Dawn E. Smilek

MHC-binding peptides for immunotherapy ofexperimental autoimmune disease

It is now well accepted that T helper cells play a central role in the induction and maintenance of autoimmune disease. Many experimental models have emphasized this fact and have illustrated the efficacy of therapeutic strategies aimed at disrupting T cell recognition of autoantigens. Antibodies directed at either class II proteins of the major histocompatibility complex (MHC) or CD4 accessory molecules have been universally successful. However, the potential use of antibodies for therapy in humans is complicated by host anti-globulin and anti-idiotype responses. An alternative approach to anti-MHC blockade with antibodies is peptide blockade of MHC molecules. In addition, peptides may be used as agonists of autoantigens in order to modulate the autoimmune response. The use of synthetic peptides for therapy is an innovative yet relatively unexplored approach and will be the subject for discussion in this article.

Antigen recognition and peptide-mediated immunotherapy in autoimmune disease.

Autoimmune disease occurs when the immune system of an individual is triggered to recognize self components. The immune system then proceeds to attack these self components with a destructive fury normally reserved for foreign invaders. CD4+ helper T lymphocytes and CD8+ cytotoxic T lymphocytes play a major role in the normal immune response to foreign antigens. These cells are activated when their specific T-cell receptors (TCR) recognize foreign antigenic peptide fragments bound to major histocompatibility complex (MHC) molecules. CD8 + T cells usually recognize peptides complexed to class I MHC molecules. In contrast, CD4+ T cells recognize peptides complexed to class II MHC molecules (AaAP and EaEy? in the mouse, and DRaDR;5, DQaDQy?, and DPaDP/? in humans). Activated CD4 + helper T cells consequently secrete a variety of lymphokines which then influence the activity of other cells in the immune system. Any given MHC molecule must be capable of binding to a variety of antigenic peptides in order to generate TCR recognition structures from all foreign proteins. Nevertheless, it has been shown that each class II MHC molecule maintains a certain degree of specificity, binding only to very characteristic antigenic peptides (Babbitt et al. 1985, Schwartz 1986, Buus et al. 1987). This binding specificity is conferred by the polymorphic amino acid residues which are clustered around

EAE: A Model for Immune Intervention with Synthetic Peptides

The cellular and molecular requirements for the autoimmune disease EAE are being defined in increasing detail through intense scrutiny of critical autoantigenic peptides, class II MHC molecules, and alpha beta TCRs involved in the disease process. This study has led to novel immunotherapeutic approaches, many of which are based on the administration of synthetic peptides. Since short peptides are understood to be the minimal antigenic units bound by MHC molecules for recognition by T cells, they are attractive experimental tools for finely modulating specific immune responses. It is clear that a large number of defined peptides can dramatically influence the course of EAE. Table IV lists a number of potential mechanisms which may mediate disease prevention. Increasing evidence supports the idea that prevention of autoimmune disease can result from MHC-blockade by peptides which competitively bind to class II molecules. However, for some peptides such as the perplexing partial agonist Ac1-11[4A], the mechanism by which these precisely defined units act is not yet fully understood. Numerous hurdles hinder immediate clinical application of peptide-based immunotherapy. Nevertheless, the knowledge gained by probing experimental autoimmunity with defined peptides promises to inspire original and practical approaches to treating human autoimmune disease.

Induction of a heterogeneous TCR repertoire in (PL/JXSJL/J)F1 mice by myelin basic protein peptide Ac1-11 and its analog Ac1-11[4A]

Experimental autoimmune encephalomyelitis (EAE) serves as a rodent model of the autoimmune disease multiple sclerosis. In mice, EAE is induced by immunizing with spinal cord homogenate, components of the myelin sheath, such as myelin basic protein (MBP) or proteolipid protein (PLP), or peptides derived from these components. EAE can be induced in H-2u or (H-2u x H-2s)F1 mice with the N-terminal peptide of MBP, Ac1-11. Coimmunization with Ac1-11 and Ac1-11[4A], an analog in which lysine at position four is substituted with alanine, prevents EAE. The mechanism of inhibition has not been elucidated, but probably does not work through MHC blockade, T cell anergy or clonal elimination of encephalitogenic T cells. We have isolated T cell clones and hybridomas from (PL/J x SJL/J)F1 mice immunized with either Ac1-11 alone or Ac1-11 and Ac1-11[4A] and analysed these cells for differences in their T cell receptor repertoire and in vitro response. Although T cells elicited by coinjection of Ac1-11 and Ac1-11[4A] expressed TCR that used V alpha and Vbeta gene elements similar to those elicited by Ac1-11 alone, they differed in the sequences of the junctional region of the alpha chain. Most of these T cells also responded less well to Ac1-11 in vitro, suggesting that coinjection of Ac1-11 and Ac1-11[4A] preferentially activates T cells bearing TCR of different affinity for Ac1-11 bound to I-A(u), and which may therefore be less encephalitogenic. Furthermore, our results show that a more diverse repertoire of V alpha and Vbeta genes are elicited by Ac1-11 in (PL/J x SJL/J)F1 mice compared to PL/J and B10.PL mice, providing further evidence that a restricted TCR repertoire is not required for the development of autoimmune disease.

A role for major histocompatibility complex-binding peptides in the immunotherapy of autoimmune disease.

ConclusionsIn conclusion, rapid advances in our understanding of the molecular basis of T cell recognition have revealed a number of approaches for immune intervention in autoimmune disease. Each procedure has been tried and tested in experimental models. Characterization of T cell recognition in human autoimmune disease is a step behind. However, their success in experimental models indicates that MHC-blocking peptides will find use both in identification of restriction elements for disease and in the prevention and treatment of human autoimmune conditions.

Role of MHC Polymorphism in Autoimmune Disease

The immune response to foreign protein antigens, and to self-protein antigens in autoimmunity, begins with an interaction between a peptide fragment of the protein antigen and an MHC class II molecule. Binding of the peptide in the binding site of the class II molecule is followed by recognition of this complex by T cells with receptors complementary for the peptide-class II molecular complex. This induces the development of memory helper T cells, and leads to both T cell and β cell immune responses to the peptide fragments of the antigen and to the intact three dimensional protein (Schwartz, R.H., 1986).