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

Abstract

Efficient T cell activation is dependent on the intimate contact between antigen-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 pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC–lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied 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.

T Cells Modulate Neutrophil-Dependent Acute Renal Failure during Endotoxemia

“…In several studies, CD28 blockade has led to significant and clinically relevant modulation of inflammatory diseases (17)(18)(19)(20)(21)(22)(23)(24). Besides reduced T cell infiltration, some of these studies have reported a diminished tissue PMN Ϫ recruitment (19,20,23,24).…”

“…In a model of bleomycin-induced lung fibrosis, CD28 gene-deficient mice demonstrated reduced concentrations of chemokines, which were crucial for leukocyte recruitment and activation (20). It is interesting that recent studies have revealed that CD28 blockade also seemed to reduce the infiltration of PMN into chronically inflamed tissues (19,20,23,24). Because these inflammatory diseases were not primarily PMN Ϫ dependent, it remains unknown whether T cells can modulate acute, PMN-dependent inflammatory syndromes and subsequent organ failure.…”

“…Blockade of CD28 signals by antibodies or by generation of CD28 gene-deficient mice caused attenuated inflammatory responses in several (experimental) diseases, including contact hypersensitivity (17), graft-versus-host disease (18), psoriasis (19), bleomycin-induced lung fibrosis (20), and asthma (21). Moreover, antibody blockade of CD28 signals during murine septic shock drastically improved survival rate.…”

Abatacept in the treatment of patients with psoriatic arthritis: Results of a six‐month, multicenter, randomized, double‐blind, placebo‐controlled, phase II trial

“…Abatacept is an approved treatment for chronic inflammatory conditions such as rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), in which T cells are involved in the pathophysiology of the disease (25)(26)(27)(28)(29)(30). In a phase I study of abatacept in patients with psoriasis vulgaris, clinical improvement was associated with a reduction of the intralesional T cell population (31,32). Taken together, these observations suggest that abatacept could be effective in the treatment of PsA.…”

Modulating Co-Stimulation

“…Reduction of epidermal hyperplasia correlating with a decrease in Tcell infiltrates and diminished epidermal proliferation were also observed. 114 No increase in T-cell apoptosis was identified in the skin lesions, suggesting that the decreased number of T cells was due to reduced proliferation and recruitment of T cells. CTLA-4Ig therapy did not induce long-term tolerance to T-cell dependent neoantigens.…”