Modulation of CD28 expression with anti-tumor necrosis factor alpha therapy in rheumatoid arthritis.
OBJECTIVE
The immune system of patients with rheumatoid arthritis (RA) is characterized by the accumulation of CD4+ T cells deficient in CD28 expression and the up-regulation of tumor necrosis factor alpha (TNFalpha). Previous in vitro studies have shown that TNFalpha induces transcriptional silencing of the CD28 gene. Because reduced expression of CD28 in T cells compromises immunocompetence, we examined whether CD28 expression is reduced in patients with RA in vivo and whether the reduction is related to TNFalpha.


METHODS
Patients with RA and age-matched individuals were recruited. Peripheral blood mononuclear cells were stained for CD3, CD4, CD8, CD28, TNF receptor I (TNFRI), and TNFRII, and analyzed by quantitative flow cytometry. The number of CD28 and TNFR molecules was monitored in a subgroup of patients with RA undergoing treatment with anti-TNFalpha.


RESULTS
In addition to higher frequencies of CD28null T cells, patients with RA had significantly reduced numbers of CD28 and TNFRI molecules on CD4+,CD28+ T cells. Normal expression could be restored in vitro by overnight culture, suggesting that CD28 in patients was modulated by exogenous factors. In contrast, treatment with TNFalpha in vitro resulted in further down-regulation. CD28 expression was normalized in patients undergoing TNFalpha-neutralizing therapy.


CONCLUSIONS
Overproduction of TNFalpha in RA induces a global down-regulation of CD28 in CD4+ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses.
Bryl
Ewa
E
Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Vallejo
Abbe N
AN
Matteson
Eric L
EL
Witkowski
Jacek M
JM
Weyand
Cornelia M
CM
Goronzy
Jorg J
JJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D018106:CD28 Antigens; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab