This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Immune modulation is a promising therapeutic avenue for several autoimmune diseases, including rheumatoid arthritis (RA). Current attempts have employed either proteic mixtures or large proteins and have not evaluated changes in the immune function of treated patients. Surrogate immune markers of disease activity and treatment efficacy are also lacking. A better knowledge of the mechanisms of immune tolerization in humans shall require an adequate monitoring of the desired immune changes in the treated patients. A peptide, rather than a protein-based approach, may also be more successful in inducing tolerization in a properly selected cohort of patients. We have collected preliminary evidence showing that dnaJP1, a peptide from the E. coli heat shock protein dnaJ, is a target of pro-inflammatory T cell responses in untreated RA patients. This peptide shares with self HLA alleles the susceptibility sequence to RA. We have also completed a Phase I trial where patients were orally administered dnaJP1. No toxicity along with encouraging biological effects were found in the dnaJP1 peptide patients with evidence of differences among dose groups. The overall objectives of this study are: i. To test for the first time in RA clinical and immunological consequences of an epitope-specific attempt at modulation of pro-inflammatory immune responses. ii. To provide a method to propose immunological analysis as secondary outcome measurements of immune intervention in humans by correlating dnaJ peptide-induced immune changes with the clinical picture. iii. To define immunological markers of T cell function to be proposed as surrogate markers of disease status and treatment efficacy. iv. To dissect at the antigen-specific T cell level mechanisms of immune modulation. This study is composed of two different parts: (a) A main application describing our proposed research to Phase II trial for this project.
The specific aims are: i. To measure reduction of signs and symptoms of RA in response to the immunomodulatory administration of dnaJP1 in a double-blind, placebo-controlled Phase II clinical trial in a population of patients with early RA. ii. To evaluate longitudinally the effects of the administration of dnaJ peptide on antigen-specific immune responses, focusing on T cell proliferation and on production of pro-inflammatory or tolerogenic cytokines in response to the administration of dnaJ peptide. iii. To evaluate correlation between clinical and immunological parameters. (b) An ancillary proposal where state-of-the-art technology, such as identification of antigen-specific T cells (T cell capture, TCC) and real time PCR for quantification of cytokine and chemokine receptors (TaqMan) will be applied.
The specific aims for the ancillary proposal are: i. To evaluate phenotypical markers of T cell functions (CD25, CD69, CD30, CD45ro, chemokine receptors) to identify surrogate immunological markers of activation state and administration of dnaJ peptide efficacy. The populations studied will include RA patients from the dnaJ peptide and placebo groups followed longitudinally. Appropriate correlation with the clinical picture will be performed. ii. To identify changes in functional phenotype included on antigen specific T cells by dnaJ peptide in samples of PBMC and SFMC obtained from the proposed Phase II of the tria. dnaJP1-specific T production measured. Correlations with clinical and immunological outcome measurement of the administration of dnaJ peptide will be performed. Altogether, this study, by testing in a pilot Phase II study a novel approach to treatment of rheumatoid arthritis, will contribute to our understanding of the molecular mechanisms associated with immune modulation in humans. The validity of immune analysis tools as surrogate markers for evaluating disease status and response to dnaJ pepetide will be tested
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