PART III. AutoimmunityAn Altered Peptide Ligand of Type II Collagen Suppresses Autoimmune Arthritis

Abstract

On the basis of the hypothesis that immunity to type II collagen (CII) contributes to joint inflammation, our goal is to develop an immunotherapy capable of selectively blocking immunity to a particular autoantigen without interfering with the beneficial functions of the immune system. CII is the major protein component of articular cartilage and autoimmunity to CII is strongly associated with rheumatoid arthritis in man. Our laboratory has previously identified a region of type II collagen (CII), CII245-270 that contains a prominent T-cell epitope in the immune response to CII. Residues critical to the I-Aq-restricted presentation of this determinant have been characterized. When synthetic analog peptides were developed that contain site-directed substitutions in critical positions, we found that that CII245-270 (A260, B261, N263) (A9), profoundly suppressed collagen-induced arthritis. When DBA/1 mice were coimmunized with CII and the analog peptide, the incidence and severity of arthritis was greatly reduced concordant with the humoral immune responses to CII. Moreover, the suppression could be transferred with A9-immune spleen cells and was accompanied by a Th2-type cytokine profile. When we compared T-cell signals in response to A9 to those of wild-type (WT) peptide, we found that APCs prepulsed with WT peptide induced strong phosphorylation of both TCR zeta chain and Zap-70, while A9 did not. Since T cells clearly respond to A9 with cytokine secretion, we hypothesize that A9 induces an alternate signaling pathway and we speculate that this pathway involves phosphorylation of Syk, a kinase ordinarily utilized by B cells. Activation of this alternative pathway is a novel observation and may represent an important means by which the phenotype of the responding T cell is altered. Elucidation of the mechanism by which A9 prevents arthritis may lead to development of novel immunotherapeutic approaches to antigen specific treatment of autoimmunity.

Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide

“…While both IL-4 and IL-10 appear to play a role in the A9 –induced suppression of arthritis, IL-4 is more potent. These data extend our previous observation the effectiveness of A9 in treating arthritis is mediated at least in part by anti-inflammatory cytokines secreted by T cells via the FcRIγ- and syk-dependent alternative TCR signaling pathway (17, 18). …”

Inhibition of bleomycin-induced pulmonary fibrosis through pre-treatment with collagen type V

“…52 In addition to oral tolerance, mice given intranasal or intravenous collagen type II develop a CD4 ϩ T-cell population that can adoptively transfer suppression of arthritis to naive mice. 53 Intravenous injection of peptide or proteins has been used successfully to induce tolerance in animal models. Collagen type I injection prevented autoimmune uveitis by inducing specific regulatory T cells.…”

Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

“…This knowledge affords the opportunity to synthesize peptides that are similar to the ideal triggering antigen of autoimmune hepatitis but sufficiently different in structure to competitively inhibit its presentation without provoking a similar autoimmune response [100]. Competitive analog peptides suppress joint inflammation in mice with collagen-induced rheumatoid arthritis by inducing an alternative non-pathogenic signaling pathway [101]. The precision of analog peptides to attenuate immunocyte activation depends on the resemblance of the analog peptide to the actual antigen and the complementary structure of the antigen binding groove of the class II MHC molecule [100,102].…”

“…T helper cell is the principal effector of autoimmune hepatitis, and it is activated by two signals that are amenable to therapeutic manipulation [104,105]. The first signal requires the optimal presentation of the autoantigen in the antigen binding groove of the class II molecule of the MHC, and this activation signal can be blocked by synthetic peptides that compete with the self antigen for presentation [47,49,50,101]. The second signal requires coupling of the CD28 molecule on the surface of the CD4?…”