Articolo

Role of TCR antagonist in human infectious disease.
Generation of antigenic variants displaying properties of altered ligand seems to be a suitable strategy used by virus and parasites to avoid immune response. Figure 5 Bertoletti et al identifyed for the first time in patients affected by epatitis antigenic variants of HBV showing a strong antagonistic activity co-expression of wilde type and antagonistic variant of HBV antigen protect cells from CTL recognition and lysis [27]. Relevance of variants of immunodominant epitopes have been extensively studied m HIV-1. Early evidences revealed that mutations in human immunodefìciency virus [HIV] cluster in cytotoxic T lymphocyte [CTL] epitopes and are subject to immune-mediated positive selection. Most asymptomatic individuals infected with HIV-1 has a cytotoxic T lymphocyte response to the virus Gag proteins which can be demonstrated in vitro. Epitopes have been mapped in pl7 Gag and p24 Gag restricted by HLA-B8. Viruses isolated from patients who make CTL responses to these peptides vary within the genetic sequences encoding these epitopes and some mutations lead to reduction in killing activity in vitro. This was attributed to either failure of the variant epitope to bind major histocompatibility complex class I or failure of T-cell receptors to bind the presented peptide. However, Most of these natural variants of class I-restricted epitopes can cause ‘antagonism’, thus their presence inhibits normal lysis of targets presenting the original epitope [28]. The emerging of virus variants with modified immunological features seems to be relevant also in modulating the efficiency of response in HCV infection. A recent reports revealed that virus variants did not appear in patients with recovery, whereas variants with altered peptide ligands capable of antagonizing CTL activity emerged rapidly in the patients in whom chronicity developed [29].
Host-parasite coevolution has been likened to a molecular arms race, with particular parasite genes evolving to evade specific host defenses. In this context, a recent study of the variants of an antigenic epitope of Plasmodium falciparum that induces a cytotoxic T cell response revealed that parasite strains to facilitate each other’s survival by down-regulating cellular immune responses, use altered peptide ligand antagonism. Potential Therapeutic Applications of MRL The discovery of TCR ligands with unexpected biological properties provides new possibilities for the manipulation of immune responses. In vaccine development, partial agonist/antagonists might be designed to selectively guide the immune response along certain pathways, avoiding immune responses that can have pathological rather that beneficial effects, and enhancing stimulation of protective pathways. The ability of partial or complete antagonists to dominantly interfere with T cell effectors function also suggests new approaches to autoimmune disease treatment. A problem with the common broadly active immunosuppressive agents such as steroids, cyclosporine A/FK 506, cyclophosphamide, or methotrexate is that they leave the patient more prone to infections and for the development of malignancies. They are also associated with a high level of undesirable side-effects, such as renal and liver damage. A more specific immunosuppressive strategy involves use of peptides that can physically block the MHC molecule binding sites and prevent presentation of the peptides involved in the disease [30].

This method requires massive amounts of material to achieve the necessary quantitative blocking effect, may be accompanied by induction of undesirable strong immune response to the blocking agent itself, and calls for continuous treatment because the effect on the T cells is not prolonged. Moreover, there is no evidence that peptides that block the MHC binding site can affect presentation of self-antigens that are pre-associated with MHC molecules, which would be necessary for treatment when active disease is already present. Complete antagonists avoid several of these problems as the antagonist are immunologically specific and thus affect only a small subset of T cells relevant to disease. This reduces the chance of adverse systemic or organ specific side-effects, and lessens the amount of material necessary for administration as compared to the MHC molecole blocking strategy. However, complete antagonists does not generate intracellular signals, which means that any effects of administration would be transient. Partial agonists and partial antagonists should be better candidates than complete antagonists for effective induction of selective immunosuppression.

This is because these classes of TCR ligands could potentially drive autoimmune T cells into a long term unresponsive state. Therefore, partial agonists/antagonists may potentially be able to block ongoing autoimmune T cell effectors activity, as might a complete MHC blocking peptide, and administration of such a TCR ligand may also lead to a lasting decrease in autoimmune disease due to anergy induction among the involved T cells. In this fashion, ligand administration could diminish or slow the progression of the autoimmune disease process. This would be accomplished with few or no side-effects, due to extreme specificity of the drug for only the disease-causing T cells. But this same high degree of specificity also poses a problem for this approach, namely, whether the entire cohort of TCR involved in the response to even simple, and more importantly, complex antigens would be susceptible to one or only a few such MRL. Preliminary data suggest that a cocktail of a few compounds might provide adequate coverage for the T cells responding to a given peptide cAG; the question will be whether in an active disease state, only one or a few such cAG are relevant Alternatively, it might be possible for pAG to generate cells that when faced with the natural self-antigen, secrete lymphokines that block the pathologic inflammatory response in the surrounding tissue; this mode of action would avoid the need to antagonize the stimulation of all the autoreactive T cells.

Luigi Racioppi
Facoltà di Farmacia Università Federico II
Napoli