Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone.

Abstract

SummaryPeptide analogues of disease-associated epitopes were studied for inhibition of experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rats. EAE-and AA-associated analogues were selected as competitors because of their in vitro inhibitory activity on proliferation of encephalitogenic and arthritogenic T cells. Although the EAE-associated competitor had a superior major histocompatibility complex (MHC) binding af~nity, the AA-associated competitor was a better inhibitor of the in vitro proliferation of arthritogenic T cells. Furthermore, although in vivo EAE was inhibited by both competitors, AA was only inhibited by the AA-associated competitor. Remarkably, in contrast to what was expected of a regular MHC competitor peptide, the AA-associated peptide analogue also prevented AA upon immunization before disease induction and appeared to induce T cell responses that crossreacted with the original disease-associated epitope. Therefore, it is concluded that antigen-specific regulatory mechanisms were involved in synergy with MHC competition. The integration of both qualities into a single "competitormodulator" analogue peptide may lead to the development of novel, more effective, disease-specific immunomodulatory peptides. C D4 helper T cells are activated upon recognition of antigen, provided the antigen is processed and its peptides are presented by cells expressing the proper MHC class II products (1-3). Competition between various peptides for binding to the same MHC molecule already has been demonstrated to occur not only in vitro but also in vivo (4-9). These findings, added to the fact that predisposition to most antoimmune diseases occurs in association with particular MHC molecules (10), have prompted several groups to investigate the possibility of inhibiting the formation of the trimolecular complex formed by MHC, peptide, and TCR in order to develop a new strategy of immunological intervention in autoimmunity. One of the best studied experimental animal models is the experimental allergic encephalomyelitis (EAE) 1 model. EAE is a CD4 + T cell-mediated disease (11-13) that can be induced by immunization with myelin basic protein (MBP) or peptides derived from MBP. Both in mice and rats, 1 Abbreviations used in thispaper: AA, adjuvant arthritis; EAE, experimental allergic encephalomyelitis; MBP, myelin basic protein; SMPS, simultaneous multiple peptide synthesis. CD4 + MBP-specific helper T cell clones have been isolated that transfer the disease into naive recipient animals (11, 13). Coadministration of anti-MHC class II antibodies has prevented the induction of EAE in mice by blocking MHC recognition of potentially encephalitogenic T helper cells (14,15). Based on these findings, several groups have searched for peptides that could inhibit, by competition for MHC class II binding, the stimulus that is turning on the dangerous anti-self T cell responses. First reports dealing with this peptide immunotherapy approach have indicated it to be successful in the EAE model in ...

AChlamydia pneumoniae-Specific Peptide Induces Experimental Autoimmune Encephalomyelitis in Rats

“…The 20-aa chlamydial peptide appears to be as effective as MBP 68 -86 peptide in causing paralysis in this model, and our data demonstrate that different MBP and Cpn0483 residues are critical for disease induction. Using alanine-substituted analogue peptides, the D residue common to the rat 68 -86 and Cpn0483 peptides (Tables I and II) has been shown to be required for proliferative responses of an encephalitogenic LEW rat T cell line to a truncated peptide (QKSQRSQDENPV), which corresponds to the core guinea pig MBP peptide (24,25). We show here that the D residue is necessary for EAE induced with MBP 68 -86 , but it is not required for encephalitogenic activity of Cpn0483 (Table III).…”

“…68 -86 MBP 68 -86 and Cpn0483 share a YGxLxxxxxRTxDxN motif (Tables I and II). The aspartic acid (D) residue is reportedly a TCR contact for reactivity of guinea pig MBP 73-86 , the minimal encephalitogenic sequence, with LEW rat T cells (24,25). To determine whether D is also required for Cpn0483-induced EAE in LEW rats, we prepared the alanine-substituted peptides Cpn0483DϾA and rat MBP 68 -86 -DϾA and tested them for encephalitogenic activity in LEW rats.…”

“…5b). Immunological specificity was demonstrated by the lack of proliferation in response to an irrelevant nonencephalitogenic peptide (MBP [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] or MBP [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] ). T cells derived from unimmunized rats showed no proliferative response to any of the peptides tested (not shown).…”

Immune regulation in adjuvant‐induced arthritis: Possible implications for innovative therapeutic strategies in arthritis

“…The pathogenic M tuberculosis Hsp60 180-188 itself can serve as a protective ligand (48,49). With a single substituent (alanine at position 183), it becomes a powerful altered peptide ligand (APL), which may act as a partial agonist or antagonist of the pathogenic process (42,43).…”

Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis

“…After 3 days of culturing, proliferation was determined by overnight incorporation of [ 3 H]thymidine (14). Proliferation was considered positive at a stimulation index (SI) Ն 2.…”