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Any sufficiently advanced technology is indistinguishable from magic.

Arthur C. Clarke

The beginning of the 21st century will be remembered by those treating autoimmune disease as the age of biologic therapies. A variety of biologic agents and targets are being explored for the treatment of rheumatoid arthritis (RA) and other rheumatic disorders. Some biologics, which directly target circulating cytokines and some lymphocyte surface proteins, have already advanced to the clinic and have provided favorable results as would be predicted from animal studies (1). However, attempts at blocking costimulation of B lymphocytes by antibody to the T cell surface protein, CD154, although successful in mice with lupus (2–4), have been problematic in treating systemic lupus erythematosus (SLE) in humans (5, 6). Recently, a novel therapeutic costimulation modulator, CTLA-4Ig, has been demonstrated to be effective therapy for RA. In this issue of Arthritis & Rheumatism, Kremer, Moreland, and colleagues extend their prior studies (7, 8) and present 12-month results of a phase IIb trial of CTLA-4Ig as therapy for RA (9). The rationale for this T lymphocyte–inhibitory approach to therapy has evolved over a decade and a half of basic and clinical research, but it is finally coming to fruition (10).

How does CTLA-4Ig work to treat RA? RA is an autoimmune disease with substantial contributions of T cells to pathogenesis as evidenced, in part, by their presence in RA synovial specimens (11). In order for T cells to become fully activated and to contribute to disease pathogenesis, they require signaling via their antigen-specific T cell receptors (TCRs) plus activation via a non–antigen-specific costimulatory receptor, typically CD28 (12). CD28 is constitutively expressed on T cells and binds to the ligands, CD80 (B7-1) or CD86 (B7-2), on activated antigen-presenting cells (APCs) (Figure 1). This interaction between CD28 and CD80 or CD86 can be effectively blocked by CTLA-4Ig, which binds CD28 with substantially higher avidity (13). If antigen-naive T cells receive TCR activation (signal 1) in the absence of costimulation (signal 2), the T cell is rendered functionally anergic and is unable to perform effector roles, such as cytokine production (Figure 1) (14). Thus, autoreactive T cells receiving signal 1 in the absence of signal 2 are unable to participate in disease pathogenesis. This is one of the primary models put forth for the use of CTLA-4Ig in the treatment of RA (Table 1).

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Figure 1. Models of T cell tolerance induced by CTLA-4Ig. TCR = T cell receptor; MHC = major histocompatibility complex; IDO = indoleamine 2,3-dioxygenase, an intracellular enzyme that degrades the amino acid tryptophan. See text for explanations.

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Table 1. Proposed mechanisms of the T cell–inhibitory action of CTLA-4
Author, year (ref.)Mechanism
Masteller et al, 2000 (18)Competition between CTLA-4 and CD28 for binding to CD80 and CD86
Lee et al, 1998 (21)Proximal blockade of signaling by CTLA-4 at the immunologic synapse
Calvo et al, 1997 (22)Distal blockade of intracellular signaling pathways
Grohmann et al, 2002 (23)Dendritic cell–mediated tolerance via tryptophan catabolism

CTLA-4Ig is a soluble fusion protein comprising the ligand-binding domain of CTLA-4 and the tail end of human immunoglobulin (15). CTLA-4 is normally expressed on the cell surface of activated T cells as well as on regulatory T cells (16), and it binds CD80 and CD86 with ∼100-fold higher avidity than CD28 (17). Competition between CTLA-4 and CD28 for binding to CD80 and CD86 is one of the best-studied mechanisms for the inhibitory action of CTLA-4 (18) (Table 1). Additionally, signaling via CTLA-4 is believed to increase the threshold for T cell activation (19, 20). This may occur either through proximal blockade at the immunologic synapse (21) or via disruption of critical downstream intracellular signaling pathways following CTLA-4 engagement (22) (Table 1). More recently, a novel mechanism of action of CTLA-4 has been proposed, in which CTLA-4 signals dendritic cells via B7 receptors to regulate tryptophan catabolism via indoleamine 2,3-dioxygenase, thus affecting nearby T cell proliferation/tolerance (23) (Figure 1 and Table 1). Theoretically, CTLA-4Ig could act either by blocking CD28 stimulation or by signaling via B7 molecules on dendritic cells.

