TABLE 1 | Human antigen-specific tolerance-based clinical trials for autoimmune disease
From the following article:
Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease
Stephen D. Miller, Danielle M. Turley & Joseph R. Podojil
Nature Reviews Immunology 7, 665-677 (September 2007)
doi:10.1038/nri2153
| Antigen-specific therapy | Autoimmune disease | Treatment | Clinical trial outcome | References |
|---|---|---|---|---|
| Oral tolerance | Type 1 diabetes | A double-blind French study; insulin or placebo fed daily at 2.5 mg or 7.5 mg for 1 year | No effect on deterioration of  -cell function | 82 |
| A multi-centre double-blind US study; insulin or placebo fed to adults and children with new-onset disease | Preliminary analysis suggested preserved -cell function* | 83 | ||
| A multi-centre double-blind Italian study; 5 mg daily insulin treatment of patients with new-onset type 1 diabetes for 12 months | No clinical effect on -cell function; increased production of TGF by PBMCs | 84,99 | ||
| Large efficacy study (DPT1) of 7.5 mg daily insulin treatment of at-risk non-diabetic subjects | No prevention of type 1 diabetes onset; however, a subgroup with high insulin autoantibody levels had delayed disease onset. A repeat study planned focusing on this subgroup. | 81 | ||
| MS | Treatment with bovine myelin | Decreased MRI lesions in HLA-DR2+ males; no effect on clinical relapse; large placebo effect | 86‡ | |
| Rheumatoid arthritis | Multi-centre double-blind Phase II clinical trial; collagen II treatment in doses from 0.02 to 2.5 mg per day for 6 months | Positive effects in the group that received the lowest dose | 87 | |
| Phase II clinical trial; 15 patients were treated with a 15mer peptide derived from Escherichia coli HSP dnaJ (dnaJP1) given at 0.25, 2.5 or 25 mg per day for 6 months | Treatments were well tolerated; immune deviation observed from a pro-inflammatory to tolerogenic T-cell response (decrease in TNF and increase in IL-10 production) | 88 | ||
| Oral APL | MS | Phase III clinical trial; copaxone (Teva Pharamceutical Industries Ltd) or placebo given daily at 5 mg or 50 mg | No clinical, MRI or immunological effects; a Phase II clinical trial with copaxone given at 300 mg or 600 mg doses in progress | 86‡ |
| Parenteral APL | MS | An MBP APL given weekly at 50 mg subcutaneously for up to 9 months. | Two out of eight patients showed increased brain lesions; one showed hypersensitivity; three others had non-specific side effects; one patient dose was lowered to 5 mg and still developed increased MS lesions; study suspended | 89 |
| Randomized, double-blind clinical trial in 142 patients; placebo or a 5 mg, 20 mg or 50 mg dose of MBP APL given weekly subcutaneously for 4 months; then decreased to 5 mg weekly | No significant difference in relapse rate of treated and placebo groups but volume of new brain lesions was reduced in some of the patients that received 5 mg throughout; 9% developed hypersensitivity to the therapy and the trial was stopped | 90 | ||
| Randomized, double-blind clinical trail; dose-comparison of 20 mg and 40 mg of copaxone given subcutaneously in relapsing–remitting MS | Higher dose was well tolerated and a decrease in relapse rate observed | 92 | ||
| Type 1 diabetes | Phase I clinical trial of the insulin APL NBI-6024 consisting of five biweekly injections subcutaneously at doses of 0.1 mg, 1 mg or 5 mg | Shift from TH1-cell responses to TH2-cell regulatory phenotype; Phase II multi-dose study underway | 93 | |
| Phase II double-blind clinical trial of DiaPep277, a HSP60-derived peptide, 1 mg given subcutaneously in 4–8 dosages during the two-stage clinical trial; male participants only | Treatment was well tolerated; preserved -cell function as measured by C-peptide concentrations in the treated group compared to placebo group; lower need for exogenous insulin in the treated group | 177,118 | ||
| TCR vaccination | MS | Phase I and II clinical trial of trivalent TCR peptide vaccine IR903 (Neurovax; Orchestra Therapeutics) | Induced specific TCR-reactive T-cell responses; increased expression of FOXP3; currently in Phase II clinical trial | 119 |
| Peptide-coupled PBLs | MS | Intravenous administration of ECDI-fixed, autologous PBLs coupled with five immunodominant myelin peptides | Phase I and II clinical trial to test safety and efficacy pending | § |
| *Only in patients over 20 years of age when diagnosed and fed 1 mg insulin. | ||||
| ‡AutoImmune Inc. | ||||
| §Immune Tolerance Network. APL, altered-peptide ligand; DPT1, diabetes prevention trial-1; ECDI, ethylene carbodiimide; FOXP3, forkhead box P3; HSP, heat shock protein; IL, interleukin; MBP, myelin basic protein; MRI, magnetic resonance imaging; MS, multiple sclerosis; PBL, peripheral-blood lymphocyte; PBMC, peripheral-blood mononuclear cells; TCR, T-cell receptor; TGF, transforming growth factor-; TH,T helper; TNF, tumour-necrosis factor. | ||||
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