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Original Article |
judith.abrams{at}pharma.novartis.com
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Key Words: psoriasis vulgaris • T cell costimulation • B7 • CTLA4Ig • dendritic cells
Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4)–immunoglobulin (CTLA4Ig; BMS-188667), a novel soluble chimeric protein, binds to B7-1 (CD80) and B7-2 (CD86) expressed on APCs and thereby inhibits a second signal required for optimal T cell activation 10111213. CTLA4Ig inhibits skin APC and T cell functional interactions in vitro 514. Administration of CTLA4Ig to patients with psoriasis vulgaris in a phase I trial produced a dose-dependent improvement in skin lesions. 9 of 11 patients in the top dosing groups achieved a 50% or greater decrease in psoriasis clinical scores 15. This use of CTLA4Ig in psoriasis patients provides a unique opportunity to ascertain the contribution of ongoing T cell costimulation to the persistence of chronic cell-mediated inflammation in a human disease 16. We will demonstrate here that the B7-targeted disruption of APC and T cell interaction effectively blocks T cell activation and reinstates a nascent phenotype to lesional tissue.
CTLA4Ig (BMS-188667) Administration.
Immunohistochemical Studies.
DC Migration Studies.
Flow Cytometry.
Statistical Analysis.
To ascertain the mechanisms by which the inhibition of the CD28/CD152 T cell costimulatory pathway moderated the chronic inflammatory cascade and resolved psoriatic lesions, a series of immunohistochemical studies was undertaken. Histologic samples were obtained from prospectively identified lesions prestudy and at study days 8, 16, 36, and 78 after initiation of CTLA4Ig infusions.
Reduction in Intralesional T Lymphocyte Subsets and Neutrophils after Administration of CTLA4Ig.
Introduction
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Materials and Methods
Results
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Psoriasis vulgaris is an inflammatory skin disease afflicting 
2% of the population. It is likely to be mediated by activated T cells, which early within the course of disease are present within the lesional skin in increased numbers 12. Dendritic cells (DCs), an APC population uniquely capable of efficiently stimulating resting T cells 3, are also increased in psoriatic lesions 4 and possess an activated phenotype 25. Cytokines released from these activated T cells and DCs are believed to contribute to the pathologic changes induced in lesional keratinocytes 67 and vascular endothelium 89.
Materials and Methods
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Patients.
A protocol outlining the use of CTLA4Ig (BMS-188667) in patients with moderate to severe psoriasis was approved by the Institutional Review Boards of participating clinical institutions. Patients providing informed consent for use of the investigational agent were enrolled into this study if they had a history of stable psoriasis vulgaris of at least 6-mo duration involving 10–49% of total body surface area, and had failed at least one prior antipsoriatic therapy. Before enrollment on study, systemic retinoids were discontinued for at least 2 yr; investigational drugs, methotrexate, cyclosporine, and systemic corticosteroids were discontinued for at least 16 wk; phototherapy and photochemotherapy were not administered for at least 4 wk; and topical treatments other than emollients were not administered for two or more weeks. The baseline demographics of this patient population were described in a previous publication 15.
CTLA4Ig (BMS-188667) was administered as a 1-h intravenous infusion on day 1 (week 1), day 3, day 16 (week 3), and day 29 (week 5). Four to six patients were accrued to each of eight dose levels in this open label dose escalation study: 0.5, 1, 2, 4, 8, 16, 25, and 50 mg/kg. Patients were monitored continuously for a 4-h period after each infusion and at weekly intervals during the first 8 wk of study, then at biweekly to monthly intervals through day 176 (week 26). Safety, immunogenicity, pharmacokinetic, and biologic activity assessments were performed at each visit.
