Shohreh Issazadeh‐Navikas

Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect the neuropathological findings. To test this hypothesis, we treated PDAPP mice, a transgenic line displaying numerous neuropathological features of AD, between the ages of approximately 5 and approximately 12 months with human Abeta synthetic peptide mucosally each week. We found significant decreases in the cerebral Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti-Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD.

Type II collagen (CII) is a candidate cartilage-specific autoantigen, which can become post-translationally modified by hydroxylation and glycosylation. T cell recognition of CII is essential for the development of murine collagen-induced arthritis (CIA) and also occurs in rheumatoid arthritis (RA). The common denominator of murine CIA and human RA is the presentation of an immunodominant CII-derived glycosylated peptide on murine Aq and human DR4 molecules, respectively. To investigate the importance of T cell recognition of glycosylated CII in CIA development after immunization with heterologous CII, we treated neonatal mice with different heterologous CII-peptides (non-modified, hydroxylated and galactosylated). Treatment with the galactosylated peptide (galactose at position 264) was superior in protecting mice from CIA. Protection was accompanied by a reduced antibody response to CII and by an impaired T cell response to the glycopeptide. To investigate the importance of glycopeptide recognition in an autologous CIA model, we treated MMC-transgenic mice, which express the heterologous CII epitope with a glutamic acid in position 266 in cartilage, with CII-peptides. Again, a strong vaccination potential of the glycopeptide was seen. Hence CII-glycopeptides may be the optimal choice of vaccination target in RA, since humans share the same epitope as the MMC mouse.

Progressive cerebral deposition of amyloid-β (Aβ) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Aβ peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect the neuropathological findings. To test this hypothesis, we treated PDAPP mice, a transgenic line displaying numerous neuropathological features of AD, between the ages of ∼5 and ∼12 months with human Aβ synthetic peptide mucosally each week. We found significant decreases in the cerebral Aβ plaque burden and Aβ42 levels in mice treated intranasally with Aβ peptide versus controls treated with myelin basic protein or left untreated. This lower Aβ burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti-Aβ antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-β. Our results demonstrate that chronic nasal administration of Aβ peptide can induce an immune response to Aβ that decreases cerebral Aβ deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD. Ann Neurol 2000;48:567–579

Multiple sclerosis is postulated to be a Th1-type cell-mediated autoimmune disease. We investigated cytokine profiles in patients with progressive multiple sclerosis by using intracytoplasmic staining. We found increased IL-12 production by monocytes and increased IFN-gamma production by T cells in untreated patients as compared with controls. In patients treated with methotrexate, methylprednisolone, or cyclophosphamide/methylprednisolone (CY/MP), only CY/MP treatment normalized the elevated IL-12 production. Furthermore, CY/MP-treated patients had decreased IFN-gamma and increased IL-4, IL-5, and TGF-beta expression. Patients followed prospectively before and after starting CY/MP treatment showed a gradual decrease in IL-12 and IFN-gamma production and an increase in IL-4 and IL-5. In vitro, addition of 4-hydroperoxycyclophosphamide, a metabolite of cyclophosphamide decreased IL-12 production in mononuclear cell cultures. When patients were classified as having active or stable disease, IL-12 production correlated with disease activity. In summary, our results demonstrate a Th1-type cytokine bias in peripheral blood mononuclear cells of untreated progressive MS patients that is reversed by CY/MP treatment and is associated with Th2 and TGF-beta (Th3) type responses. These findings provide a basis for immune monitoring of patients with MS and suggest that treatments that downregulate IL-12 may prove to be beneficial in progressive MS.