T cell receptor peptides in treatment of autoimmune disease: Rationale and potential

Abstract

The natural tendency in T cell‐mediated autoimmune conditions to develop focused antigen‐specific responses that over‐utilize certain T cell receptor (TCR) V region segments prompts the induction of anti‐TCR‐specific T cells and antibodies that can inhibit the pathogenic T cells and promote recovery from disease. This natural regulatory network can be manipulated by injecting synthetic peptide vaccines that correspond to segments of the over‐expressed V genes. In experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis (MS), the pathogenic T cells are directed at myelin components, including basic protein (MBP). In some strains such as the Lewis rat and the PL/J mouse, the encephalitogenic BP‐specific T cells overexpress a particular V region gene (Vβ8.2) in their TCR. In vivo administration of Vβ8.2 peptides in rats or mice can prevent and treat EAE by boosting regulatory anti‐Vβ8.2‐specific T cells that inhibit but do not delete the encephalitogenic specificities. This regulation is mediated by soluble factors, suggesting that the presence of regulatory TCR‐specific T cells within the target organ (the central nervous system) may inhibit not only the stimulating Vβ8.2+ T cells, but also bystander T cells bearing different V genes. Parallel studies in MS patients have revealed striking V gene biases among BP‐specific T cell clones from some patients that provided a rationale for TCR peptide therapy. Injection of Vβ5.2 and Vβ6.1 peptides boosted the frequency of TCR peptide‐specific T cells and reduced responses to BP, in some cases with clinical benefit, indicating the presence of an anti‐TCR regulatory network in humans that may also be manipulated with TCR peptide therapy. © 1996 Wiley‐Liss, Inc.

Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis

“…Vaccination with BV8S2 protein in incomplete Freund's adjuvant (IFA) before EAE induction reduced incidence and severity of disease and stimulated TCRspecific T cells to secrete elevated levels of both IFN-γ and IL-10 (29) These regulatory T cells expressed the same Tg BV8S2 chain and the same AV2S3 chain as the encephalitogenic T cells, differing only in the AV-CDR3 junctional region (30), and could inhibit activation and transfer of EAE after coculture with the MBP-Ac1-11-specific T cells (29) through release of IL-10, IL-4, and IFN-γ, but not TGF-β (31). These data demonstrate that immune regulation in this model occurs through a nondeletional cytokine-driven suppressive mechanism involving TCR-specific T cells (32). We now show that, in contrast to males, female littermate mice developed more severe EAE and were only transiently protected from EAE after vaccination with BV8S2 protein.…”

Autoimmunity and Apoptosis - Therapeutic Implications

“…This is based on the observation that in several animal models of autoimmune diseases antigen receptors of autoaggressive T-cells are formed by a limited number of CDR regions [230,231]. Immunizing animal models with synthetic peptides corresponding to CDR3 [228] or CDR2 [229] segment of TCR of the T-cells which are activated against myelin basic protein (MBP) conferred resistant to the following induction of EAE and promoted recovery from the disease [232]. This approach has also been used in pilot clinical trials to immunize MS patients with either attenuated autologous MBP-reactive T-cells [233][234][235] or synthetic peptides [236,237].…”

Circulating regulatory anti–T cell receptor antibodies in patients with myasthenia gravis

“…The nonresponsiveness of T cells to self-antigens is controlled by several mechanisms including clonal deletion, T cell anergy, T cell ignorance, and specific regulatory T (T reg ) cells (1,2). One type of T reg cell, the T cell receptor (TCR) peptide-specific regulatory CD4 T cell (anti-idiotypic T cell), has been shown to play a key role in the control of autoimmune diseases (3,4). Anti-idiotypic T cells have been found in the unprimed immune system (5) as well as in the course of T cell or TCR vaccination in autoimmune diseases, and may arise as a consequence of the natural development of autoimmune T cells (reviewed in ref.…”

“…6). TCR-specific CD4 + T reg cells may control pathogenic CD4 + T cells either directly or through CD8 + TCR-specific T reg cells (3,4,7,8). The action of these TCR-specific T reg cells at the molecular level may involve either cytotoxicity against autoreactive T cells (9-11) or a shift in the cytokine phenotype of the autoimmune response (7,10,12,13).…”

“…The action of these TCR-specific T reg cells at the molecular level may involve either cytotoxicity against autoreactive T cells (9-11) or a shift in the cytokine phenotype of the autoimmune response (7,10,12,13). Striking similarities in the induction and characteristics of T cells specific for TCR peptides have been found in rodents and humans (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), supporting the generality of the observations. Anti-TCR Ab's may constitute another significant level of regulation, but their occurrence and regulatory role have been poorly investigated, mainly in studies on TCR vaccination (14)(15)(16)(17)(18)(19).…”