Samples for histological analysis were obtained with a 6-mm punch biopsy from representative lesions before administration of CTLA4Ig (BMS-188667) and at study days 8, 16, 36, and 78. Each specimen was split for routine histopathology and for histochemical analysis on cryostat-cut 6-mm sections. Immunohistochemical staining procedures using 3-amino-9-ethylcarbazol as the chromagen were performed as described previously 17. Antibodies used for histochemical analysis had the following specificities: CD3, CD25, HLA-DR, CD1a, and CD80 (clones SK7, 2A3, L243, SK9, and L307, respectively; Becton Dickinson), CD8 (clone OKT8; American Type Culture Collection), CD86 and CD11c (clones FUN-1 and B-ly6, respectively; BD PharMingen), CD54 (RR 1/1; Biosource International), CD40, P-selectin, and E-selectin (clones G28.5, 5G4, and 5G11, respectively; Bristol-Myers Squibb), CD83 (clone HB15a; Immunotech), DC–lysosomal-associated membrane glycoprotein (DC-LAMP) and macrophage mannose receptor (MMR) (gifts from Ralph Steinman, The Rockefeller University), neutrophil elastase (clone 204; Biodesign), Factor XIIIa (FXIIIa; Calbiochem), or laminin (clone 2E8; a gift from Eva Engvall, La Jolla Cancer Research Foundation, La Jolla, CA). Quantitative measures of epidermal area and length (used to compute mean thickness) and cell numbers reactive with specific antibodies were obtained using a Macintosh computer using public domain IMAGE program from the National Institutes of Health (http://rsb.info.nih.gov/nih-image).
Split thickness biopsies of psoriatic skin lesions were obtained in The Rockefeller University General Clinical Research Center using a protocol approved by The Rockefeller University Institutional Review Board. Three psoriatic patients, who provided informed consent and did not receive infusions with CTLA4Ig (BMS-188667), underwent biopsy of psoriatic lesional skin. Split thickness samples were also prepared from the skin of four healthy donors undergoing corrective surgery of face, breast, or abdomen. The skin was stored at 4°C and used in the assays described below within 6 h of collection. Each explant was trimmed (psoriatic lesional skin: 30-mm2; normal skin: 400-mm2) and floated in 5–10 ml of culture medium. 3-d in vitro cultures of skin explants were established with the subsequent preparation of single emigrant cell suspensions as described previously 18. Skin explants were incubated in the presence of either CTLA4Ig (100 µg/ml) or media alone throughout the culture period.
Single cell suspensions of emigrant skin cells were incubated with saturating concentrations of the following mouse anti–human fluorochrome-conjugated antibodies, for 15 min at room temperature: PE-conjugated anti-CD3 (clone SK7; Becton Dickinson); peridinin chlorophyll protein (PerCP)-conjugated anti-CD45 (clone 2D1; Becton Dickinson); allophycocyanin-coupled HLA-DR (clone L243; Becton Dickinson), and FITC-conjugated anti-CD80 (clone L307; Becton Dickinson), anti-CD86 (clone FUN-1; BD PharMingen), anti-CD40 (clone 5C3; BD PharMingen), or anti-CD1a (clone HI149; BD PharMingen). CTLA4Ig (100 µg/ml) was added before staining in some experiments as a control for steric inhibition of binding of CD80- and CD86-specific mAbs. The controls for nonspecific Ig binding were mouse IgG1 directly conjugated to FITC (clone MOPC-21; BD PharMingen), PE, or PerCP (clone X40; Becton Dickinson), and IgG2a directly conjugated to allophycocyanin (clone X39; Becton Dickinson). 5,000 DC-gated events (CD3–, DR+, CD45+) were collected for quadruple staining on a FACSCaliburTM flow cytometer (Becton Dickinson), and data were analyzed using CELLQuestTM software (Becton Dickinson). For publication purposes, flow cytometry profiles were scanned, converted to digital files, and imported into Adobe Illustrator® v8.0 for Macintosh (Adobe Systems) where curve-fitting was performed.
Data were summarized as mean ± SD. Comparisons between experimental groups were performed using the two-sided Wilcoxon signed rank test for paired data. A significance level of 5% was used for all comparisons.
Results
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CTLA4Ig Administration Improves Psoriasis Clinical Activity.
Psoriasis patients receiving four infusions with the soluble chimeric protein CTLA4Ig (BMS-188667) displayed a dose-dependent improvement in their global clinical parameters of psoriasis 15. Though meaningful clinical responses were observed in all but the lowest dosing cohort, the most consistent responses were observed in the top two dose groups (CTLA4Ig 25 and 50 mg/kg dose). 9 of 11 patients accrued to these 2 dosing cohorts demonstrated a 50% or greater improvement from baseline psoriasis evaluation. The duration of clinical response was sustained in many cases throughout the 147-d median observation period after the final CTLA4Ig infusion. Clinical quiescence, therefore, often persisted well after the elimination of detectable CTLA4Ig from the circulation. No discernible changes in B7-bearing target cell populations or alterations in lymphocyte subset distributions were observed in the peripheral blood.
The number of CD3, CD25, and CD8 positively staining T lymphocytes was serially reduced in specimens obtained after the initial (day 1) infusion with CTLA4Ig in 9 of 11 patients accrued to the 2 top dosing cohorts (Fig. 1A–I). The most rapid reductions were observed within the CD25+ (IL-2 receptor 
subunit) T cell subset. Normalization of intralesional T cell counts correlated with meaningful clinical improvement in these patients. T (CD3+) lymphocytes, including the CD8+ and CD25+ subsets, were clustered in the papillary dermis and the suprapapillary epidermis in baseline biopsies. At day 78, the few remaining T lymphocytes were predominantly distributed within the dermis. Progressive epidermal thinning was also evident in these serial biopsies.
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Reduction in Intralesional T Lymphocytes Is Associated with Alterations in Keratinocyte Proliferation and the Diminished Expression of Keratinocyte Accessory Molecules.
Soluble factors released from activated T lymphocytes are believed to contribute to the hyperproliferation of keratinocytes within psoriatic lesions 67. Therefore, intralesional T lymphocyte counts were correlated with epidermal thickness in serial lesional biopsies obtained from patients accrued to the 25 and 50 mg/kg dose groups. Peak reductions in intralesional T lymphocytes were observed at day 78 with an 88% mean decrease in the epidermal compartment (P < 0.001) and a 73% mean reduction in the dermal compartment compared with baseline examination (P < 0.001) (Fig. 2 A). A statistically meaningful decline in epidermal thickness was observed as early as day 8 (19% reduction; P = 0.016); at day 78, a 56% mean percent reduction from baseline epidermal thickness was observed (P < 0.001). The decrease in lesional epidermal T lymphocytes correlated most closely with the observed reductions in epidermal thickness (r = 0.73). Individual patient correlation plots for each of the four biopsies obtained after the day 1 infusion are illustrated in Fig. 2 B.
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The density of CD40, CD54, and HLA-DR staining on intralesional DCs decreased progressively in clinically responding patients. Weak residual CD40, CD54, and HLA-DR reactivity was evident on infiltrating dermal mononuclear cells at day 78 (Fig. 3A–I). A diminished number of FXIIIa-staining dermal DCs was also observed in clinical responders 4, particularly in the upper reticular and papillary dermis (Fig. 3J–L).
The morphology of the lesional DC population also changed over time. DCs possessing long, branching processes evident at the time of the initial skin biopsy (Fig. 3G and Fig. J, inset) were replaced with a population of smaller cells that had less numerous, clipped processes (Fig. 3H, Fig. I, Fig. K, and Fig. L, inset). The morphological features of this latter population resembled immature DCs. mAbs to CD1a, expressed on immature but not mature LCs 3032, displayed serial increases in reactivity predominantly within the suprabasal layer of the epidermis, in the majority of patients accrued to the top two dosing cohorts (Fig. 4A–C). Thus, CD1a positivity originally "displaced" to the upper zone of the thickened epidermis at day 1 was replaced by a more equitable CD1a staining distribution at day 78.
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To confirm that the diminished density of DC activation markers and the modified DC morphology within lesional biopsies were associated with decreased numbers of mature DCs, immunohistochemical studies of serial lesional biopsies were performed using DC-restricted, maturation-associated markers (CD83, DC-LAMP, and MMR) and the leukocyte integrin CD11c. CD83 and DC-LAMP, expressed at high levels on mature DCs 3435, displayed markedly increased staining in day 1 lesional biopsy specimens in a pattern similar to CD80 and CD86 expression (Fig. 5A and Fig. C). Little residual staining was evident at day 78 in clinical responders (Fig. 5B and Fig. D). In contrast, unaffected skin from psoriatic patients showed no significant staining in the epidermis or dermis with these antibodies (data not shown). CD11c, expressed at high levels on some DCs 36, demonstrated increased staining on DCs in both the dermis and epidermis at day 1 (Fig. 5 E). Marked reductions in CD11c immunoreactivity were observed at day 78 in clinical responders, with residual staining exclusively in the dermal compartment (Fig. 5 F). A pattern of CD11c immunoreactivity similar to the day 78 biopsy findings was observed in nonlesional biopsies from psoriatic patients (data not shown). MMR, a carbohydrate-recognizing receptor important in the uptake and delivery of antigens to MHC class II compartments for antigen processing and presentation, is expressed on immature DCs. MMR expression on DCs is downregulated in vitro by inflammatory stimuli 37. Immunohistochemical studies in human tissue have not detected expression of MMR on LCs 38. Day 1 and 78 biopsy specimens demonstrated MMR staining within the dermis with little apparent alteration in the density of staining (Fig. 5G and Fig. H). Therefore, psoriatic epidermis, and to a lesser extent psoriatic dermis, were heavily infiltrated with activated/mature DCs. Lesional biopsies at day 78 possessed a lower density of the requisite accessory/costimulatory molecules for T cell activation compared with pretreatment biopsies. These findings may also be contributory to the observed reduction in lesional T cells.
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The harvest of DCs from explant cultures was unchanged in the presence of CTLA4Ig. The mean recovery of emigrating cells across the seven paired experiments (lesional and normal skin) was 1.37 x 105 in the presence of CTLA4Ig or 1.41 x 105 in control cultures (P = 0.447). Approximately 60% of exfiltrators were CD3–HLA-DR+ CD45+ regardless of the culture conditions (control mean percent: 58.2 ± 13.2; CTLA4Ig mean percent: 62.8 ± 18.4; P = 0.375). Cell viability in all experiments was >90% as assessed by trypan blue exclusion. Therefore, the presence of CTLA4Ig in the culture medium had no major effect on the migration or survival of DCs from skin explants after 3 d of incubation.
Flow cytometric analyses of DCs emigrating either under control conditions or in the presence of CTLA4Ig failed to demonstrate significant differences in the levels of CD86, CD80, CD40, or CD1a expression (Table , and Fig. 6). The proportion of CD3–HLA-DR+CD45+ cells expressing each of these cell surface proteins was equivalent across the paired experimental conditions. Further fractionation of the CD3–CD45+ emigrating cell population into high and medium HLA-DR expression indicated that the CD80/CD86 mean fluorescence intensities (MFIs) correlated with the level of HLA-DR expression after culture of skin explants but not with the presence of CTLA4Ig during culture (data not shown). DCs, upon activation or emigration from explants, are known to increase in size 43. Forward scatter flow cytometric analyses failed to discern a difference in the mean cell size when comparisons were made between those explants cultured in the presence of CTLA4Ig versus media alone (data not shown). These data indicated that the maturation of DCs and their acquisition of costimulatory/accessory molecules were not inhibited by the presence of CTLA4Ig in short term culture. The diminished density of DC activation/maturation markers and the modified DC morphology observed on study are therefore likely attributable to an altered lesional milieu resulting from decreased T cell activation, with secondary effects on DC extravasation into skin and/or DC maturation.
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, IFN-
, IL-1β, and IL-4 89. CD54 mediates the firm adhesion of tethered leukocytes to endothelium, and its expression is upregulated by many of the same cytokines 5253. Lesional vessels displayed progressively reduced ectasia and tortuosity after day 1 infusions with CTLA4Ig (Fig. 7A–C). At day 1, CD62E and CD62P were strongly expressed in the superficial and deep vascular plexus. Expression of both selectins was diminished in serial biopsy specimens (Fig. 7D–I). Though modest decreases in CD62P immunoreactivity were selectively observed in the superficial capillaries at days 36 and 78, these changes were detected consistently across all clinically responding patients. CD54 also displayed progressively decreased vascular immunoreactivity (Fig. 3D–F). Downmodulation of these vascular adhesion molecules likely impaired the ability of endothelial cells to activate and recruit circulating leukocytes to the psoriatic lesions, as evidenced by the diminished inflammatory infiltrate present at day 78. Human endothelial cells do not express CD80 or CD86 54. Thus, it appears that the observed immunohistochemical changes were indirectly mediated through the binding of CTLA4Ig to other local cellular B7-bearing targets.
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Many models have been proposed to explain the interplay of keratinocytes with lesional T cells in the immunopathogenesis of psoriasis. The upregulated expression of MHC class II HLA-DR antigens on activated keratinocytes could be regarded as an in vivo bioassay for the presence of IFN- released from activated T cells 622. The adequacy of keratinocytes to provide T cell activation signals, however, has been a matter of some debate 5556. The clinical resolution of psoriatic lesions after the specific disruption of B7 engagement with CD28/CD152 on T cells has demonstrated that keratinocytes, which do not express detectable B7, are not sufficient for perpetuating T cell activation in psoriatic lesions.
