CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.
Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.
Abrams
J R
JR
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.abramsj@bms.com
Lebwohl
M G
MG
Guzzo
C A
CA
Jegasothy
B V
BV
Goldfarb
M T
MT
Goffe
B S
BS
Menter
A
A
Lowe
N J
NJ
Krueger
G
G
Brown
M J
MJ
Weiner
R S
RS
Birkhofer
M J
MJ
Warner
G L
GL
Berry
K K
KK
Linsley
P S
PS
Krueger
J G
JG
Ochs
H D
HD
Kelley
S L
SL
Kang
S
S
D000069594:Abatacept; D000328:Adult; D000917:Antibody Formation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000097:blood / Q000627:therapeutic use*; D060908:CTLA-4 Antigen; D015331:Cohort Studies; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept