Based on the concept that activated T cells are the key mediators of chronic autoimmune inflammation, various T cell-directed therapeutic interventions have been introduced for the treatment of RA. Comprehensive reviews have discussed the concepts and the clinical efficacy of T cell-directed therapy in RA (Panayi 1999; Schulze-Koops and Lipsky 2000; Schulze-Koops and Kalden 2003; Yocum 1999). Here, we will review those approaches that target the pathogenetically important alterations of CD4 T cell functions as outlined above.
As RA is driven by pro-inflammatory Th1 cells with impaired differentiation of immunoregulatory Th2 cells, a shift in the balance of Th1/Th2 effector cells toward anti-inflammatory Th2 cells would be expected to be clinically beneficial. The concept of modulating the Th1/Th2 balance as a treatment for chronic autoimmunity has been successfully applied in a number of animal models of autoimmune diseases (Bessis et al. 1996; Joosten et al. 1999). It is therefore of interest to note that several recent studies have indicated that DMARDs appear to be able to modulate the Th1/Th2 balance. For example, leflunomide, a potent nontoxic inhibitor of the rate-limiting enzyme of the de novo synthesis of pyrimidines, dihydroorotate dehydrogenase (Bruneau et al. 1998), selectively decreases the activation of pro-inflammatory Th1 cells while promoting Th2 cell differentiation from naive precursors (Dimitrova et al. 2002). Sulfasalazine potently inhibits the production of IL-12 in a dose-dependent manner in mouse macrophages stimulated with LPS. Importantly, pretreatment of macrophages with sulfasalazine either in vitro or in vivo reduces their ability to induce the Th1 cytokine IFN-y and increases the ability to induce the Th2 cytokine IL-4 in antigen-primed CD4 T cells (Kang et al. 1999). Methotrexate significantly decreases the production of IFN-y and IL-2 by in vitro stimulated peripheral blood mononuclear cells while increasing the concentration of IL-4 and IL-10 (Constantin et al. 1998). Likewise, clinical efficacy of cyclosporine is associated with decreased serum levels of IFN-y, IL-2 and IL-12 and with significant increases in IL-10 (de Groot and Gross 1998). Bucillamine decreases the frequency of IFN-y-producing CD4 T cells generated after a priming culture of mononuclear cells from the peripheral blood (Morinobu et al. 2000). Finally, reports have suggested that glucocorticoids inhibit cytokine expression indirectly through promotion of a Th2 cytokine secretion profile, presumably by their action on monocyte activation (Almawi et al. 1999). Together, the data suggest that the anti-inflammatory effect of a number of current treatment modalities in RA is characterized by an inhibition of Th1 cell activation and effector cell generation and by favoring Th2 differentiation, thereby shifting the Th1/Th2 balance toward the Th2 direction.
In an attempt to target only those cells perpetuating the chronic inflammation specifically, with minimal effects on other aspects of the immune or inflammatory systems, therapeutic tools ("biologicals") with defined targets and effector functions have been designed and tested in clinical applications. As CD4 T cells are central in initiating and perpetuating the chronic autoimmune response in rheumatic diseases, a large number of biologicals has aimed to interfere with T cell activation and/or migration.
A major advance in the understanding of T cell activation has been the identification of the critical co-stimulatory molecules on T cells, such as CD28, LFA-1, CD2, CD4, CD30, CD44, and CD154 (CD40L), and their interacting ligands on APCs or B cells. Although these molecules act through different mechanisms, some delivering co-stimulatory biochemical signals to the T cell, some enhancing adhesion to target tissues, they all have the ability to augment the T cell proliferative responses to antigenic stimuli. Biologicals designed to interfere with co-stimulation via inhibiting engagement of co-stimulatory ligands have been used in several animal models of inflammatory arthritis and in treatment trials in RA. In experimental autoimmune diseases in animals, mAbs to CD4 have been used to prevent the induction of the disease (Ranges et al. 1985; Waldor et al. 1985). Of relevance to human disease, mAbs to CD4werealsoabletoinhibitfurther progressionwhengiven afterthe initial inflammation has already become manifest (Waldor et al. 1985; Wofsy and Seaman 1987), although, with one notable exception (Schulze-Koops et al. 1998), controlled human trials have largely failed to demonstrate favorable results to date (Schulze-Koops and Lipsky 2000). Interaction of CD2 with its ligand, CD58 has been blocked by application of a soluble fully human recombinant fusion protein comprising the first extracellular domain of CD58 and the hinge, CH2 and CH3 sequences of human IgG1 (LFA-3-IgG1, ale-facept). Alefacept has been employed in patients with psoriasis with substantial clinical response (Ellis and Krueger 2001). Inhibition of CD28-mediated co-stimulatory signals is a potent means of immunosuppression that can be achieved by blocking either CD28 or CD80 and CD86, for example by coating CD80 and CD86 with a soluble Ig fusion protein of the extracellular domain of CTLA-4 (CD152). CTLA-4 is a homolog to CD28 and is expressed by activated T cells. It can bind both CD80 and CD86 with higher affinity than CD28. Because CD152 has a high affinity for CD80 and CD86, soluble forms of CTLA-4 inhibit the interaction of CD28 with its ligands. In clinical trials, CTLA4-Ig (CTLA-4-IgG1, abatacept) demonstrated favorable effects in patients with psoriasis vulgaris (Abramsetal. 1999) and in patients with rheumatoid arthritis (Kremer et al. 2003; Moreland et al. 2002). The adhesion receptor/counter-receptor pair, LFA-1 (CD11a/CD18) and ICAM-1, is critical for transendothe-lial migration of T cells and their subsequent activation (Kavanaugh et al. 1991). Therefore, mAbs to LFA-1 and ICAM-1 have been employed in autoimmune diseases in an attempt to block migration of T cells into sites of inflammation and their subsequent stimulation by locally expressed antigenic peptides in vivo (Kavanaughet al. 1994;Schulze-Koops et al. 1995). Significant clinical benefit was achieved with the mAb to ICAM-1 in patients with active RA (Kavanaugh et al. 1994). It is of interest that clinical benefit was restricted to those patients who showed a marked increase in the levels of Th1 cytokine-producing T cells in their circulation immediately following the administration of the mAb (Schulze-Koops et al. 1995). Thus, it can be reasoned that in the responding patients the circulatory pattern of activated Th1 cells was altered by inhibiting their migration into the inflamed synovium. These data emphasize the pathogenic Th1 drive in those patients responding to therapy.
Together, T cell-directed therapy in RA is based on the idea that CD4 T cells initiate and continuously drive systemic rheumatoid inflammation. T cell-directed DMARDs and some of the recently employed mAbs have been successful in ameliorating signs and symptoms of the diseases and some also seem to be able to slow disease progression. Thus, although sustained clinical improvement has not been achieved with a short course of the biologicals, the idea that targeting the CD4 T cells as the motor of rheumatoid inflammation will interrupt chronic autoimmune inflammation and subsequent tissue destruction has been strongly supported.
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