Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells
Jr. Abrams et al., Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells, J EXP MED, 192(5), 2000, pp. 681-693
Efficient T cell activation is dependent on the intimate contact between an
tigen-presenting cells (APCs) and T cells. The engagement of the B7 family
of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte-associated
antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s)
important in T cell activation. We investigated the dependence of pathologi
c cellular activation in psoriatic plaques on B7-mediated T cell costimulat
ion. Patients with psoriasis vulgaris received four intravenous infusions o
f the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, op
en label dose escalation study. Clinical improvement was associated with re
duced cellular activation of lesional T cells, keratinocytes, dendritic cel
ls (DCs), and vascular endothelium Expression of CD40, CD54, and major hist
ocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinoc
ytes was markedly reduced in serial biopsy specimens. Concurrent reductions
in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associ
ated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on
lesional DCs, which also decreased in number within lesional biopsies. Ski
n explant experiments suggested that these alterations in activated or matu
re DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased
lesional vascular ectasia and tortuosity were also observed and were accom
panied by reduced presence of E-selectin, P-selectin, and CD54 on vascular
endothelium. This study highlights the critical and proximal role of T cell
activation through the B7-CD28/CD152 costimulatory pathway in maintaining
the pathology of psoriasis, including the newly recognized accumulation of
mature DCs in the epidermis.