Portal de Periódicos da CAPES

Immunotherapy of skin diseases by targeting T cells

2003; Wiley; Volume: 12; Issue: 6 Linguagem: Inglês

10.1111/j.0906-6705.2003.0156i.x

1600-0625

H. Bachelez,

Dermatology and Skin Diseases

Recent insights into the immunopathogenesis of T-cell-mediated skin diseases provided a rational basis for the design of new therapeutic tools aiming the in vivo modulation of effector cells which are likely to play a key deleterious role in several autoimmune or inflammatory skin diseases such as psoriasis and atopic dermatitis. Promising results have already been provided by immunotherapeutic strategies focussing on the deletion or downregulation of activated T cells, the suppression of pathogenic T-cell-derived cytokines, or the shift of polarized T-cell subsets. Furthermore, recent advances in the knowledge of mechanisms linking innate and adaptive immunity led to reconsidering key initiating events in inflammatory skin disorders. This review will focus on results from clinical therapeutic trials, as well as on lessons from animal models of cutaneous or extracutaneous diseases which appear as the most relevant with respect to future therapeutic applications in T-cell-mediated autoimmune and inflammatory skin diseases. In view of the pathogenic role of T cells in inflammatory skin disorders such as psoriasis, it designed to eliminate in vivo pathogenic T cells. However, chimeric molecules which do not exclusively target pathogenic T cells have been recently designed, such as alefacept, an LFA-3–IgG1 fusion molecule which targets the CD2–LFA-3 interactions and consequently downregulates T-cell activation. Moreover, alefacept has been shown to induce apoptosis of memory effector CD4 and CD8 T cells, while preserving the naïve T-cell pool, probably due to different levels of CD2 surface expression between these two subsets (1). This strategy, focussing on memory T lymphocytes, has been proven to be beneficial in patients with psoriasis, providing a clinical response which is correlated with decrease of peripheral blood memory T-cell pool (2). These results support the deleterious role of effector T cells in psoriasis, while relapses observed following treatment withdrawal suggest that reconstitution of the autoreactive T-cell pool occurs in vivo. Indeed, designing of therapeutic tools aiming at the elimination of autoreactive clonotypes through the targeting of their specific receptor, i.e. the T-cell receptor, is an attractive strategy. So far, only the major histocompatibility complex (MHC)–peptide complexes allow a specific targeting of antigen-specific T cells. Indeed, this approach has been developed to produce MHC class II complex peptide chimera on an immunoglobulin scaffold, linked with doxorubicin. This latter method allowed to induce in vitro and in vivo apoptosis of antigen-specific T cells (3). More recently, adoptive transfer of genetically modified T lymphocytes expressing chimeric receptors linking an autoantigenic peptide, its class II MHC, and the ζ chain of the TCR was shown to be beneficial in the course of experimental allergic encephalomyelitis (EAE) (4). So far, the lack of identification of harmful clonotypes and of their recognized self-epitopes in most immune-mediated skin diseases clearly hampers the development of strategies focussing on the specific elimination of autoreactive T cells. Nevertheless, recent identification of autoreactive cytotoxic T-cell epitopes in autoimmune skin disorders such as vitiligo might increase the therapeutic interest of such strategies (5). Several clinical open-label studies reported the short-term benefit of anti-CD4 monoclonal antibodies in patients with recalcitrant psoriasis using humanized, depleting or non-depleting monoclonal antibodies (6,7). Even though these results are according to the demonstrated contribution of CD4 T cells to the psoriatic phenotype in animal models of psoriasis, one might consider that incomplete responses obtained in most cases argue for the non-univocal role of CD4 T helper type 1 (Th1) cells in the pathogenesis of the disease and support the notion that other lymphocyte subsets, mostly cytotoxic T lymphocytes (CTLs), also participate in skin inflammation (8). Interactions of the costimulatory T-cell molecules CD28 and CTLA-4 (CD152) with their ligand counterpart on antigen-presenting cell B7 have been targeted in studies using the CTLA-4-Ig chimeric molecule (9). These latter studies indirectly showed evidence for requirement of these costimulatory pathways in the activation and/or the recruitment of T-cell effectors in lesional skin, even though this therapeutic strategy may also interfere with regulatory T cells. More recently, the anti-CD11a antibody efalizumab, which interferes with LFA-1/ICAM-1 interactions, appeared to provide some benefit in psoriatic patients (10). Besides the widely recognized efficacy of immunosuppressive drugs such as cyclosporin A in inflammatory skin diseases, there is now compelling evidence that biological therapies which are able to inhibit the effects of lesional T-cell-derived cytokines may be beneficial in these diseases, with most convincing results coming from the example of psoriasis. Indeed, the development of antibodies or chimeric proteins neutralizing tumor necrosis factor (TNF) has shown efficacy in skin and articular psoriatic involvement (11). On the other hand, several authors recently used immunoregulatory cytokines interleukin-10 (IL-10) and IL-4 on IFN-γ-producing cells to attenuate T-cell-mediated skin inflammation in plaque-type psoriasis, a prototypic Th1-mediated skin disease. The rational basis of the study investigating the effects of IL-10 relied on the properties of this latter cytokine to induce T-cell anergy and to downregulate Th1 immune responses, and studies in psoriatic patients showed the in vivo relevance of this concept (12). More recently, other authors demonstrated that IL-4 was capable of inducing a shift from an IFN-γ-producing (Th1) to an IL-4-producing phenotype, which correlated with the clinical response (13). Regulatory CD4+CD25+ T cells (Tregs) are thought to play a key role in the control of the intensity and of the duration of host effector T-cell responses toward pathogens, through both contact- and cytokine-dependent control of activated T cells, mostly through the production of IL-10 and TGF-β (14,15). Although the mechanisms controlling Tregs in vivo remained largely elusive, immunomodulatory treatments have shown to influence this latter subset. Thus, a humanized anti-CD3 monoclonal antibody with two alanine substitutions at residues critical for binding to Fc receptor (FcR) has allowed to reduce the mitogenicity of OKT3 and to favor the production of IL-10 (16). Moreover, clinical trials in patients affected with type 1 diabetes, a Th1-mediated autoimmune disease, provided evidence for a clinical benefit which paralleled the induction of CD4+CD45RO+ CTLA4–IL-10+ T cells, some of which producing TGF-β (16,17). This mechanism differs from the immune regulation induced by the FcR-binding form of OKT3, which requires T-cell depletion related to mitochondria-dependent apoptosis (18). Furthermore, a recent open-labeled, escalating dose study carried out in patients with psoriatic arthritis suggests that hOKT3γ1 (Ala-Ala) might alleviate psoriasis (19). On the other hand, the hypothesis that Tregs would be involved in the tolerance of most tumors has received confirmation in the B16 murine model of melanoma. In this latter model, treatment with depleting anti-CD25 and blocking anti-CTLA-4 antibodies allowed to reach tumor rejection that correlated with the development of autoreactive CTLs (20). These results should lead to reconsidering the use of anti-CD25 antibody when aiming at the depletion of activated T cells, since Tregs are also targeted by this latter treatment. IL-12 is a heterodimeric cytokine which has been shown to promote differentiation of naïve CD4 and CD8 T cells into cells preferentially producing IFN-γ and IL-2 (21). This latter cytokine is secreted as a heterodimer composed of p40 and p35 subunits, and its role in inflammatory and autoimmune Th1-mediated disorders, mostly EAE, has been demonstrated in vivo by using p40 gene-targeted mice or antibodies reacting with p40 (22). In inflammatory skin conditions, IL-12 has been shown to play a major role in the induction of contact hypersensitivity, and administration of anti-p40 neutralizing antibodies allows inhibition of sensitization in this latter model (23). Nevertheless, the role of IL-12 in inflammatory T-cell-mediated disorders has been recently reconsidered in light of characterization of other dimeric cytokines belonging to the same family and regulating IFN-γ production by T cells. In this field, several recent studies focussed on IL-23, which is formed by the association of p40 with a p19 subunit, conferring to this cytokine functions similar yet distinct from IL-12 (24). Interestingly, keratinocyte-specific transgenic expression of p40 results in an inflammatory skin disease in which IL-23 and not IL-12 plays a key role (25). Together with recent evidence that IL-23 rather than IL-12 is involved in the initiation and the promotion of Th1-mediated brain lesions in EAE, it appears that the respective roles of IL-12 and IL-23 and the interpretation of results from blocking experiments using anti-p40 antibodies should be cautiously reconsidered (26). Of note, results from recent studies showing that IL-23 is expressed in lesional psoriatic skin open new therapeutic perspectives in the treatment of psoriasis, such as the use of anti-p40 or anti-p19 neutralizing antibodies (Lee E et al., Communication in International Investigative Dermatology Meeting, Miami, 2003). The interest of this strategy is reinforced by the recent demonstration that a single infusion of anti-IL-12 antibodies induced a marked regression of lesions which followed the reduction of type 1 cytokines expression in the skin (Toichi E et al and Lee E et al., Communication in International Investigative Dermatology Meeting, Miami, 2003). Taking this set of preliminary data, further clinical trials using antibodies of defined specificities against IL-23 subunits or IL-23 receptor chains are clearly warranted. The rapidly increasing knowledge in the control of skin immune responses, mostly mechanisms linking innate and adaptive immunity and those involved in the regulation of the effectors at the periphery, provide a rational basis for therapeutic immunointervention protocols in skin diseases. In the future, the identification of self-antigens targeted by pathogenic T cells in autoimmune diseases should provide additional help for the elaboration of more specific T-cell-directed therapeutic tools. Thanks to the help of Chanel, Galderma International, Laboratoires Bailleul, Laboratoires Pierre Fabre, Laboratoires Sérobiologiques, Leo Pharma, and L.V.M.H.