Though the role of CD28/CD152 costimulation in T cell activation and cytokine production is well understood 111213, comparatively little is known regarding the possible direct effects of this pathway on DC activation. In this study, we have demonstrated that the presence of saturating CTLA4Ig concentrations in short term skin explant cultures did not impair DC maturation, migration, or survival. These ex vivo data contrast with the immunohistochemical observations in serial biopsies harvested over a 78-d period after systemic administration of CTLA4Ig. The clinical samples displayed a progressively less mature complement of lesional DCs. The apparently conflicting observations suggest that CTLA4Ig did not block DC activation through direct inhibition of the B7 axis on DCs. Instead, these data support a model in which the primary blockade of T cell costimulatory signals leads to progressive diminution in the number, activation status, and cytokine elaboration of lesional T cells, with secondary effects on keratinocyte activation and cytokine release. A gradual transformation of the skin microenvironment ensued. Under this scenario, immature DCs recruited to lesional skin after initiation of CTLA4Ig infusions presumably could no longer acquire sufficient stimuli required to be optimally activated, further compromising T cell activation signals. This model is in accord with the view of DCs as the consummate immunologic "rheostats," integrating a variety of activating signals, which ultimately "tune" the capacity to stimulate T cells 29. The cadence of the clinical response in this study was slower than that observed with antipsoriatic agents that directly inhibit T cell activation and may be explained by these observations 155758.
Our immunohistochemical data indicate that T cell costimulatory signals delivered through B7/CD28 are pivotal in creating a microenvironment, which facilitates the activation of tissue DCs and the perpetuation of autoimmune inflammation. However, these B7/CD28 signals in isolation are not likely sufficient to initiate a chronic inflammatory cascade. The key requirements in constructing a microenvironment conducive to T cell–mediated, organ-specific autoimmune inflammation have been characterized in transgenic models of pancreatic islet β cell inflammation. Autoimmune inflammation of the pancreas in these animals requires not only ectopic and/or increased expression of CD80 but also either a genetically predisposed host 59, increased levels of autoantigen and autoreactive T cells 60, elevated MHC class II antigens 61, or enhanced levels of an inflammatory cytokine 62. Mice expressing any of these transgenes alone maintain normal pancreatic islet architecture 606364. A repertoire of inflammatory stimuli analogous to this array of transgenes was identified within the day 1 psoriatic lesional tissue. At day 78, the intrinsic T cell activating capacity was likely vastly different, with lesional mononuclear cells possessing fewer of the requisite class II antigens, accessory and costimulatory molecules for T cell activation. The downregulation via B7-CD28/CTLA-4 blockade of a variety of proinflammatory stimuli required for disruption of immunologic homeostasis may explain the profound and durable clinical response, well beyond the active treatment period, when contrasted with other T cell–based therapies 1517. Additional explanations for the durable response could include the possible induction of tolerance or the emergence of regulatory T cells. Currently, no data exist in support of either of these possible explanations.
In addition to the functional modulation of the T cell activating capacity of lesional APCs, the alteration in endothelial expression of CD54, E-selectin, and P-selectin likely impaired the ability to recruit neutrophils, lymphocytes, and DCs to inflamed skin 40415051. These selectins and integrins have been demonstrated to be important in the large scale influx of mononuclear cells to a variety of other inflamed tissues including synovium and respiratory tract 5165. Their presence on vascular endothelium at heightened levels is important in the reseeding of peripheral tissues with DCs to replenish the pool of tissue DCs lost through DC migration–invoking stimuli 4648. Thus, vascular recruitment of effector cells, an additional common pathway important in sustaining chronic inflammation, is also potentially impacted by B7/CD28 costimulatory blockade.
In summary, we have shown that CTLA4Ig blockade of the B7-CD28/CD152 pathway of T cell costimulation in patients with psoriasis modulates the state of chronic inflammatory activation of T cells, DCs, and endothelial cells in psoriatic plaques. These observations could have important implications for the treatment of other acute or chronic T cell–mediated diseases, where these effector cells may play an important role in the pathogenesis of the disease.
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Acknowledgments |
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Submitted: 8 May 2000
Revised: 7 July 2000
Accepted: 14 July 2000
Portions of this work have been published in abstract form (1997. J. Invest. Dermatol. 108:555).
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References |
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