
A
Conesa-Botella
Ronnett
R
Seldon
Molebogeng X
MX
Rangaka
Kevin
K
Rebe
Dominique J
DJ
Pepper
Chelsea
C
Morroni
Robert
R
Colebunders
Gary
G
Maartens
Robert J
RJ
Wilkinson
D000328:Adult; D058501:Enzyme-Linked Immunospot Assay / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000627:therapeutic use*; D015658:HIV Infections / Q000150:complications / Q000276:immunology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D011241:Prednisone / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016896:Treatment Outcome; D014376:Tuberculosis / Q000150:complications / Q000276:immunology
D005938:Glucocorticoids; D011241:Prednisone