Modulation of epitope-specific immune responses would represent a major addition to available therapeutic options for many autoimmune diseases. The objective of this work was to induce immune deviation by mucosal peptide-specific immunotherapy in rheumatoid arthritis (RA) patients, and to dissect the related immunological mechanisms by using a technology for the detection of low-affinity class II-restricted peptide-specific T cells. A group of patients with early RA was treated for 6 months orally with dnaJP1, a peptide that induces proinflammatory T cell responses in naive RA patients. Immunological analysis at initial, intermediate and end treatment points showed an intriguing change from proinflammatory to regulatory T cell function. In fact, dnaJP1-induced T cell production of IL-4 and IL-10 increased significantly when initial and end treatment points were compared, whereas dnaJP1-induced T cell proliferation and production of IL-2, IFN-␥, and tumor necrosis factor-␣ decreased significantly. The total number of dnaJP1-specific cells did not change over time, whereas expression of foxP3 by CD4 ؉ CD25 bright cells increased, suggesting that the treatment affected regulatory T cell function. Thus, rather than clonal deletion, the observed change in immune reactivity to dnaJP1 was the outcome of treatment-induced emergence of T cells with a different functional phenotype. This study contributes to our knowledge of mechanisms and tools needed for antigen-specific immune modulation in humans, thus laying the foundation for exploitation of this approach for therapeutic purposes.
Objective. Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement.Methods. One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months.Results. The dnaJP1 peptide was safe and welltolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor ␣ and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. AnalyClinicalTrials.gov identifier: NCT00000435.
The purpose of this study was to evaluate and compare the kinetics, biodistribution, and tumor-depicting properties of three intact indium-111-labeled murine monoclonal antibodies (MoAb) and to determine if use of In-111-labeled F(ab')2 fragments of one of them had advantages over its intact counterpart for immunoscintigraphy. Ten patients with prostate cancer were studied with an anti-prostatic acid phosphatase MoAb (PAY-276), with a resultant tumor detection rate of 15%. Twenty-eight patients with melanoma were studied with ZME-018, a MoAb that targets the KD-240 melanoma antigen. Forty-three percent of the known lesions were detected. Forty patients with carcinoembryonic antigen (CEA)-producing tumors were studied, 24 with intact ZCE-025, and anti-CEA MoAb, and 16 with its F(ab')2 fragment. With use of intact ZCE-025, 34% of known lesions were detected versus 83% with its F(ab')2 fragment. The distribution of each MoAb appears unique unto itself with regard to kinetics, normal tissue distribution, and response to MoAb mass.
Objective. To determine if weekly oral 2-chlorodeoxyadenosine (2-CdA) can induce selective lymphocytopenia, and reduce inflammation, in patients with refractory psoriatic arthritis.Methods. Seven patients with psoriatic arthritis were treated with oral 2-CdA at weekly dosages of 0.3 mg/kg to 0.45 mgkg for 12 weeks, followed by monthly maintenance therapy. The patients were evaluated after 6 months.Results. The drug treatment produced selective lymphocytopenia, and reduced lymphocyte infiltration into involved skin. One patient did not complete 12 weeks of therapy because of perceived lack of efficacy. Four of the 6 remaining patients had improved joint disease, and 5 of 6 had improved psoriasis.Conclusion. Weekly oral 2-CdA appears to be a well-tolerated regimen for the inducement of peripheral lymphocytopenia in patients with psoriatic arthritis. Larger-scale, controlled trials may be warranted.Psoriasis is a common inflammatory skin disease, characterized by abnormal keratinocyte proliferation and local vascular changes. Psoriatic skin lesions contain activated CD4+ T helper cells and macrophages (1). Adhesion molecules and other skin cell Supported in part by NIH grants AR-40770 and RR-00827.
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