CTLA-4Ig was first used in vivo in mice to prolong xenogeneic pancreatic graft survival (24) and to prevent T cell–dependent antibody responses (25). Since these pioneering studies, CTLA-4Ig has been employed to successfully treat a variety of animal models of autoimmune disease (26–31), including collagen-induced arthritis (29) (Table 2). In addition, CTLA-4Ig, in combination with cyclophosphamide, was shown to reverse established renal disease in a mouse model of lupus (32). CTLA-4Ig was also shown to be effective in a nonhuman primate model of allogeneic islet cell transplantation, paving the way for the eventual use of this procedure in humans (33).

Table 2. Successful use of CTLA-4Ig to treat autoimmunity in selected animal models
Author, year (ref.)Disease model
Finck et al, 1994 (26)Murine lupus
Lenschow et al, 1995 (27)Diabetes in the nonobese diabetic mouse
Khoury et al, 1995 (28)Experimental autoimmune encephalomyelitis
Webb et al, 1996 (29)Collagen-induced arthritis
McIntosh et al, 1998 (30)Experimental autoimmune myasthenia gravis
Matsui et al, 2002 (31)Experimental autoimmune myocarditis

The first use of CTLA-4Ig in humans was in a phase I trial to treat psoriasis (34). In that phase I, open-label, dose-escalation study, 43 individuals with chronic psoriasis received 5 intravenous doses (0.5–50 mg/kg/dose) of CTLA-4Ig over a 5-week period. Approximately half of the patients achieved ≥50% sustained improvement (for up to 26 weeks) in clinical disease activity, particularly those individuals receiving the highest doses of CTLA-4Ig (34). CTLA-4Ig was also well tolerated, with 16% of patients developing uncomplicated upper respiratory tract infections and no patients discontinuing treatment because of adverse events. Thus, the utility of this agent for the therapy of other human T cell–mediated autoimmune disorders appeared encouraging.

Three years following the report of that trial (34), Moreland and colleagues first reported the use of CTLA-4Ig and LEA29Y, a second-generation version of CTLA-4Ig with increased avidity for CD86, for treatment of RA (7). The therapeutic agents were considered generally safe and well tolerated, and soon thereafter a report of a randomized trial of CTLA-4Ig treatment of RA, assessing the results of 6 months of therapy, was presented (8). The authors of that report concluded that in RA patients concomitantly receiving methotrexate (MTX), CTLA-4Ig was safe, well tolerated, and significantly improved the signs and symptoms of RA as well as the health-related quality of life.

In the most recent phase IIb extension of the study conducted by Kremer and colleagues, 2 concentrations (2 mg/kg or 10 mg/kg) of abatacept (CTLA-4Ig) were infused intravenously at monthly intervals in combination with MTX for an entire year to a total of 164 patients with active RA that was refractory to MTX (9). A significantly greater percentage of patients treated with 10 mg/kg CTLA-4Ig met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) (35) at 1 year compared with patients who received placebo. Significantly greater percentages of patients treated with 10 mg/kg CTLA-4Ig also achieved ACR50 and ACR70 responses as well as improvements in scores on the modified Health Assessment Questionnaire (36) compared with patients who received placebo. Beneficial effects were also seen at the lower dose (2 mg/kg), but not to the degree seen at 10 mg/kg. This finding is consistent with a dose-dependent biologic response. Overall, CTLA-4Ig was well tolerated, and numbers of adverse events were comparable in the treatment and placebo groups, with the possible exception of an increased frequency of nasopharyngitis in the CTLA-4Ig–treated groups (9). Together, these studies indicate that treatment of MTX-refractory RA with CTLA-4Ig plus MTX is well tolerated for 1 year and yields significant improvements in function and considerable reductions in disease activity (9).

Thus, another arm in the biologic armamentarium appears to be available as therapy for patients with RA. Currently, CTLA-4Ig has primarily been studied in conjunction with MTX to treat RA. This combination appears safe, but it is not currently known whether the addition of MTX is adjunctive to the effect of CTLA-4Ig. Future study designs may attempt to address this issue. Ultimately, CTLA-4Ig may prove to be useful in patients who either do not respond to or do not tolerate more conventional tumor necrosis factor α (TNFα) inhibitors (37–39). Future studies designed to compare the efficacy of CTLA-4Ig with that of TNFα inhibitors would be useful, as would trials in children with juvenile idiopathic arthritis. CTLA-4Ig will most likely also be studied in the treatment of SLE and other autoimmune disorders (17). At present, the future looks bright for this promising inhibitor of T cell costimulation (40), as the era of biologic therapies continues to have an impact on the treatment of RA and to provide an ever-increasing number of novel agents and targets.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. REFERENCES

The author thanks Dr. Edward M. Behrens for generation of the diagram in Figure 1.

REFERENCES

  1. Top of page
  2. Acknowledgements
  3. REFERENCES